New loci of Lychnophora ericoides and transferability to Lychnophora pinaster, endangered medicinal species from Brazil.

Lychnophora ericoides and Lychnophora pinaster are species used in popular medicine as analgesic or anti-inflammatory agents to treat contusions, rheumatism, and insect bites. In this study, 21 simple sequence repeat loci of L. ericoides were developed and transferred to L. pinaster. Three populations of L. ericoides and 2 populations of L. pinaster were evaluated; they were collected in the State of Minas Gerais. Population parameters were estimated, and the mean values of observed and expected heterozygosity were 0.297 and 0.408 (L. ericoides) and 0.228 and 0.310 (L. pinaster), respectively. Greater genetic variability was observed within populations than between populations of L. ericoides (62 and 37%) and L. pinaster (97 and 2.8%). These results provide information for genetic conservation and taxonomic studies of these endangered species.

Report of an independent peer review of an acrylonitrile risk assessment.

A peer review panel made up of experts in toxicology, epidemiology, cancer mode of action (MOA), cancer mechanisms, carcinogenicity, genotoxicity, dose-response, US Environmental Protection Agency (EPA) cancer and noncancer methods, pharmacokinetic modeling and acrylonitrile, met on 22-23 September 2003 in Cincinnati, OH. The purpose of the meeting was to provide an independent review of a risk assessment of acrylonitrile that had been prepared by the Acrylonitrile Group (AN Group). Toxicology Excellence for Risk Assessment (TERA) organized the peer review and selected the panel. The panel discussed the toxicity and epidemiology literature of acrylonitrile and MOA information, and reached conclusions regarding its MOA, weight of evidence (WOE) for carcinogenicity, preferred approach for dose-response assessment and risk values. This paper summarizes the discussion and conclusions of the panel regarding the acrylonitrile assessment. Subsequent to the peer review, the authors of the acrylonitrile assessment revised their report and the panel reviewed the revised report. A manuscript of the revised assessment is being published in Regulatory Toxicology and Pharmacology.

Electrophysiological response properties of spinoreticular neurons in the monkey.

Extracellular recordings were made from 29 spinoreticular cells in the spinal cords of anesthetized monkeys. The cells were in either the cervical or the lumbar enlargement, and they were identified by antidromic activation from the medial part of the pontomedullary reticular formation. More spinoreticular neurons were sampled in the cervical than in the lumbar cord. Most of the cells were contralateral to the side from which antidromic activation was observed, but a higher proportion of the spinoreticular neurons in the cervical enlargement than in the lumbar enlargement was ipsilateral to the antidromic stimulus. Three cells in the lumbar cord were antidromically activated not only from the reticular formation but also from the contralateral thalamus, confirming that some spinoreticular projections are formed by collaterals from spinothalamic cells. Most of the spinoreticular neurons were in the ventral horn in laminae VII and VIII, although a few were in laminae IV-VI. Nearly half of the spinoreticular cells in the sample could not be activated by any form of peripheral stimulation tested. The other cells could be activated by stimulation of receptive fields that varied from small to large, that were sometimes bilateral regions of the skin or deep tissues. Although some spinoreticular cells could be classified as low threshold or wide dynamic range, the largest proportion were high threshold, requiring noxious stimulation for their activation. Descending volleys resulting from stimulation in the reticular formation could often be shown to inhibit or to excite spinoreticular neurons. It can be concluded that at least some spinoreticular neurons may play a role in nociception.

Cells of origin of the spinoreticular tract in the monkey.

The distribution of the cells of origin of the primate spinoreticular tract was determined following injections of horseradish peroxidase (HPR) into the pontomedullary reticular formation in Macaca fascicularis. Five animals received large bilateral injections which included the raphe nuclei and seven monkeys received smaller, unilateral injections. Sections sampled were from upper cervical levels, the cervical enlargement, upper and lower thoracic levels, and lumbosacral levels. The laminar distribution of spinoreticular cells in all spinal cord levels was comparable. More than half of the labeled cells were located ventromedially, in laminae VII and VIII. HRP-labeled cells were also found in the dorsal horn, primarily in the lateral reticulated part of lamina V. Some cells were also found in laminae I and X. Spinoreticular cells in the lumbosacral spinal cord mainly projected to the contralateral brainstem. In the cervical enlargement, however, a bilateral distribution of cells was observed following unilateral injections of HRP. Most spinoreticular cells were multipolar neurons with extensive dendritic ramifications. The distribution of spinoreticular cells is similar to the distribution of spinal cord neurons that project to the medial thalamus, but different from that of spinal neurons projecting to the ventrobasal complex. The anatomical organization of the spinoreticular tract is consistent with a role for this pathway in nociception.

