Surface-associated astrocytes, not endfeet, form the glia limitans in posterior piriform cortex and have a spatially distributed, not a domain, organization.

"Surface-associated astrocytes" (SAAs) in posterior piriform cortex (PPC) are unique by virtue of a direct apposition to the cortical surface and large-caliber processes that descend into layer I. In this study additional unique and functionally relevant features of SAAs in PPC of the rat were identified by light and electron microscopy. Examination of sections cut parallel to the surface of PPC and stained for glial fibrillar acidic protein revealed that, in addition to descending processes, SAAs give rise to an extensive matrix of "superficial processes." Electron microscopy revealed that these superficial processes, together with cell bodies, form a continuous sheet at the surface of PPC with features in common with the glia limitans that is formed by endfeet in other cortical areas. These include a glia limiting membrane with basal lamina and similar associated organelles, including a striking array of mitochondria. Of particular interest, SAAs lack the domain organization observed in neocortex and hippocampus. Rather, superficial processes overlap extensively with gap junctions between their proximal regions as well as between cell bodies. Study of the descending processes revealed thin extensions, many of which appose synaptic profiles. We conclude that SAAs provide a potential substrate for bidirectional signaling and transport between brain and the pial arteries and cerebrospinal fluid in the subarachnoid space. We postulate that the spatially distributed character of SAAs in PPC reflects and supports the spatially distributed circuitry and sensory representation that are also unique features of this area.

Effect of myeloablative bone marrow transplantation on growth in children with sickle cell anaemia: results of the multicenter study of haematopoietic cell transplantation for sickle cell anaemia.

Although haematopoietic cell transplantation (HCT) is curative for sickle cell anaemia (SCA), concerns about its short- and long-term toxicities limit its application. A potential toxicity is an adverse effect on growth. To identify an HCT growth effect, serial height and weight measurements from 53 children and adolescents with SCA after receiving a transplant were compared to historical controls. Hierarchical Linear Models for longitudinal data were used for analysis. In general growth was not impaired by HCT for SCA in young children; however, diminished growth may occur if HCT is carried out near or during the adolescent growth spurt.

The differential distribution of the growth-associated protein-43 in first and higher order thalamic nuclei of the adult rat.

Corticothalamic axons from layer 5 of primary and secondary auditory and visual areas have large terminals that make multiple synaptic contacts on proximal dendrites of relay cells in higher order thalamic nuclei and have been termed "driver" inputs. The corticothalamic cells express mRNA for the presynaptic growth-associated protein-43, in the adult rat [Feig SL (2004) Corticothalamic cells in layers 5 and 6 of primary and secondary sensory cortex express GAP-43 mRNA in the adult rat. J Comp Neurol 468:96-111]. In contrast, ascending driver afferents to first order nuclei (e.g. retinal, inferior collicular, and lemniscal) lose growth-associated protein-43 as mature synaptic terminals are established. Levels of immunoreactivity for growth-associated protein-43 are compared for first and higher order visual (lateral geniculate and lateral posterior), auditory (ventral and dorsal divisions of the medial geniculate), and somatosensory (ventral posterior and posterior) thalamic nuclei. At one week postnatal, staining for growth-associated protein-43 is uniform throughout first and higher order thalamic nuclei. By three weeks and thereafter, staining is denser in the higher order than first order thalamic nuclei. Electron microscopy shows growth-associated protein-43 in profiles with characteristics of afferents from layer 5 in LP and medial geniculate nucleus and no such label in retinal afferents in lateral geniculate nucleus. In these nuclei, approximately 25% of the profiles with characteristics of cortical afferents from layer 6 have label for growth-associated protein-43. The superficial layers of the superior colliculus also show growth-associated protein-43 positive profiles with characteristics of terminals from cortical layer 5. Some growth-associated protein-43 positive terminals were also positive for GABA in the thalamic nuclei studied and in the superior colliculus. The data suggest that sensory afferents to first order thalamocortical relays become stabilized once mature synaptic patterns are established, but the higher stages of information processing involving higher order thalamic relays, via cells in cortical layer 5, retain plasticity related to growth-associated protein-43 in the adult.

Postremission therapy for children with acute myeloid leukemia: the children's cancer group experience in the transplant era.

