Microsecond Isomer at the N=20 Island of Shape Inversion Observed at FRIB.

Excited-state spectroscopy from the first experiment at the Facility for Rare Isotope Beams (FRIB) is reported. A 24(2)-µs isomer was observed with the FRIB Decay Station initiator (FDSi) through a cascade of 224- and 401-keV γ rays in coincidence with ^{32}Na nuclei. This is the only known microsecond isomer (1 µs≤T_{1/2}<1 ms) in the region. This nucleus is at the heart of the N=20 island of shape inversion and is at the crossroads of the spherical shell-model, deformed shell-model, and ab initio theories. It can be represented as the coupling of a proton hole and neutron particle to ^{32}Mg, ^{32}Mg+π^{-1}+ν^{+1}. This odd-odd coupling and isomer formation provides a sensitive measure of the underlying shape degrees of freedom of ^{32}Mg, where the onset of spherical-to-deformed shape inversion begins with a low-lying deformed 2^{+} state at 885 keV and a low-lying shape-coexisting 0_{2}^{+} state at 1058 keV. We suggest two possible explanations for the 625-keV isomer in ^{32}Na: a 6^{-} spherical shape isomer that decays by E2 or a 0^{+} deformed spin isomer that decays by M2. The present results and calculations are most consistent with the latter, indicating that the low-lying states are dominated by deformation.

Crossing N=28 Toward the Neutron Drip Line: First Measurement of Half-Lives at FRIB.

New half-lives for exotic isotopes approaching the neutron drip-line in the vicinity of N∼28 for Z=12-15 were measured at the Facility for Rare Isotope Beams (FRIB) with the FRIB decay station initiator. The first experimental results are compared to the latest quasiparticle random phase approximation and shell-model calculations. Overall, the measured half-lives are consistent with the available theoretical descriptions and suggest a well-developed region of deformation below ^{48}Ca in the N=28 isotones. The erosion of the Z=14 subshell closure in Si is experimentally confirmed at N=28, and a reduction in the ^{38}Mg half-life is observed as compared with its isotopic neighbors, which does not seem to be predicted well based on the decay energy and deformation trends. This highlights the need for both additional data in this very exotic region, and for more advanced theoretical efforts.

Upper extremity impairments, pain and disability in patients with diabetes mellitus.

OBJECTIVES: To determine the severity of, and relationships between, upper extremity impairments, pain and disability in patients with diabetes mellitus, and to compare upper extremity impairments in patients with diabetes with non-diabetic controls. DESIGN: Case-control, cross-sectional design. SETTING: University-based, outpatient diabetes centre and physical therapy research clinic. PARTICIPANTS: Two hundred and thirty-six patients with diabetes attending an outpatient diabetes clinic completed the Shoulder Pain and Disability Index (SPADI) questionnaire. A detailed shoulder and hand examination was conducted on a subgroup of 29 volunteers with type 2 diabetes, and 27 controls matched for age, sex and body mass index. INTERVENTIONS: None. MAIN OUTCOME MEASURES: SPADI score, passive shoulder range of motion (ROM) and strength, grip strength, hand sensation, dexterity and limited joint mobility of the hand. RESULTS: Sixty-three percent (149/236) of patients with diabetes reported shoulder pain and/or disability [median SPADI score 10.0 (interquartile range 0.0 to 39.6)]. Compared with the control group, the subgroup of patients with diabetes had substantial reductions in shoulder ROM, shoulder muscle strength, grip and key pinch strength (P<0.05). Patients with diabetes had a greater prevalence of decreased sensation (26/27 vs 14/27) and limited joint mobility of the hand (17/27 vs 4/27) compared with the control group. Total SPADI score was negatively correlated (P<0.05) with shoulder ROM (r=-0.42 to -0.74) and strength measures (r=-0.44 to -0.63) in patients with diabetes. CONCLUSIONS: Upper extremity impairments in this sample of patients with diabetes were common, severe and related to complaints of pain and disability. Additional research is needed to understand the unique reasons for upper extremity problems in patients with diabetes, and to identify preventative treatments.