Midbrain nuclei projecting to the medial medulla oblongata in the monkey.

To identify the midbrain nuclei that project to the medial part of the lower brainstem in the monkey, labeled cells were mapped in the midbrain following the injection of horseradish peroxidase into the medial medulla oblongata. After the general distribution of labeled cells was observed in three animals with large injections, more discrete injections of HRP were made in different locations in six additional animals. The small injections were centered in the nucleus raphe magnus, nucleus reticularis gigantocellularis, or nucleus medullae oblongatae centralis. The five labeled midbrain nuclei were the periaqueductal gray, nucleus cuneiformis, deep layers of the superior colliculus, nucleus of Darkschewitsch, and the interstitial nucleus of Cajal. In addition, the parvocellular division of the red nucleus and the posterior pretectal nucleus contained large numbers of cells when the injection spread into the inferior olive. No major differences in the distribution of labeled cells between different injection sites were found with the exception that the superior colliculus did not contain any labeled cells when the injection was restricted to midline structures. The functional implications of these anatomical findings are discussed in relation to the descending control of pain.

Ipsilateral extinction in the hemineglect syndrome.

Data suggest right-hemisphere dominance for attention. Right-hemisphere lesions reduce attentional capacity that may manifest as neglect or extinction. Attention can be assessed with the Face-Hand Test where touch on the face may extinguish simultaneous touch on the hand. Extinction ipsilateral to unilateral lesions suggests abnormal attention to ipsilateral hemispace. We tested patients with left- and right-hemisphere lesions without neglect and right-hemisphere lesions with neglect with stimuli applied exclusively ipsilateral to lesions. In experiment 1, stimuli were applied in face-hand combinations. In experiment 2, the Face-Hand Test was ranked from 0 (no extinction) to 7 (marked extinction) using progressively greater stimulation. In both experiments, right-hemisphere patients with neglect made significantly more errors than left-hemisphere patients without neglect. These data support models of bidirectional right-hemisphere attentional dominance.

Anosognosia and visuoverbal confabulation.

OBJECTIVE: To examine the relationship between verbal confabulation and anosognosia for hemiplegia (AHP). DESIGN: We compared patients with right hemisphere lesions and AHP with a control group with right hemisphere lesions without anosognosia. Patients attempted visual identifications of objects exposed to the left hemifield with brief (condition 1) or prolonged (condition 2) presentations. Responses were recorded as correct, incorrect, or admission of failure to perceive. SETTING: Inpatients at Beth Israel Medical Center, New York, NY. PATIENTS: A consecutive sample of nine patients with right hemisphere infarcts who demonstrated left hemiparesis, extrapersonal neglect, and left-sided visual field defects. MAIN OUTCOME MEASURES: Rates of correct, incorrect, and admission of failure to perceive responses. RESULTS: Patients with AHP had higher error rates (confabulations) and lower admission of failure to perceive rates than nonanosognosic patients in condition 1. Patients with AHP continued to have higher error rates in condition 2. Nonanosognosic patients had higher correct rates in condition 2 than condition 1. Groups did not differ in degree of neglect, lesion size or location, atrophy, sensory loss, or disorientation. CONCLUSION: Verbal confabulation is an important determinant in anosognosia.

Verbal asomatognosia.