We reviewed consolidation therapy results and analyzed postremission outcomes for 1464 children less than 21 years old at diagnosis in five consecutive Children's Cancer Group acute myeloid leukemia trials between 1979 and 1996. Children in remission were allocated to allogeneic bone marrow transplantation (BMT) (N=373) in first remission, if a matched family donor was available. Remaining children were assigned consolidation chemotherapy (N=688) or autologous purged BMT (N=217), or withdrew from study before assignment, or with unknown data (N=186). Overall and disease-free survival were superior for children assigned allogeneic transplants. High (>50,000/microl) diagnostic white blood cell (WBC) count was prognostic for inferior outcome, but French-American-British (FAB) subtypes were not. Inv(16) is a favorable karyotypic feature for children in first remission and t(8;21) is not. Allogeneic transplantation benefit was evident in most children, including those with high or low diagnostic WBC count, each FAB subtype, and t(8;21), but was not seen in children with inv(16). Therefore, these data suggest reserving matched related donor allogeneic transplantation for children with inv(16) for second remission, but not those with t(8;21).

Prognostic variables in newly diagnosed children and adolescents with acute myeloid leukemia: Children's Cancer Group Study 213.

The objective of this study was to identify biologic parameters that were associated with either exceptionally good or poor outcome in childhood acute myeloid leukemia (AML). Among the children with AML who entered Children's Cancer Group trial 213, 498 patients without Down syndrome or acute promyelocytic leukemia (APL) comprise the basis for this report. Univariate comparisons of the proportion of patients attaining complete remission after induction (CR) indicate that, at diagnosis, male gender, low platelet count (< or =20 000/microl), hepatomegaly, myelodysplastic syndrome (MDS), French-American- British (FAB) category M5, high (>15%) bone marrow (BM) blasts on day 14 of the first course of induction, and +8 are associated with lower CR rates, while abnormal 16 is associated with a higher CR rate. Multivariate analysis suggests high platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 are independent prognostic factors associated with better CR. Univariate analysis demonstrated a significant favorable relationship between platelet count at diagnosis (>20 000/microl), absence of hepatomegaly, low percentage of BM blasts (< or =15%), and abnormal 16 with overall survival. Absence of hepatomegaly, < or =15% day 14 BM blast percentage, and abnormal 16 were determined to be independent prognostic factors associated with better survival.

Connections of higher order visual relays in the thalamus: a study of corticothalamic pathways in cats.

Axonal markers injected into layers 5 and 6 of cortical areas 17, 18, or 19 labeled axons going to the lateral geniculate nucleus (LGN), the lateral part of the lateralis posterior nucleus (LPl), and pulvinar (P). Area 19 sends fine axons (type 1, Guillery [1966] J Comp Neurol 128:21-50) to LGN, LPl, and P, and thicker, type 2 axons to LPl and P. Areas 17 and 18 send type 1 axons to LGN, and a few type 1, but mainly type 2 axons to LPl and P. Type 1 and 2 axons from a single small cortical locus distribute to distinct, generally nonoverlapping parts of LP and P; type 1 axons have a broader distribution than type 2 axons. Type 2 axons, putative drivers of thalamic relay cells (Sherman and Guillery [1998] Proc Natl Acad Sci USA 95:7121-7126; Sherman and Guillery [2001] Exploring the thalamus. San Diego: Academic Press), supply small terminal arbors (100- to 200-microm diameter) in LPl and P, and then continue into the midbrain. Each thalamic type 2 arbor contains two terminal types. One, at the center of the arbor, is complex and multilobulated; the other, with a more peripheral distribution, is simpler and may contribute to adjacent arbors. Type 2 arbors from a single injection are scattered around and along "isocortical columns" in LPl, (i.e., columns that represent cells having connections to a common cortical locus). Evidence is presented that the connections and consequently the functional properties of cells in LP change along these isocortical columns. Type 2 driver afferents from a single cortical locus can, thus, be seen as representing functionally distinct, parallel pathways from cortex to thalamus.

Second malignant neoplasms after successful treatment of childhood cancers.

