Cerebral blood flow relationships associated with a difficult tone recognition task in trained normal volunteers

Tone recognition is partially subserved by neural activity in the right frontal and primary auditory cortices. First we determined the brain areas associated with tone perception and recognition. This study then examined how regional cerebral blood flow (rCBF) in these and other brain regions correlates with the behavioral characteristics of a difficult tone recognition task. rCBF changes were assessed using H2(15)O positron emission tomography. Subtraction procedures were used to localize significant change regions and correlational analyses were applied to determine how response times (RT) predicted rCBF patterns. Twelve trained normal volunteers were studied in three conditions: REST, sensory motor control (SMC) and decision (DEC). The SMC-REST contrast revealed bilateral activation of primary auditory cortices, cerebellum and bilateral inferior frontal gyri. DEC-SMC produced significant clusters in the right middle and inferior frontal gyri, insula and claustrum; the anterior cingulate gyrus and supplementary motor area; the left insula/claustrum; and the left cerebellum. Correlational analyses, RT versus rCBF from DEC scans, showed a positive correlation in right inferior and middle frontal cortex; rCBF in bilateral auditory cortices and cerebellum exhibited significant negative correlations with RT These changes suggest that neural activity in the right frontal, superior temporal and cerebellar regions shifts back and forth in magnitude depending on whether tone recognition RT is relatively fast or slow, during a difficult, accurate assessment.     

Neuropeptides in the insect brain: a review

Thirty-seven plants are listed, which are used by traditional healers in the central and southern parts of Somalia. For each species are listed: the botanical name with synonyms, collection number, vernacular name, medicinal use, preparation of remedy and dosage. Results of a literature survey are also reported including medicinal use, substances isolated and pharmacological effects. Three plants which should have been included in Part I of the series have been added and some corrections to that paper have been made. With these additions the series comprises 180 different plant species, distributed in 59 plant families.     

The importance of geriatrics to family medicine: a position paper by the Group on Geriatric Education of the Society of Teachers of Family Medicine

The role of geriatrics and geriatricians in family medicine remains unsettled. Despite a rapidly aging population, a tremendous shortage now exists of faculty with interest and expertise in geriatrics. Relatively few family practice residents choose to enter geriatric fellowship programs, and federal funding for such programs has been reduced. Despite accreditation requirements, residency programs are not always able to provide the range of geriatric experiences needed to properly prepare graduates to provide care for the broad range of older patients. Medical students' exposure to geriatrics remains limited. The Group on Geriatric Education of the Society of Teachers of Family Medicine believes that family medicine faculty must recognize and be committed to the notion that geriatrics is integral to family medicine. Both undergraduate and residency training programs should emphasize experience with geriatric patients in multiple settings. In particular, the nursing home should not be the main focus of geriatric training. The small number of certified geriatric faculty will be able to provide leadership, but a broad range of faculty must become involved in teaching geriatrics. Faculty development activities and continuing education programs to foster the necessary expertise will be essential to the accomplishment of this task.     

Young children''s understanding of pretense expressions of independent agency

Data from the Cancer Registry of Slovenia were used in a cohort study to determine whether the incidence of second primary cancers in patients with first primary breast cancer differs from the incidence expected in the general population. Special interest was given to long-term survivors. The expected numbers of second primary cancers were calculated by multiplying the number of appropriate person-years at risk by the corresponding age- and calendar-period-specific cancer incidence rates for women in Slovenia. The risk of a second primary cancer was expressed as the standardized incidence ratio (SIR). Of the 8,917 patients newly diagnosed in the period 1961-85 and followed-up to the end of 1994, 547 (6.2 percent) developed second primary cancers, whereas 410 (4.7 percent) were expected (SIR = 1.3, 95 percent confidence interval [CI] = 1.2-1.4). The risk was higher among younger patients. In long-term survivors, the risk was increased significantly for second primary cancer of the breast (SIR = 1.4, CI = 1.1-1.7), lung cancer (SIR = 1.6, CI = 1.1-2.3), melanoma (SIR = 2.7, CI = 1.5-4.4) and non-melanoma skin cancers(SIR = 2.0, CI = 1.6-2.4), corpus uteri cancer(SIR = 1.6, CI = 1.2-2.1), ovarian cancer(SIR = 2.3, CI = 1.7-3.0), and thyroid cancer (SIR = 2.5, CI = 1.2-4.6). Our results confirm the findings of several cohort studies carried out in Europe, the United States, and Japan, indicating that breast cancer patients should be monitored carefully for the occurrence of second primary cancers.     