Verbal asomatognosia is a form of neglect in which a patient denies ownership of a limb contralateral to a brain lesion. To establish the neuroanatomic substrate of this syndrome, we analyzed the CTs of 12 right-hemisphere stroke patients with neglect and verbal asomatognosia and 4 patients with neglect but without asomatognosia. Of 16 cortical and subcortical brain regions analyzed, supramarginal gyrus and its subcortical connections within posterior corona radiata were most consistently involved in the asomatognosia cases. One or both of these regions were spared in all cases of neglect without asomatognosia. Our data confirm Nielsen's localization of asomatognosia to the right supramarginal gyrus and thalamoparietal peduncle. Converging lines of evidence from experiments in humans and monkeys suggest that damage to area PF may be necessary for the production of personal neglect of a limb.

Two alien hand syndromes.

Review of the clinical characteristics and neuroanatomy of 20 reported cases of alien hand syndrome (AHS) and a patient of our own confirm that AHS is actually two distinct syndromes. Frontal AHS occurs in the dominant hand; is associated with reflexive grasping, groping, and compulsive manipulation of tools; and results from damage to the supplementary motor area, anterior cingulate gyrus, and medial prefrontal cortex of the dominant hemisphere and anterior corpus callosum. Callosal AHS is characterized primarily by intermanual conflict and requires only an anterior callosal lesion. the occurrence of frontal AHS in the dominant limb can be explained by an increased tendency for dominant limb exploratory reflexes coupled with release from an asymmetrically distributed, predominant nondominant-hemisphere inhibition. Callosal AHS is best explained by hemispheric disconnection manifested during behaviors requiring dominant-hemisphere control.

Depression of primate spinothalamic tract neurons by iontophoretic application of 5-hydroxytryptamine.

The effects of iontophoretic applications of 5-hydroxytryptamine (5-HT) were tested upon primate spinothalamic tract neurons recorded extracellularly in the spinal cord of anesthetized monkeys. The activity of most high threshold and wide dynamic range spinothalamic tract cells was depressed. 5-HT also reduced the responses of the cells to glutamate pulses which by themselves had a powerful excitatory action. It is concluded that 5-HT has a depressant action upon the postsynaptic membranes of spinothalamic tract cells, although the action has a slow time course. The observations are consistent with, but by no means prove, the hypothesis that serotonergic pathways descending from the brain stem produce a postsynaptic inhibiton of spinothalamic tract neurons.

Immunohistochemical demonstration of the endothelial nature of aortic intimal sarcoma.

Primary sarcomas of the aorta are rare; fewer than 30 cases have been reported. Among these, the majority are intraluminal and apparently intimal in origin. Extensive histochemical and electron-microscopic evaluation of these tumors has not previously been performed. We present a case of aortic intimal sarcoma in a 70-year-old man whose resected aorta showed multifocal, intimal tumor that appeared on light microscopy to be undifferentiated sarcoma. Electron microscopy was not helpful; however, immunohistochemical studies confirmed the endothelial nature of this neoplasm. The multifocal pattern of the tumor and the presence of intervening, atypical, proliferative endothelial cells suggests that endothelial dysplasia may have been a precursor lesion.

Decreased bone mineral density in Prader-Willi syndrome: comparison with obese subjects.

Bone density, anthropometric data, and markers of bone turnover were collected on 21 subjects diagnosed with Prader-Willi syndrome (PWS) and compared with 9 subjects with obesity of unknown cause. In addition, urinary N-telopeptide levels were obtained in all subjects. N-telopeptides are the peptide fragments of type I collagen, the major bone matrix material. During periods of active bone degradation or high bone turnover, high levels of N-telopeptides are excreted in the urine. However, no significant difference was detected in the urinary N-telopeptide levels when corrected for creatinine excretion (raw or transformed data) between our subjects with obesity or PWS and the observed effect size of the between-group difference was small. Although N-telopeptide levels were higher but not significantly different in the subjects with PWS compared with obese controls, the subjects with PWS had significantly decreased total bone and spine mineral density and total bone mineral content (all P < 0.001). No differences in N-telopeptide levels or bone mineral density were observed between subjects with PWS and chromosome 15q deletion or maternal disomy. Thus, decreased bone mineral density in subjects with PWS may relate to the lack of depositing bone mineral during growth when bones are becoming more dense (e.g., during adolescence), possibly because of decreased production of sex or growth hormones and/or long-standing hypotonia. It may not be caused by loss, or active degradation, of bone matrix measurable by the methods described in this study further supporting the possible need for hormone therapy during adolescence.