Improved treatment and supportive care have increased the survival of children diagnosed with cancer. This success has resulted in a growing population at risk of long-term complications of therapy, including secondary malignancy. These neoplasms may result from the direct effect of the modalities used in treatment of the primary tumor, more indirect effects of the treatment or supportive care, the genetic predisposition of the patient, or to interactions among these factors. The increasing success of cancer therapy is producing a rapidly growing population of patients at risk of second malignancy. This is a result of the increasing intensity of treatments and the increasing duration of survival, which provides the time to manifest the late effects of therapy. The concept that a patient is "cured" at some arbitrary time after treatment does not diminish the need for follow-up of all cancer survivors to identify and treat secondary malignancies. These risks have led to an increased effort to define phenotypic and genotypic categories of patients that may be cured with less intensive therapy and to develop molecularly targeted drugs that have fewer noxious effects on normal tissues.

Congenital thrombocytopenia and radio-ulnar synostosis: a new familial syndrome.

The association of bone marrow failure and skeletal defects has been frequently noted, however, the genetic basis for most of these syndromes remains unclear. We describe a previously uncharacterized autosomal dominant syndrome of amegakaryocytic thrombocytopenia associated with radial-ulnar synostosis. The clinical features of this syndrome appear to be distinct from other similar conditions, including Fanconi's anaemia and thrombocytopenia-absent radii (TAR). The physical findings at diagnosis and clinical management of each case are detailed, as well as a discussion of this disorder in the context of other syndromes in which marrow failure and skeletal defects are prominent features. We also review recent developments in molecular genetics that may provide important clues to the underlying aetiology of this condition.

A new subdivision of anterior piriform cortex and associated deep nucleus with novel features of interest for olfaction and epilepsy.

The anterior part of the piriform cortex (the APC) has been the focus of cortical-level studies of olfactory coding and associative processes and has attracted considerable attention as a result of a unique capacity to initiate generalized tonic-clonic seizures. Based on analysis of cytoarchitecture, connections, and immunocytochemical markers, a new subdivision of the APC and an associated deep nucleus are distinguished in the rat. As a result of its ventrorostral location in the APC, the new subdivision is termed the APC(VR). The deep nucleus is termed the pre-endopiriform nucleus (pEn) based on location and certain parallels to the endopiriform nucleus. The APC(VR) has unique features of interest for normal function: immunostaining suggests that it receives input from tufted cells in the olfactory bulb in addition to mitral cells, and it provides a heavy, rather selective projection from the piriform cortex to the ventrolateral orbital cortex (VLO), a prefrontal area where chemosensory, visual, and spatial information converges. The APC(VR) also has di- and tri-synaptic projections to the VLO via the pEn and the submedial thalamic nucleus. The pEn is of particular interest from a pathological standpoint because it corresponds in location to the physiologically defined "deep piriform cortex" ("area tempestas") from which convulsants initiate temporal lobe seizures, and blockade reduces ischemic damage to the hippocampus. Immunostaining revealed novel features of the pEn and APC(VR) that could alter excitability, including a near-absence of gamma-aminobutyric acid (GABA)ergic "cartridge" endings on axon initial segments, few cholecystokinin (CCK)-positive basket cells, and very low gamma-aminobutyric acid transporter-1 (GAT1)-like immunoreactivity. Normal functions of the APC(VR)-pEn may require a shaping of neuronal activity by inhibitory processes in a fashion that renders this region susceptible to pathological behavior.

Immunocytochemical analysis of basket cells in rat piriform cortex.

Basket cells, defined by axons that preferentially contact cell bodies, were studied in rat piriform (olfactory) cortex with antisera to gamma-aminobutyric acid (GABA)ergic markers (GABA, glutamate decarboxylase) and to peptides and calcium binding proteins that are expressed by basket cells. Detailed visualization of dendritic and axonal arbors was obtained by silver-gold enhancement of staining for vasoactive intestinal peptide (VIP), cholecystokinin (CCK), parvalbumin, and calbindin. Neuronal features were placed into five categories: soma-dendritic and axonal morphologies, laminar distributions of dendritic and axonal processes, and molecular phenotype. Although comparatively few forms were distinguished within each category, a highly varied co-expression of features from different categories produced a "combinatorial explosion" in the characteristics of individual neurons. Findings of particular functional interest include: dendritic distributions suggesting that somatic inhibition is mediated by feedforward as well as feedback pathways, axonal variations suggesting a differential shaping of the temporal aspects of somatic inhibition from different basket cells, evidence that different principal cell populations receive input from different combinations of basket cells, and a close association between axonal morphology and molecular phenotype. A finding of practical importance is that light microscopic measurements of boutons were diagnostic for the molecular phenotype and certain morphological attributes of basket cells. It is argued that the diversity in basket cell form in the piriform cortex, as in other areas of the cerebral cortex, reflects requirements for large numbers of specifically tailored inhibitory processes for optimal operation that cannot be met by a small number of rigidly defined neuronal populations.