The web and the structure of taxonomy.

An easily accessible taxonomic knowledge base is critically important for all biodiversity-related sciences. At present, taxonomic information is organized and regulated by a system of rules and conventions that date back to the introduction of binomial nomenclature by Linnaeus. The taxonomy of any particular group of organisms comprises the sum information in the taxonomic literature, supported by designated type specimens in major collections. In this article, the way modern means of disseminating information will change the practice of taxonomy, in particular the Internet, is explored. Basic taxonomic information, such as specimen-level data, location of types, and name catalogues are already available, at least for some groups, on the Web. Specialist taxonomic databases, key-construction programs, and other software useful for systematists are also increasingly available. There has also been a move towards Web-publishing of taxonomic hypotheses, though as yet this is not fully permitted by the Codes of Nomenclature. A further and more radical move would be to transfer taxonomy completely to the Web. A possible model of this is discussed, as well as a pilot project, the "CATE" initiative, which seeks to explore the advantages and disadvantages of such a move. It is argued that taxonomy needs to forge better links with its user-communities to maintain its funding base, and that an important part of this is making the products of its research more accessible through the Internet.

Elastic scattering spectroscopy accurately detects high grade dysplasia and cancer in Barrett's oesophagus.

BACKGROUND AND AIMS: Endoscopic surveillance of Barrett's oesophagus currently relies on multiple random biopsies. This approach is time consuming, has a poor diagnostic yield, and significant interobserver variability. Elastic scattering spectroscopy is a real time in vivo optical technique which detects changes in the physical properties of cells. The aim of this study was to assess the potential for elastic scattering to detect high grade dysplasia or cancer within Barrett's oesophagus. METHODS: Elastic scattering spectroscopy measurements collected in vivo were matched with histological specimens taken from identical sites within Barrett's oesophagus. All biopsies were reviewed by three gastrointestinal pathologists and defined as either "low risk" (non-dysplastic or low grade dysplasia) or "high risk" (high grade dysplasia or cancer). Two different statistical approaches (leave one out and block validation) were used to validate the model. RESULTS: A total of 181 matched biopsy sites from 81 patients, where histopathological consensus was reached, were analysed. There was good pathologist agreement in differentiating high grade dysplasia and cancer from other pathology (kappa = 0.72). Elastic scattering spectroscopy detected high risk sites with 92% sensitivity and 60% specificity and differentiated high risk sites from inflammation with a sensitivity and specificity of 79%. If used to target biopsies during endoscopy, the number of low risk biopsies taken would decrease by 60% with minimal loss of accuracy. A negative spectroscopy result would exclude high grade dysplasia or cancer with an accuracy of >99.5%. CONCLUSIONS: These preliminary results show that elastic scattering spectroscopy has the potential to target conventional biopsies in Barrett's surveillance saving significant endoscopist and pathologist time with consequent financial savings. This technique now requires validation in prospective studies.

W/Wv marrow stromal cells engraft and enhance early erythropoietic progenitors in unconditioned Sl/Sld murine recipients.