Pulmonary talc embolization.

A young woman with a history of drug abuse rapidly developed cor pulmonale, restrictive pulmonary defect, low diffusion capacity, and a suggestion of left ventricular dysfunction. She died from complications after a lung biopsy. Microscopic examination showed talc granulomas and arteritis. Some form of closed biopsy is probably safer, and trial of corticosteroid therapy seems warranted for this diagnosis. Talc ia a dangerous ingredient for any oral preparation that is likely to be used parenterally.

Fat overload syndrome. An autopsy study with evaluation of the coagulopathy.

Fat overload syndrome is a rare complication of intravenous fat emulsion therapy. It is characterized by sudden elevation of the serum triglyceride level, fever, hepatosplenomegaly, coagulopathy, and variable end-organ dysfunction. The illness is generally discrete, and symptoms regress as the lipemia clears. The transient nature of the syndrome has allowed only speculation as to its pathogenesis. The authors report an autopsy study of a child who died during an acute episode of fat overload and document the causative role of fat sludging in the associated end-organ failure. In addition, they offer evidence that the coagulopathy, previously an enigma, results from primary fibrinolysis, possibly caused by release of tissue plasminogen activators from the damaged endothelial cells.

Strategy for breakpoint cluster region analysis in chronic myelocytic leukemia in a routine clinical laboratory.

Despite the increasing reliance on breakpoint cluster region (bcr) determinations in diagnosis of chronic myelocytic leukemia (CML), few reports have dealt with the practical aspects of specimen analysis. In the setting of a routine molecular diagnostics laboratory, samples from 68 patients with active CML were evaluated for bcr rearrangements, with the use of a variety of enzymes and two probes. The data have been used to develop an efficient strategy for bcr screening and breakpoint determination. Screening with the universal bcr (UBCR) probe on Xba I and BgI II digests yielded bcr rearrangements in 100% of the Ph1-positive patients and three of the seven Ph1-negative patients, giving bcr analysis a sensitivity of 100%. A single-enzyme screen using the UBCR probe would have resulted in a false negative rate of 10%. The false negative rate was determined during the breakpoint site analysis from additional digests hybridized to both the 3' and UBCR probes. The false negative rate for the 3' probe was 26.5%, because of deletions or 5' rearrangements. The method of breakpoint site determination was dependent on screening results. In 78% of cases, one additional hybridization with two enzyme digests was required. During breakpoint site analysis, a rare false negative result was also demonstrated with Bam HI and Eco RI. This screening strategy has made bcr analysis competitive with cytogenetic analysis at the authors' institution; although turnaround time may be slightly longer, bcr analysis can yield information (such as detecting bcr-positive/Ph1-negative patients and determining breakpoint site) that cannot be obtained by cytogenetics.

Non-cancer risk assessment for nickel compounds: issues associated with dose-response modeling of inhalation and oral exposures.

This report presents the results of noncancer dose-response modeling for inhalation and oral exposures to nickel compounds using the NOAEL/LOAEL and benchmark dose (BMD) approaches. Several key issues associated with the implementation of the BMD approach were examined. Primary among them are difficulties associated with use of data for which the dose-response shape is poorly defined: nonuniqueness of maximum likelihood estimates and lower bounds equal to zero. In addition, several generalizable properties of the "hybrid approach" for modeling continuous endpoints were identified. A hybrid modeling approach allows one to consider "biological significance" on an individual (rather than group) basis; differences between individual- and group-based biological significance in the definition of benchmark response (BMR) levels are elucidated. In particular, it is shown that BMDs defined using group-based BMRs may be more like LOAELs than NOAELs. Application of cross-chemical and cross-endpoint comparisons suggest that, for chronic inhalation exposure, nickel sulfate appears to be as toxic or more toxic than nickel subsulfide and nickel oxide, although the high response rates for the latter two compounds at the lowest chronically administered concentration make such conclusions problematic. A nickel reference concentration could be derived based on the most sensitive benchmark concentration for chronic inhalation exposure to nickel sulfate, 1.7 x 10(-3) mg Ni/m3 for lung fibrosis in male rats. Analyses of oral studies of nickel sulfate and nickel chloride suggest that an appropriate basis for the nickel oral reference dose would be a BMD of 4-5 mg Ni/kg/day, based on increased prenatal mortality. (Uncertainty factors were not determined and neither an RfD nor an RfC was derived in this paper.) The BMD approach provides appropriate quantitative support for toxicological judgment; this paper addresses specific issues associated with the role of the BMD approach in noncancer risk assessment. Resolution of these and other issues may require the accumulation of a number of case studies such as the one presented here.