Marrow transplants from unrelated donors for patients with aplastic anemia: minimum effective dose of total body irradiation.

Patients with aplastic anemia who do not have suitably HLA-matched, related donors generally receive immunosuppressive treatment as first-line therapy and are considered for transplantation from an unrelated donor only if they fail to respond to immunosuppressive treatment. In this setting, rates of transplantation-related morbidity and mortality have been high. We conducted a prospective study to determine the minimal dose of total body irradiation (TBI) sufficient to achieve sustained engraftment when it is used in combination with 3 cycles of 30 mg/kg of antithymocyte globulin (ATG) and 4 cycles of 50 mg/kg of cyclophosphamide (CY). We also wanted to determine the tolerability and toxicity of the regimen. The starting dosage of TBI was 3 x 200 cGy given over 2 days following CY/ATG. The TBI dose was to be escalated in increments of 200 cGy if graft failure occurred in the absence of prohibitive toxicity, and de-escalated for toxicity in the absence of graft failure. Twenty-one female and 29 male patients aged 1.3 to 46.5 years (median age, 14.4 years) underwent transplantation at 14 medical centers. The time interval from diagnosis to transplantation was 2.8 to 264 months (median, 14.5 months). All patients had been transfused multiple times and all had received 1 to 11 courses (median, 4 courses) of immunosuppressive treatment and other modalities of treatment. In 38 cases, the donors were HLA-A, -B and -DR phenotypically matched with the patients, and, in 12 cases, the donor phenotype differed from that of the recipient by 1 HLA antigen. Recipients of mismatched transplants were considered separately for TBI dose modification, and this study is still ongoing. Seven patients did not tolerate ATG and were prepared with 6 x 200 cGy of TBI plus 120 mg/kg of CY. Of the HLA-matched recipients prepared with CY/ATG/TBI, all 20 who received 3 x 200 or 2 x 200 cGy of TBI achieved engraftment, and 10 are alive. Of the 13 patients who received 1 x 200 cGy of TBI, 1 failed to engraft, and 8 are alive. Each of 10 patients who received an HLA-nonidentical transplant achieved engraftment, and 3 of 6 who were given 3 x 200 cGy of TBI, and 4 of 4 who were given 2 x 200 cGy are alive. Pulmonary toxicity occurred in 8 of 30 patients who were given 3 x 200 or 2 x 200 cGy of TBI concurrently with ATG and CY at 200 mg/kg, and in 2 of 13 patients who received 1 x 200 cGy of TBI, a pattern that suggests a decrease in toxicity with TBI dose de-escalation. Overall, the highest probability of survival (73%) was observed among patients who underwent transplantation within 1 year of diagnosis, compared with patients who underwent transplantation after a longer period of disease. In addition, younger patients (aged < or = 20 years) were more likely to survive than older patients (aged > 20 years). Thus, for patients with an HLA-matched, unrelated donor, a TBI dose of 200 cGy (in combination with CY/ATG) was sufficient to allow for engraftment without inducing prohibitive toxicity. As in previous studies, patient age and pretransplantation disease duration remain important prognostic factors.

Unrelated umbilical cord stem cell transplantation for X-linked immunodeficiencies.