Pharmacodynamic modeling of the electroencephalographic effects of flumazenil in healthy volunteers sedated with midazolam

The purpose of this study was to model pharmacodynamically the reversal of midazolam sedation with flumazenil. Ten human volunteers underwent four different sessions. In session 1, individual midazolam pharmacokinetics and electroencephalographic pharmacodynamics were determined. In sessions 2 and 3, a computer-controlled infusion of midazolam with individual volunteer pharmacokinetic data was administered, targeting a plasma concentration corresponding to a light or deep level of sedation (20% or 80% of the maximal midazolam electroencephalographic effect) for a period of 210 minutes. After obtaining a stable electroencephalographic effect and constant midazolam plasma concentrations, a zero-order infusion of flumazenil was started until complete reversal of midazolam electroencephalographic effect was obtained. The flumazenil infusion was then stopped and the volunteer was allowed to resedate because of the constant midazolam drug effect. The electroencephalographic response was measured during a 180-minute period and analyzed by aperiodic analysis and fast-Fourier transforms. In session 4, a midazolam plasma concentration corresponding to a deep level of sedation was targeted for 210 minutes to examine for the possible development of acute tolerance. No flumazenil was given in session 4. For a light sedation level, with a mean midazolam plasma concentration of 160 +/- 64 ng/ml, the mean half-life of the equilibration rate constant of flumazenil reversal is 5.0 +/- 2.5 minutes, and the mean effect site concentration causing 50% of Emax is 13.7 +/- 5.8 ng/ml. For a deep level of sedation, with a mean midazolam plasma concentration of 551 +/- 196 ng/ml, the mean half-life of the equilibration rate constant is 3.9 +/- 1.5 minutes, and the mean effect site concentration causing 50% of Emax is 20.6 +/- 6.8 ng/ml. This study provides an estimate of the magnitude of the blood/central nervous system equilibration delay for flumazenil antagonism of midazolam sedation and further defines the usefulness of the electroencephalogram as a measure of midazolam pharmacodynamic effect.     

Modification of the calcium and calmodulin sensitivity of the type I adenylyl cyclase by mutagenesis of its calmodulin binding domain

The type I adenylyl cyclase is directly stimulated by Ca2+ and calmodulin in vitro, and the enzyme is also stimulated by increases in intracellular Ca2+ in vivo. Ca2+ stimulation of the enzyme in vivo may be due to direct interactions of the enzyme with Ca2+ and calmodulin or to an indirect mechanism involving stimulation of the enzyme by Ca(2+)-activated protein kinases. In this study, we have made several point mutations within the calmodulin binding domain to determine if the Ca2+ sensitivity of the enzyme can be modified by mutagenesis. The catalytic activities of the mutant enzymes were comparable to wild type type I adenylyl cyclase. Substitution of Cys-507 with Ser-507 did not have significant effects on the calmodulin or Ca2+ sensitivity of the enzyme. However, replacement of Lys-504 with Asp caused a 4-fold decrease in sensitivity to Ca2+. Ca2+ and calmodulin stimulation were abolished by substitution of Phe-503 with Arg-503. Stimulation of type I adenylyl cyclase activity in vivo by intracellular Ca2+ was also greatly diminished with the Arg-503 mutant indicating that Ca2+ stimulation of the enzyme in vivo is due primarily to direct interactions with calmodulin and Ca2+. These data demonstrate that the Ca2+ sensitivity of this enzyme can be modulated by point mutagenesis within the putative calmodulin binding domain and indicate that the enzyme can be directly regulated by Ca2+ and calmodulin in vivo.     

A population study of the natural history of Wolff-Parkinson-White syndrome in Olmsted County, Minnesota, 1953-1989

BACKGROUND: Virtually all natural history studies of Wolff-Parkinson-White (WPW) syndrome have been case series and, as such, have been constrained by referral biases, skewed age and sex distributions, or brief follow-up periods. The purpose of our study was to examine the natural history, the development of arrhythmias, and the incidence of sudden death in an entire cohort of pediatric and adult WPW patients from a community-based local population. METHODS AND RESULTS: We identified 113 residents of Olmsted County, Minnesota, during the period 1953-1989 using the centralized records-linkage system provided by the Mayo Clinic and the Rochester Epidemiology Program Project. Medical records and ECGs were reviewed to confirm the diagnosis and to establish pathway location by ECG criteria. Follow-up, via record review and telephone interview, was complete in 95% of subjects through 1990. The incidence of newly diagnosed cases was approximately four per 100,000 per year. Preexcitation was not present on the initial ECG of 22% of the cohort. Approximately 50% of the population was asymptomatic at diagnosis, with 30% subsequently having symptoms related to arrhythmia at follow-up. Two sudden cardiac deaths (SCD) occurred over 1,338 patient-years of follow-up, yielding an overall SCD rate of 0.0015 (95% confidence interval, 0.0002-0.0054) per patient-year. No SCD occurred in patients asymptomatic at diagnosis. CONCLUSIONS: The incidence of sudden death in a local community-based population is low and suggests that electrophysiological testing should not be performed routinely in asymptomatic patients with WPW syndrome. Nevertheless, young, asymptomatic patients, particularly those < 40 years old, should return for medical follow-up should symptoms develop.