Transplantation of marrow stromal cells may provide a means of modulating hematopoiesis and serve as a form of cell therapy. We employed a murine transplant model using Sl/Sl(d) mice, which have macrocytic anemia due to defective expression of stem cell factor (SCF) on bone marrow stromal cells. Donor cells were derived from the complementary mutant strain W/W(v), which also exhibit anemia, due to mutations in c-kit, the SCF receptor expressed on hematopoietic stem cells. The strength of this model is that any correction of the Sl/Sl(d) anemia from the infusion of W/W(v) stromal cells can be attributed to the effect of the stromal cells and not to contaminating W/W(v) hematopoietic stem cells, a major concern in experiments involving wild-type animals. Cultured stromal cells were infused into unconditioned non-splenectomized Sl/Sl(d) mice. Engraftment of donor stromal cells reached levels of up to 1.0% of total marrow cells 4 months post transplant. However, stromal engraftment was not detectable in the spleen. Recipients of W/W(v) stroma showed a significant increase in the committed erythroid progenitors compared with those receiving Sl/Sl(d) stromal cells: 109 +/- 26 vs 68 +/- 5 CFU-E per 10(5) BMC, P = 0.002; 25 +/- 10 vs 15 +/- 5 BFU-E per 10(5) BMC, P = 0.037, for W/W(v) and Sl/Sl(d) stroma recipients, respectively. Despite this increase in erythroid progenitors, the anemia was not corrected. Our data suggest that in this murine model, splenic erythropoiesis may influence stromal cell therapy, and that higher levels of marrow engraftment may be necessary to obtain a clinically significant effect.

Chronic intraventricular infusion of glial cell line-derived neurotrophic factor (GDNF) rescues some cerebellar Purkinje cells from heredodegeneration.

Cerebellar Purkinje cells degenerate in shaker mutant rats. Glia cell line-derived neurotrophic factor (GDNF) was chronically infused intraventricularly in an attempt to rescue mutant Purkinje cells from dying. Four weeks of chronic GDNF infusion delayed the degeneration of many but not all Purkinje cells. Surviving Purkinje cells formed spatially related groups interrupted by other groups of degenerated Purkinje cells. There was a positive correlation in GDNF-supported Purkinje cell survival and persistence of normal motor behaviors.

Olivocerebellar projections modify hereditary Purkinje cell degeneration.

Brainstem inferior olivary neurons, through their olivocerebellar efferent projections, dynamically regulate the structure and function of Purkinje neurons. To test the hypothesis that the inferior olive can epigenetically modify adult-onset hereditary Purkinje cell death, olivocerebellar projections were destroyed by 3-acetylpyridine chemoablation of the inferior olive in Shaker mutant rats. Starting around seven weeks of age, mutant Purkinje cells degenerate in a highly predictable spatial and temporal pattern. Chemoablation of the inferior olive at the onset of hereditary Purkinje cell degeneration accelerated the temporal pattern of Purkinje cell death from a natural phenotypic course of six to eight weeks to one and two weeks. When chemoablation of the inferior olive was performed three and a half weeks earlier, the onset of Purkinje cell death was accelerated by seven to 10days, but the spatial pattern and natural rate of temporal degeneration was maintained. Chemoablation of the inferior olive in normal rats did not result in any apparent death of Purkinje cells. These findings indicate that the olivocerebellar system can markedly modify hereditary Purkinje cell death. The accelerated death of Purkinje cells following chemoablation of the inferior olive can result from either the interruption of a trophic signal by climbing fiber deafferentation or parallel fiber excitotoxicity due to cortical disinhibition, but not due to olivocerebellar excitotoxicity.

X-linked transmission of the shaker mutation in rats with hereditary Purkinje cell degeneration and ataxia.

This study reports on the mode of inheritance of the shaker mutation and the development of an inbred strain of the shaker rat mutation from Sprague Dawley outbred stock onto a Wistar Furth background. Neuroanatomical and behavioral expression of the affected phenotype, through seven generations of backcross and intercross breeding, has confirmed the mode of inheritance to be X-linked. Behaviorally, affected mutants present with a wide-based ataxic gait and whole body tremor. In affected mutants calbindin immunostaining for surviving cerebellar Purkinje cells revealed widespread degeneration in the anterior lobe and in limited areas of the posterior lobe. Fast Fourier transform analysis of the tremor revealed a frequency of 3-5 Hz. As predicted by X-linked inheritance, female descendants of an affected male are carriers for the genotype and the phenotype is expressed in one-half of her male offspring. There was spatially random and limited degeneration of Purkinje cells in carrier females, but they did not display overt clinical signs of ataxia and tremor. These data provide further support for using the shaker mutant rat as an animal model for studies of mechanisms underlying human heredodegenerative diseases.