Applications of mechanistic data in risk assessment: the past, present, and future.

Mechanistic data, when available, have long been considered in risk assessment, such as in the development of the nitrate RfD based on effects in a sensitive group (infants). Recent advances in biology and risk assessment methods have led to a tremendous increase in the use of mechanistic data in risk assessment. Toxicokinetic data can improve extrapolation from animals to humans and characterization of human variability. This is done by the development of improved tissue dosimetry, by the use of uncertainty factors based on chemical-specific data, and in the development of physiologically based pharmacokinetic (PBPK) models. The development of the boron RfD illustrates the use of chemical-specific data in the improved choice of uncertainty factors. The draft cancer guidelines of the U.S. Environmental Protection Agency emphasize the use of mode of action data. The first choice under the guidelines is to use a chemical-specific, biologically based dose-response (BBDR) model. In the absence of a BBDR model, mode of action data are used to determine whether low-dose extrapolation is done using a linear or nonlinear (margin of exposure) approach. Considerations involved in evaluating a hypothesized mode of action are illustrated using 1,3-dichloropropene, and use of a BBDR model is illustrated using formaldehyde. Recent developments in molecular biology, including transgenic animals, microarrays, and the characterization of genetic polymorphisms, have significant potential for improving risk assessments, although further methods development is needed. Overall, use of mechanistic data has significant potential for reducing the uncertainty in assessments, while at the same time highlighting the areas of uncertainty.

Anatomical distribution of flexor carpi radialis and flexor carpi ulnaris motor nuclei in the cat spinal cord.

The distribution of motoneurons innervating the flexor carpi radialis (FCR) and flexor carpi ulnaris (FCU) muscles was studied utilizing retrograde labeling with horseradish peroxidase (HRP). The motor nuclei showed considerable differences in their longitudinal extents. The FCR nucleus occupied spinal segments C6-T1 while FCU ranged from the C7-C8 junction to T1. Results with localized i.m. injection of HRP suggested a somatotopic distribution of these motoneurons.

Coexistence of multiple arteriovenous malformations and an anomalous aortic arch.

An unusual case of multiple congenital arteriovenous malformations (AVM) coexistent with an anomalous aortic arch is described. Our patient had been asymptomatic, with physical findings limited to a low grade systolic murmur, until the onset of acute subarachnoid hemorrhage. Arteriography was technically difficult and failed to demonstrate the origin of his hemorrhage or the configuration of his aortic arch. However, an AVM within the neck muscles was visualized. Magnetic resonance imaging of his chest revealed a right-sided, retroesophageal aortic arch with an anomalous pattern of branching. The intracranial AVM and the course of the great vessels was clearly revealed at autopsy. A possible embryologic mechanism underlying the origin and distribution of the arch vasculature is discussed.

A description of the Maternal Addiction Program of the University of Miami/Jackson Memorial Medical Center.

The MAP of the University of Miami/Jackson Memorial Medical Center/Highland Park Pavilion is a comprehensive inpatient and outpatient chemical dependency rehabilitation program that serves mostly lower socioeconomic, African-American perinatal substance-abusing women. The multidisciplinary treatment team incorporates a broad spectrum of group and individual therapeutic modalities, including 12-step, psychoeducational, and RP components. Within MAP programs, significant attention is given to issues and experiences that are unique to this population and that must be addressed if rehabilitation is to be successful. These topics include, but are not limited to, physical, emotional and sexual abuse, empowerment, family and parenting concerns, and HIV prevention and coping skills for HIV-seropositive women.