Determination of dosimetric perturbations caused by aneurysm clip in stereotactic radiosurgery using gel phantoms and EBT-Gafchromic films.

Some radiotherapy patients are treated with titanium surgical aneurysm clips in the radiation field. This is of particular importance for stereotactic radiosurgery brain treatments, where the length of the blade of the clip may be comparable to the size of the radiation field. This study seeks to determine the extent of the dosimetric effects caused by surgical clips in stereotactic radiosurgery, using polyacrylamide gel phantoms and EBT type Gafchromic films. Using gel phantoms scanned with magnetic resonance imaging scanner, dose enhancement of around 20% was noted at distances less than 2 mm away from the clip surface. Gafchromic films showed about 6% variations in the dose up to few millimeters from the clip. These experimental results confirmed results predicted by Monte Carlo simulation techniques for higher density material surgical clips such as lead and platinum. Moreover, these experimental measurements clearly indicate dose reduction due to radiation attenuation behind the clip of about 4%.

Stereotactic dose perturbation from an aneurysm clip measured by Gafchromic EBT film.

Aneurysm clips within stereotactic treatment volumes enhance spatial accuracy but perturb the dose distribution. The dose perturbations caused by a standard titanium alloy aneurysm clip (Ti6Al4V) have been measured with Gafchromic EBT film. The maximum dose perturbation was an increase of 6 % within 0.5 mm of the beam entry surface of the clip, and a decrease of 7 % within 0.5 mm of the beam exit surface of the clip. Results also showed perturbations to film readout due to the presence of micro dust particles on the film affecting optical properties at high spatial resolution (21um) scanning. Special procedures should be used when film is immersed in water, dried and then read at high spatial resolution. We recommend that films should be immersed only in distilled water and tools such as canned air puffs should be used to clean films without scratches.

High-resolution measurements of small field beams using polymer gels.

Small field sizes are increasingly becoming important in radiotherapy particularly since the introduction of intensity-modulated radiation therapy (IMRT) techniques. It is normally a challenging task to reliably measure the delivered dose and to determine its distribution in a medium for such small fields using conventional-type dosimeters such as gas ionisation chambers. Recently, attempts have been made to use films, but they are not tissue equivalent, they measure the dose only in two dimensions and they are not as responsive to radiations. In the present work, polyacrylamide gel (PAG) dosimeters are employed to measure the dose and its distribution in three dimensions for very small field sizes, such as those typically used in stereotactic radiosurgery. Field sizes of 6 x 6 and 18 x 18 mm in width are investigated. The results show an agreement with radiochromic film and ionisation diode measurements, with some variation in measured doses near the edge of the field, where the gel data decreases more rapidly than the other methods.

Afferent and efferent connections of the diencephalic prepacemaker nucleus in the weakly electric fish, Eigenmannia virescens: interactions between the electromotor system and the neuroendocrine axis.

The afferent and efferent connections of the gymnotiform central posterior nucleus of the dorsal thalamus and prepacemaker nucleus (CP/PPn) were examined by retrograde and anterograde transport of the small molecular weight tracer, Neurobiotin. The CP/PPn was identified by physiological assay and received a local iontophoretic injection of Neurobiotin. Retrogradely labeled somata were observed in the ventral telencephalon, hypothalamus, and the pretectal nucleus electrosensorius. Anterogradely labeled fibers were traced from the CP/PPn to the ventral telencephalon, the hypothalamus, the neuropil immediately adjacent to the most rostral subdivision of the nucleus electrosensorius, the optic tectum, and the pacemaker nucleus. Retrograde transport of tracer following injections into the ventral telencephalon, preoptic area, lateral hypothalamus, tectum, and pacemaker nucleus confirmed these efferent targets. A rostromedial subarea of the CP/PPn can be identified that projects to basal forebrain regions and to a lateral region of the CP/PPn that contains afferents to the pacemaker. Many of the targets, which are connected with the CP/PPn, have been linked to reproductive behavior or neuroendocrine control in other fishes. A comparative analysis reveals that the efferent pathways of the CP/PPn appear similar and may be homologous to efferent pathways of some components of the auditory thalamus among tetrapods.