Banked unrelated umbilical cord blood matched at 5 of 6 human leukocyte antigen loci was used to reconstitute the immune system in 2 brothers with X-linked lymphoproliferative syndrome and 1 boy with X-linked hyperimmunoglobulin-M syndrome. Pretransplant cytoreduction and posttransplant graft-versus-host prophylaxis were given. Hematopoietic engraftment and correction of the genetic defects were documented by molecular techniques. Two years after transplantation, all 3 patients have normal immune systems. These reports support the wider use of banked partially matched cord blood for transplantation in primary immunodeficiencies.

Stereotactic core-needle breast biopsy: a multi-institutional prospective trial.

PURPOSE: To assess the accuracy of stereotactic core-needle biopsy (CNB) of nonpalpable breast lesions within the context of clinically important parameters of anticipated tissue-sampling error and concordance with mammographic findings. MATERIALS AND METHODS: CNB was performed in 1,003 patients, with results validated at surgery or clinical and mammographic follow-up. Mammographic findings were scored according to the American College of Radiology Breast Imaging Reporting and Data System with a similar correlative scale for histopathologic samples obtained at either CNB or surgery. Agreement of CNB findings with surgical findings or evidence of no change during clinical and mammographic follow-up (median, 24 months) for benign lesions was used to determine results. Three forms of diagnostic discrimination measures (strict, working [strict conditioned by tissue sampling error], applied [working conditioned by concordance of imaging and CNB findings) were used to evaluate the correlation of CNB, surgical, and follow-up results. RESULTS: Strict, working, and applied sensitivities were 91% +/- 1.9; 92% +/- 1.8, and 98% +/- 0.9, respectively; strict, working, and applied specificities were 100%, 98% +/- 0.8, and 73% +/- 0.9; strict, working, and applied accuracies were 97%, 96%, and 79%. CONCLUSION: Percutaneous stereotactic CNB is an accurate method to establish a histopathologic diagnosis of nonpalpable breast lesions. Accuracy increases when additional surgery is performed for lesions with anticipated sampling error or when CNB findings are discordant with mammographic findings. An understanding of the interrelationship among these parameters is necessary to properly assess results.

Relationship between phantom failure rates and radiation dose in mammography accreditation.

The American College of Radiology Mammography Accreditation Program (ACR MAP) reviews both clinical mammograms and a phantom image to assess clinical and technical quality from each mammography unit. The phantom contains details representing fibers (speculations), speck groups (microcalcifications), and masses. The depiction of these structures by the mammographic system is scored by medical physicists. The phantom image is taken using the facility's exposure technique for a 4.2-cm thick breast of average composition. The mean glandular dose (MGD) is determined from a set of thermoluminescent dosimeters placed on top of the chest wall edge of the phantom. Phantom scores and MGD data collected from 1993 to 1999 based on 31 535 unit evaluations are presented in this paper. The relationship between the failure rate for phantom image quality and MGD has been analyzed. While over all doses the phantom failure rate was 11%, for doses of 0.26 to 0.50 mGy the failure rate was 43%. The phantom failure rate fell continuously to about 6% for MGDs in the range of 1.51-2.0 mGy. With further increases in dose, failure rates began to rise. Factors that may account for these results are presented and discussed.

Radiologists' preferences for digital mammographic display. The International Digital Mammography Development Group.

PURPOSE: To determine the preferences of radiologists among eight different image processing algorithms applied to digital mammograms obtained for screening and diagnostic imaging tasks. MATERIALS AND METHODS: Twenty-eight images representing histologically proved masses or calcifications were obtained by using three clinically available digital mammographic units. Images were processed and printed on film by using manual intensity windowing, histogram-based intensity windowing, mixture model intensity windowing, peripheral equalization, multiscale image contrast amplification (MUSICA), contrast-limited adaptive histogram equalization, Trex processing, and unsharp masking. Twelve radiologists compared the processed digital images with screen-film mammograms obtained in the same patient for breast cancer screening and breast lesion diagnosis. RESULTS: For the screening task, screen-film mammograms were preferred to all digital presentations, but the acceptability of images processed with Trex and MUSICA algorithms were not significantly different. All printed digital images were preferred to screen-film radiographs in the diagnosis of masses; mammograms processed with unsharp masking were significantly preferred. For the diagnosis of calcifications, no processed digital mammogram was preferred to screen-film mammograms. CONCLUSION: When digital mammograms were preferred to screen-film mammograms, radiologists selected different digital processing algorithms for each of three mammographic reading tasks and for different lesion types. Soft-copy display will eventually allow radiologists to select among these options more easily.