Development of young children's understanding that the recent past is causally bound to the present.

The results of 6 studies (involving 304 children) suggested that 4- and 5-year-olds, but not 3-year-olds, understand that very recent past events determine the present. In Studies 1-3, 3- and 4-year-old children were introduced to 2 empty hiding locations. With children's backs to these locations, a camera recorded an experimenter secretly hiding a puppet in one of them. Children then viewed the videotape of what had just happened, along with another tape that depicted identical events except with a different child and with the puppet hidden in the other location. Only 4-year-olds were subsequently able to locate the puppet, even though 3-year-olds remembered the contents of the tapes and understood the equivalence between the video events and the real world. In Study 4, similar effects were obtained when a verbal analog of the test was presented to 3-5-year-olds. Studies 5 and 6 showed that when children observed 2 events in which they had just participated, only 5-year-olds understood that the most recent events were relevant.

Genetically corrected autologous stem cells engraft, but host immune responses limit their utility in canine alpha-L-iduronidase deficiency.

Canine alpha-L-iduronidase (alpha-ID) deficiency, a model of the human storage disorder mucopolysaccharidosis type I (MPS I), is an ideal system in which to evaluate the clinical benefit of genetically corrected hematopoietic stem cells. We performed adoptive transfer of genetically corrected autologous hematopoietic cells in dogs with alpha-ID deficiency. Large volume marrow collections were performed on five alpha-ID-deficient dogs. Marrow mononuclear cells in long-term marrow cultures (LTMCs) were exposed on three occasions during 3 weeks of culture to retroviral vectors bearing the normal canine alpha-ID cDNA. Transduced LTMC cells from deficient dogs expressed enzymatically active alpha-ID at 10 to 200 times the levels seen in normal dogs. An average of 32% of LTMC-derived clonogenic hematopoietic cells were provirus positive by polymerase chain reaction and about half of these expressed alpha-ID. Approximately 10(7) autologous gene-modified LTMC cells/kg were infused into nonmyeloablated recipients. Proviral DNA was detected in up to 10% of individual marrow-derived hematopoietic colonies and in 0.01% to 1% of blood and marrow leukocytes at up to 2 to 3 years postinfusion. Despite good evidence for engraftment of provirally marked cells, neither alpha-ID enzyme nor alpha-ID transcripts were detected in any dog. We evaluated immune responses against alpha-ID and transduced cells. Humoral responses to alpha-ID and serum components of the culture media (fetal bovine and horse sera and bovine serum albumin) were identified by enzyme-linked immunosorbent assay. Cellular immune responses to autologous alpha-ID but not neo(r) transduced cells were demonstrated by lymphocyte proliferation assays. To abrogate potential immune phenomena, four affected dogs received posttransplant cyclosporine A. Whereas immune responses were dampened in these dogs, alpha-ID activity remained undetectable. In none of the dogs engrafted with genetically corrected cells was there evidence for clinical improvement. Our data suggest that, whereas the alpha-ID cDNA may be transferred and maintained in approximately 5% of hematopoietic progenitors, the potential of this approach appears limited by the levels of provirally derived enzyme that are expressed in vivo and by the host's response to cultured and transduced hematopoietic cells expressing foreign proteins.

What is the role of the HIV liaison psychiatrist?

In this article we review the field of HIV liaison psychiatry and illustrate the manner in which psychiatric care can contribute to the health and quality of life of this group of patients. To illustrate our discussion we review experience and findings in relation to affective illness, cognitive impairments, and personality disorder in HIV infection. We also highlight some of the areas where psychiatric care of people with HIV infection is unique from other types of psychiatric liaison work.

Human hematopoiesis in SCID mice implanted with human adult cancellous bone.