Connections of the basal forebrain of the weakly electric fish, Eigenmannia virescens.

The organization of the ventral nucleus of the ventral telencephalon (Vv) was examined in the weakly electric fish, Eigenmannia virescens. This nucleus, which is considered the teleost homologue to the basal forebrain nuclei of other vertebrates, was subdivided into dorsal and ventral subdivisions, based upon cytoarchitectonic, immunohistochemical, and connectional criteria. Afferent projections were observed from the medial olfactory bulb as well as the terminal nerve ganglion. Telencephalic afferents to the Vv were very restricted, consisting of the supracommissural and the dorsal intermediate nuclei of the ventral telencephalon, the nucleus taenia, and the medial region of the posterior nucleus of the dorsal telencephalon. However, the major afferents to the Vv were diencephalic, particularly those originating from the rostral preoptic area and other hypothalamic nuclei. Additional afferents included the posterior tubercular nucleus, the locus coeruleus, the medial perilemniscal nucleus, and the periventricular nucleus of the posterior tuberculum. Relatively weak projections were observed from the ventral thalamus and the dorsal posterior thalamic nucleus. As described previously, the diencephalic complex of the central posterior thalamic nucleus/prepacemaker nucleus (CP/PPn), which also has cells that innervate the pacemaker circuitry controlling the production of an electric organ discharge, projects to the Vv. Terminal fields of the Vv were observed to be coextensive with afferent cell groups in the preoptic area, lateral and caudal hypothalamic nuclei, and thalamus. An additional efferent target of the Vv was the pretectal nucleus electrosensorius. That many cell groups that are connected with the Vv are also connected with the CP/PPn, particularly the preoptic and hypothalamic nuclei, suggests that the electrocommunicatory system is intimately linked with basal forebrain limbic pathways.

Clinical correlates of white-matter changes on magnetic resonance imaging scans of the brain.

We report our observations on the clinical and radiologic correlates of changes in cerebral white matter based on 94 subjects undergoing magnetic resonance imaging in a prospective study of dementia. Periventricular hyperintensity occurred twice as often in patients with Alzheimer's disease as in healthy control subjects. Within the control group, the presence of periventricular hyperintensity correlated significantly with one measure of cerebral atrophy and with the presence of changes in the adjoining deep white matter. The significance of white-matter changes distinct from the ventricles (leuko-araiosis) remains unsettled. Leuko-araiosis on the magnetic resonance imaging scan, unlike its correlate on the computed tomographic scan, was not shown to relate to cognitive decline or to the presence of focal abnormalities on neurologic examination. This is likely to reflect the heterogeneity of the changes detected with magnetic resonance imaging and their limited extent in our subjects.

Improved recognition of leukoaraiosis and cognitive impairment in Alzheimer's disease.

We identified 85 patients in a longitudinal study of dementia who had uncomplicated Alzheimer's disease and in whom computed tomography of the head and psychometric testing were conducted within a 6-month period following their entry into the study. Thirty-four patients (40%) had leukoaraiosis, which was disproportionately common in female patients (62% vs 15% in male patients). Analysis of covariance demonstrated a relative reduction of scores on the Extended Scale for Dementia in those patients who had leukoaraiosis, after adjusting for the confounding effects of age, sex, educational level, and duration of illness. Leukoaraiosis was also much more common in women, even after adjusting for the possible confounding effects of age, duration of illness, Extended Scale for Dementia score, and hypertension. Multiple regression analysis showed that leukoaraiosis accounted for 11.6% of the variance of the Extended Scale for Dementia scores. Leukoaraiosis, together with duration of illness, accounted for 18.2% of the variance. Leukoaraiosis is associated with a greater degree of cognitive impairment in patients with Alzheimer's disease.

Interrater variability with the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. The Canadian Cooperation MS Study Group.