Ductal carcinoma in situ. Implications for screening mammography.

Ductal carcinoma in situ (DCIS) now represents 20% of all newly diagnosed breast cancers because of increased detection by screening mammography. Twenty year relative survival rates are 97%. Postsurgical and histological studies and recent molecular biological studies indicate that most cases of DCIS will progress to invasive carcinoma if not detected by mammography. Screening mammography studies support the need for annual versus less frequent screenings to detect DCIS before further progression.

An introduction to economic issues in breast imaging.

Marked increases in national health care costs, along with governmental coverage of health care costs for the elderly under Medicare, have resulted in increased government regulation of medical reimbursement rates. Private insurers and HMOs now provide reimbursements that are frequently the same or lower than those from Medicare. Reimbursement rates for mammography have been particularly restricted. Although screening mammography appears to be as cost-effective as other commonly accepted medical interventions, some third-party payors have been reluctant to reimburse screening mammography because of its perceived effect on overall health care costs. An objective analysis shows that inclusion of coverage for screening mammography, however, even beginning at age 40 years, has only a slight effect on total health care costs. Adequate reimbursement for screening mammography supports an effort that provides substantial reduction in deaths from breast cancer.

Economic challenges in breast imaging. A survivor's guide to success.

Most breast imaging centers today operate under financial strain. Among strategies designed to improve their bottom line, more efficient use of the radiologist's time is the most fundamental strategy and the one most likely to succeed in all breast imaging centers. Tasks performed by the radiologist that are not directly related to interpretation and consultation should be shifted to other personnel. Other strategies that may help some breast imaging centers include accepting only self-paying patients, renegotiating the hospital contract, performing more interventional procedures, and extending the hours of operation. Measures that can improve the economic efficiency of screening mammography include batch interpretation of mammograms; paperwork reduction; brief automated reports; limiting requests for previous films from other facilities to only potentially necessary cases; dedicated screening mammography examination rooms; reduction in recall rates; and, in certain circumstances, extension of breast center hours. Measures that can improve the economic efficiency of diagnostic mammography performance and interpretation include dedicated diagnostic mammography examination rooms, automated film rotators, improved scheduling, and efficient work-flow patterns for examination performance. Measures that can improve the economic efficiency of both screening and diagnostic mammography include improved triage of screening and diagnostic patients, reminder telephone calls to confirm mammography appointments, greater use of medical assistants to help the radiologists and technologists, and streamlined film library procedures and operations. Measures that can improve the economic efficiency of breast interventional procedures include preprocedure work-up, establishment of scheduling protocols, and greater involvement of technologists and medical assistants in assisting the radiologist who performs the interventional procedures. All of these methods are intended to create a breast imaging center that is cost efficient while maintaining a patient-friendly atmosphere and diagnostic accuracy.

Society of Breast Imaging residency and fellowship training curriculum.

A recently developed Society of Breast Imaging curriculum for residency training is intended to provide guidance to residents and their mentors, and to practicing radiologists who want to keep up to date in screening, diagnosis, and interventional procedures. The curriculum contains lists of key concepts in 14 subject areas: epidemiology; anatomy; pathology, and physiology; equipment and technique; quality control; interpretation; problem-solving mammography; ultrasound; interventional procedures; reporting and medicolegal aspects; screening; MR imaging; therapeutic considerations; and patient management principles. The curriculum also makes recommendations about residency training, including the number of examinations the resident should interpret, and the time the resident should spend in breast imaging. Recommendations for fellowship training are also discussed.

Corticothalamic axons contact blood vessels as well as nerve cells in the thalamus.

Corticothalamic axons in cats and rats were studied after labelling by intracortical injections of axonally transported markers. Individual axons were traced to their terminal branches. Many preterminal segments had a tightly spiral or winding course which was often closely adjacent to a thalamic blood vessel. Electron micrographs of such axons showed them lying immediately adjacent to the vascular basement membrane, without the astrocytic cytoplasm that generally separates neural processes from the basement membrane of vessels. The functional nature of this neurovascular relationship remains to be explored.