The persistence of hematopoietic cells from human adult cancellous bone fragments implanted subcutaneously into CB-17 scid/scid mice was studied. Recipient mice received either no pretreatment (control group) or pretreatment with 3 Gy total-body irradiation and anti-asialo GM1 sera (ASGM1; pretreated group) before implantation. Pretreated severe combined immunodeficient (SCID) mice implanted with human bone were subsequently given ASGM1 every 7 days for the duration of the experiments. At 12 weeks postimplantation, flow cytometry of cells from pretreated and control animal tissues detected human CD45+ cells in the mouse spleen (mean, 7.8% and 3.4% positive cells, pretreated and control animals, respectively), bone marrow (BM; mean, 16.5% and 4.8% positive cells, respectively), and blood (mean, 5.5% and < 2% positive cells, respectively), and in the implanted human bone (73% and 8.9% positive cells, respectively). At 12 weeks, pretreated mice had human granulocyte-macrophage colony-forming cells (GM-CFC) and burst-forming units-erythrocyte (BFU-E) in the implanted human bone in the murine BM and in some of the spleens. The spleens also had extensive infiltration of human B cells and macrophages. Mean serum levels of human IgG in pretreated animals were 14 micrograms/mL during weeks 6 to 12, compared with trace levels (< 1 microgram/mL) in control mice. Bone from patients with acute myeloblastic leukemia (AML) was also implanted in pretreated SCID mice, and retrieved at 8 weeks for analysis. Comparison of preimplantation and implanted samples showed that the original histology was maintained, and massive infiltration of human CD68+ cells was observed in the mice spleens and BM. Implantation of AML bone in SCID mice facilitates analysis of in situ AML cell interaction with stromal cells in the leukemic state, and therapies against AML can be tested in this system, especially the selective killing of AML cells in the presence of other BM cells. Furthermore, this model requires no exogenous administration of cytokines to maintain human hematopoiesis with both normal or AML bone. Because the structure and function of both normal and diseased human adult bone is maintained, this animal model should facilitate investigation of both normal human hematopoiesis and hematopoietic malignancies.

Biology of bone marrow stroma.

The marrow microenvironment is a complex, three-dimensional structure composed of many cell types and abundant extracellular matrix. Much of the data are derived from analysis of the adherent layer of murine and, especially, human long-term marrow cultures. An essential feature of this in vitro counterpart to the marrow microenvironment is the presence of flat angulated cells functionally defined as marrow stromal cells with the following phenotype: type IV collagen(+), laminin(+), vimentin(+), CD10(+), muscle actin(+), Stro-1(+), and negative for CD45, Mac-1, and HLA-DR. Stromal precursors are Stro-1(+) and CD34(+). Regulation of hematopoietic precursors by the microenvironment occurs by elaboration of regulatory molecules such as hematopoietic cytokines, by cell-cell contact via adhesion molecules such as alpha 4 beta 1 integrin, and by interactions with components of the extracellular matrix as in the case of the glycosaminoglycan hyaluronic acid with cell-associated CD44. Although little about the regulation of stromal cell development itself is known, several studies indicate the transplantability of marrow stromal cells under specific conditions. These developments suggest a potential role of stromal cells in cell therapy. Transfected stromal cells may serve as suitable vehicles for gene delivery to correct single gene disorders in which the product of the target gene does not require stringent regulation as, for example, in the correction of Factor VIII and Factor IX deficiency. Further studies are warranted to investigate marrow stromal cell physiology and regulation to better understand hematopoiesis and to explore the possible use of stroma in therapy.

Fate of intercellular MHC-peptide-T-cell receptor complexes during T-cell activation.