We describe the interrater variability in the Expanded Disability Status Scale (EDSS) and Functional Systems (FS) in a multiple sclerosis clinical trial. Two physicians blinded to their previous assessments and to each other's scores consecutively examined 168 patients (545 paired examinations). Perfect agreement on the assignment of the disability scores ranged from 48% (cerebellar functional group) to 69% (EDSS and pyramidal functional group). Only 31% to 62% of this agreement occurred independently of that expected by chance (kappa). With the exception of the cerebellar and sensory functional groups, agreement within 1 step occurred in at least 92% of cases. These findings suggest that differences of a single step on these scales may not reflect an important functional change. We recommend that at least a 2-step change (1.0 point on the EDSS and 2 points on the FS) is needed to be confident of an important change in the degree of disability or response to treatment in this disease.

Intravenous cocaine decreases cardiac vagal tone, vagal index (derived in lorenz space), and heart period complexity (approximate entropy) in cocaine abusers.

We assessed the effects of i.v. cocaine on parasympathetic and sympathetic nervous system activity, and on the complexity vs. regularity of changes in heart rate over time. Fourteen otherwise healthy men with histories of i.v. cocaine abuse received bolus injections of cocaine (20 mg or 40 mg) and placebo (saline) on different days. Cardiovascular measures derived from the electrocardiogram, including heart rate, Porges' vagal tone (respiratory sinus arrhythmia), the 0.10 Hz rhythm, Toichi's vagal index, Toichi's sympathetic index, and approximate entropy (ApEn), were measured continuously. As predicted, cocaine produced tachycardia, accompanied by pronounced decreases in response to 40 mg cocaine in two different vagal tone indexes that precisely mirrored the increases in heart rate. The measure of sympathetic (and vagal) neural influences on the heart (0.10 Hz wave) also decreased in response to cocaine. Converging evidence from Toichi's vagal index supported the conclusion that the tachycardia from cocaine was due to withdrawal of cardiac vagal tone. These findings, and evidence that cocaine decreased cardiovascular complexity, contradict the prevailing assumption that the mechanism by which cocaine produces tachycardia is sympathetic (beta-adrenergic). We discuss implications for cardiac arrhythmias associated with cocaine abuse and death due to overdose.

Local-regional recurrence in breast cancer after mastectomy and adriamycin-based adjuvant chemotherapy: evaluation of the role of postoperative radiotherapy.

In an attempt to determine whether patients treated for breast cancer with radical or modified radical mastectomy and adjuvant chemotherapy benefit from postoperative radiotherapy, 400 women with Stages II-III breast cancer who received adjuvant chemotherapy based on the combination of Adriamycin and Cytoxan were analyzed retrospectively. Prognostic features which predicted a high risk of isolated local-regional relapse were identified. Thirty-eight percent of these patients were also treated with postoperative radiation in addition to adjuvant chemotherapy and were compared to those patients treated only with adjuvant chemotherapy. With a median follow-up of 60 months, 15% of the patients reviewed developed local-regional disease as the first site of relapse without concommitant systemic relapse. When examined univariately, stage of disease, tumor size, nodal status, and estrogen receptor status were strong prognostic variables. Age, cell type, location of tumor within the breast, menstrual status, radiation dose, and type of treatment were not significantly related to isolated local-regional relapse. However, patients who received postoperative radiation were significantly more advanced in their disease condition. When the factors were examined multivariately, the type of treatment along with stage of disease were found to be statistically significant prognostic indicators. About half of the patients were tested for estrogen receptor status. Multivariate analysis performed on this subset of patients showed that estrogen receptor status, type of treatment, and axillary nodal status were significant predictors of the risk of isolated local-regional relapse. This study suggests that patients treated with mastectomy and Adriamycin and Cytoxan-based adjuvant chemotherapy may benefit from postoperative radiation in reducing the risk of isolated local-regional recurrence.

Role of Ca2+ stores in dopamine- and PACAP-evoked growth hormone release in goldfish.

Growth hormone (GH) secretion, evoked by either pituitary adenylate cyclase-activating polypeptide (PACAP) or dopamine (DA), is dependent on both voltage-sensitive calcium channels (VSCC) and cAMP signaling in goldfish. We further characterized the involvement of Ca2+ in evoked release by PACAP and DA, by examining the sensitivity of evoked GH release to perturbations of Ca2+ signaling. Both VSCC and calmodulin/calmodulin-dependent kinase are involved in PACAP signaling as had been shown for DA. In spite of this apparent dependence on VSCC, blockade of TMB-8 but not ryanodine-sensitive intracellular Ca2+ stores inhibited both PACAP- and DA-evoked GH release. Using sarcoplasmic/endoplasmic reticulum Ca-ATPases (SERCA) inhibitors, we found BHQ blocked, whereas thapsigargin (Tg) enhanced stimulated GH release, suggesting that Tg-sensitive SERCA may counteract these cAMP-mobilizing neuroendocrine regulators by sequestering [Ca2+]i. As GH secretion stimulated by two endogenous gonadotropin-releasing hormones is not affected by Tg, it appears that distinct multiple Ca2+ stores mediate the hormone releasing response to different neuroendocrine regulators.

Agonist-specific Ca2+ signaling systems, composed of multiple intracellular Ca2+ stores, regulate gonadotropin secretion.

Ca2+ signals regulate many cellular functions, including hormone secretion. Agonist-specific Ca2+ signaling may arise from the differential mobilization of multiple Ca2+ stores. Although they act through the same receptor subtype, two gonadotropin-releasing hormones (sGnRH and cGnRH-II) generate quantifiably different Ca2+ signals in goldfish gonadotropes, suggesting that their Ca2+-dependent signaling cascades may differ. We combined electrophysiology, Ca2+ imaging, and radioimmunoassay detection of gonadotropin (GTH-II) secretion to determine the role of intracellular Ca2+ stores in GnRH-stimulated exocytosis. Our findings suggest that voltage-gated Ca2+ channels do not mediate acute GnRH-signaling. Instead, both sGnRH- and cGnRH-II-stimulated GTH-II releases are dependent on Ca2+ mobilized from TMB-8/CPA-sensitive compartments. However, sGnRH, but not cGnRH-II, utilizes intracellular stores sensitive to caffeine and xestospongin C. We also identified a homeostatic mechanism where reduced extracellular Ca2+ availability increase GTH-II release by mobilizing Ca2+ stores. Our results are the first to suggest that several classes of intracellular Ca2+ stores differentially participate in agonist signaling and homeostasis in gonadotropes.

Does self-administration of a quality of life index for inflammatory bowel disease change the results?

We assessed the effect of self-administration of a disease-specific health-related quality of life instrument, the Inflammatory Bowel Disease Questionnaire (IBDQ), on score results. Patients were assessed at two visits in two tertiary centers. "Experienced" patients (N = 31) with Crohn's disease had previously completed the IBDQ several times while "novices" (N = 37) with Crohn's disease or ulcerative colitis had no prior exposure to the IBDQ. At each visit a self-administered IBDQ followed by a nurse-administered IBDQ (score range, 1-7; absolute score range, 32-224) and disease activity were assessed. At visit 1, the mean rates of discrepant responses between nurse and self-administered scores were 24 +/- 15% in experienced patients and 34 +/- 17% in novice patients (p = 0.018), which fell to 21 +/- 16 and 23 +/- 10%, respectively, by visit 2 (p = NS). However, discrepancy rates were not significantly different between novice and experienced patients when adjusted by center. Discrepancies occurred randomly in all 32 IBDQ items. Eighty percent of all discrepant responses differed by only one grade of a seven-point Likert scale. Baseline self-administered scores for all patients were 4.80 +/- 1.24 (absolute score, 153.0 +/- 39.9). Mean score differences at each visit (nurse minus self) were very small, ranging from 0.029 to 0.136, and would not be considered clinically important. Intraclass correlation coefficients between the nurse and self-administered IBDQ and the four dimensional scores were > or = 0.97 by visit 2, indicating excellent concordance and minimal observer error. Mean changes in score over time were of comparable magnitude for both self (0.320 +/- 0.819) and nurse (0.260 +/- 0.831) assessments. We conclude that the IBDQ may be reliably used as a self-administered instrument in clinical trials.

A randomized study of the influence of perfusion technique and pH management strategy in 316 patients undergoing coronary artery bypass surgery. I. Mortality and cardiovascular morbidity.

UNLABELLED: The impact of perfusion technique and mode of pH management during cardiopulmonary bypass has not been well characterized with respect to postoperative cardiovascular outcome. METHODS: This double-blind, randomized study comparing outcomes after alpha-stat or pH-stat management and pulsatile or nonpulsatile perfusion during moderate hypothermic cardiopulmonary bypass was undertaken in 316 patients undergoing coronary artery bypass operations. RESULTS: Cardiovascular morbidity and mortality were not affected by pH management, and the incidence of stroke (2.5%) did not differ between groups. Overall in-hospital mortality was 2.8%, eight of the nine deaths occurring in the nonpulsatile group (5.1% versus 0.6%; p = 0.018). The incidence of myocardial infarction was 5.7% in the nonpulsatile group and 0.6% in the pulsatile group (p = 0.010), and use of intraaortic balloon pulsation was significantly more common in the nonpulsatile group (7.0% versus 1.9%; p = 0.029). The overall percentage of patients having major complications was also significantly higher in the nonpulsatile group (15.2% versus 5.7%; p = 0.006). Duration of cardiopulmonary bypass, age, and use of nonpulsatile perfusion all correlated significantly with adverse outcome. CONCLUSIONS: Use of pulsatile perfusion during cardiopulmonary bypass was associated with decreased incidences of myocardial infarction, death, and major complications.

A randomized study of the influence of perfusion technique and pH management strategy in 316 patients undergoing coronary artery bypass surgery. II. Neurologic and cognitive outcomes.

UNLABELLED: This double-blind, randomized comparison of pulsatile or nonpulsatile perfusion and alpha-stat or pH-stat management during cardiopulmonary bypass was designed to assess postoperative central nervous system outcomes. METHODS: Neurologic and cognitive testing was conducted before the operation and 7 days and 2 months after the operation in 316 patients having coronary artery bypass and in a reference cohort of 40 patients having major vascular and thoracic operations. RESULTS: As detailed in part I of this study, mortality in patients having coronary bypass was 2.8%. The incidence of stroke was 2.5% and did not differ among bypass groups. Mortality was 2.5% for the major surgery cohort. The incidence of cognitive (p = 0.003) and either neurologic or cognitive dysfunction (p = 0.0002) was higher at 7 days for the coronary bypass group than for the major surgery cohort. The incidence of neurologic dysfunction remained higher (p = 0.050) at 2 months in the coronary bypass group. Cognitive dysfunction at 2 months was less prevalent after 90 minutes of cardiopulmonary bypass in patients managed with alpha-stat than with pH-stat strategy (27% versus 44%, p = 0.047). CONCLUSIONS: Postoperative central nervous system dysfunction is more prevalent in patients having coronary bypass than in those having major operations. Pulsatility has no effect on central nervous system outcomes, but alpha-stat management is associated with a decreased incidence of cognitive dysfunction in patients undergoing prolonged cardiopulmonary bypass.

Modulation of gonadotropin II release by K+ channel blockers in goldfish gonadotropes: a novel stimulatory action of 4-aminopyridine.

The effects of K+ channel blockers on basal gonadotropin II (GTH-II) release were examined in cultured goldfish gonadotropes. Tetraethylammonium (TEA) inhibited basal GTH-II release, whereas 4-aminopyridine (4-AP) increased basal release, although both K+ channel blockers generated increases in [Ca2+]i. Other K+ channel blockers had no significant effect on GTH-II release. We examined whether Ca2+ entry that arises from blockade of K+ channels by 4-AP mediates the secretory response. Secretion evoked by 4-AP was slightly reduced by TEA but was unaffected by reducing Ca2+ entry using either an inhibitor of Ca2+ channels, verapamil, or nominally Ca2+-free medium. In contrast, the Ca2+ signal evoked by 4-AP was largely blocked by Ca2+-free medium, as predicted by its inhibitory action on K+ channels. Together, these data suggest that the hormone release response to 4-AP is independent of entry of extracellular Ca2+. Finally, the mechanism of hormone release evoked by 4-AP appeared to be independent of mechanism(s) evoked by caffeine since 4-AP did not affect caffeine-evoked release and caffeine did not affect 4-AP evoked release. That both 4-AP and TEA generated Ca2+ signals but affected hormone release in either an extracellular Ca2+ independent (4-AP) or inhibitory (TEA) manner suggests that Ca2+ entry is linked to GTH-II secretion in a highly nonlinear fashion.

Successful pregnancies resulting from the use of prolonged-incubation human spermatozoa in gamete intrafallopian transfer.

Human spermatozoa that were incubated overnight at room temperature before intrafallopian transfer with freshly collected oocytes gave rise to successful pregnancies and normal live births. The resulting pregnancy rate per transfer of 50% (4 of 8) compared favorably with the average pregnancy rate of 41.8% (38 of 91), achieved by our standard spermatozoal preparation procedure that prepared the spermatozoa approximately 2 hours before the GIFT operation. This new approach for the preparation of human spermatozoa would be applicable to oligospermic patients and some GIFT patients whose partners may have difficulties in producing a semen specimen immediately before the GIFT operation.

Shaping cocaine abstinence by successive approximation.

Cocaine-using methadone-maintenance patients were randomized to standard contingency management (abstinence group, n = 49) or to a contingency designed to increase contact with reinforcers (shaping group, n = 46). For 8 weeks, both groups earned escalating-value vouchers based on thrice-weekly urinalyses: The abstinence group earned vouchers for cocaine-negative urines only; the shaping group earned vouchers for each urine specimen with a 25% or more decrease in cocaine metabolite (first 3 weeks) and then for negative urines only (last 5 weeks). Cocaine use was lower in the shaping group, but only in the last 5 weeks, when the response requirement was identical. Thus, the shaping contingency appeared to better prepare patients for abstinence. A 2nd phase of the study showed that abstinence induced by escalating-value vouchers can be maintained by a nonescalating schedule, suggesting that contingency management can be practical as a maintenance treatment.

Contingent reinforcement increases cocaine abstinence during outpatient treatment and 1 year of follow-up.

This study assessed whether contingent incentives can be used to reinforce cocaine abstinence in dependent outpatients. Seventy cocaine-dependent outpatients were randomized into 2 conditions. All participants received 24 weeks of treatment and 1 year of follow-up. The treatment provided to all participants combined counseling based on the community reinforcement approach with incentives in the form of vouchers exchangeable for retail items. In 1 condition, incentives were delivered contingent on cocaine-free urinalysis results, whereas in the other condition incentives were delivered independent of urinalysis results. Abstinence-contingent incentives significantly increased cocaine abstinence during treatment and 1 year of follow-up compared with noncontingent incentives.

Broad beneficial effects of cocaine abstinence reinforcement among methadone patients.

Escalating reinforcement for sustained abstinence has been effective in treating cocaine abuse. Under this schedule, patients receive vouchers for cocaine-free urine samples; vouchers have monetary values that increase with the number of consecutive cocaine-free urine samples. Cocaine-abusing methadone patients were randomly assigned to receive vouchers for 12 weeks under (a) an escalating schedule (n = 20), (b) an escalating schedule with start-up bonuses (n = 20), or (c) a noncontingent schedule (n = 19). Start-up bonuses were designed to provide added reinforcement for initiating abstinence; however, they did not improve outcomes. Both contingent interventions significantly increased cocaine abstinence. In addition, the contingent interventions increased abstinence from opiates and decreased reports of cocaine craving. These results replicate the efficacy of cocaine abstinence reinforcement and show that it can have broad beneficial effects.