Antigen-specific T-cell activation requires the formation of a transient cell-cell conjugate between a T cell and an appropriate antigen presenting cell (APC). Focal aggregation of T-cell receptor (TCR) molecules at the T-cell-APC membrane interface accompanies formation of multiple non-covalent intercellular bridges consisting of TCRs on the T cell and cognate MHC-peptide complexes on the APC. Enhanced adhesiveness and T-cell activation follow the T-cell signalling that results from crosslinking of T-cell receptors (TCR). Models of T-cell activation propose that the APC and activated T cell separate following a decline in the enhanced adhesiveness. The rate of intercellular TCR-(MHC-peptide) complexes formed during T-cell activation is unknown. Based on the reported CD4-positive T-cell internalization of the peptide moiety of preformed cognate MHC II-peptide complexes, it is proposed here that translocation of the peptide moiety leads to destabilization and decomposition of intercellular trimolecular TCR-(MHC-peptide) complexes in the T-cell-APC interface. This decomposition accompanies or results in the decline in enhanced adhesiveness leading to separation of the APC and activated T cell.

Development and testing of nursing home quality indicators.

In this article, the authors report on the development and testing of a set of indicators of quality of care in nursing homes, using resident-level assessment data. These quality indicators (QIs) have been developed to provide a foundation for both external and internal quality-assurance (QA) and quality-improvement activities. The authors describe the development of the QIs, discuss their nature and characteristics, address the development of a QI-based quality-monitoring system (QMS), report on a pilot test of the QIs and the system, comment on methodological and current QI validation efforts, and conclude by raising further research and development issues.

Chronic NMDA receptor blockade or muscimol inhibition of cerebellar cortical neuronal activity alters the development of spinocerebellar afferent topography.

The requirement for cerebellar cortical neuronal activity in the development of spinocerebellar afferent topography was investigated in neonatal rats. In adult rats lower thoracic-upper lumbar spinocerebellar projections are localized to sharply circumscribed patches in the granule cell layer of the cerebellar anterior lobe. In transverse sections these patches appear as sagittally oriented stripes. This pattern develops postnatally as many spinal axons which initially project between the incipient stripes are eliminated thereby sharpening the stripe boundaries. We attempted to alter cerebellar cortical neuronal activity in neonatal animals to study the effects of these changes on the development of spinocerebellar stripes. In some experiments glutaminergic excitatory synaptic transmission was chronically blocked with the N-methyl-D-aspartate (NMDA) receptor antagonist 2-aminophosphovaleric acid (APV). In other experiments postsynaptic activity was directly inhibited by the gamma-aminobutyric acid agonist muscimol. Chronic exposure to APV or to muscimol did not affect the initial development of spinocerebellar projections; many spinal axons were present in the anterior lobe and arranged in incipient stripes. Both the APV and the muscimol appeared to prevent the elimination of interstripe projections; consequently the boundaries of the stripes remained poorly defined. These findings suggest that cerebellar cortical neuronal activity is a necessary requirement for the refinement of spinal afferent topography in the anterior lobe.

Antigen-specific deletion of cloned T cells using peptide-toxin conjugate complexed with purified class II major histocompatibility complex antigen.

In a previous report, we showed that cloned T cells incubated with soluble, cognate major histocompatibility complex (MHC) II-peptide complex internalized the peptide moiety of the complex. Here, we report antigen-specific deletion of cloned T cells by treatment with soluble, cognate MHC II-(peptide-toxin) complexes. Toxin (doxorubicin or mycophenolic acid) was attached to synthetic AcMBP(1-14)Ala4 peptide, an analog of the natural acetylated NH2-terminal segment, AcMBP(1-14), of rat myelin basic protein (MBP). IAk-restricted, AcMBP(1-14)-Specific AJ1.2 and 4R3.9 cloned murine T cells were killed by IAk-(AcMBP(1-14)Ala4-toxin). No killing resulted from incubating AJ1.2 and 4R3.9 cells with irrelevant MHC II-(peptide-toxin) or treating IEk-restricted, pigeon cytochrome c-specific A.E7 cloned murine T cells with IAk-(AcMBP(1-14)Ala4-toxin). T cell receptor-mediated T cell uptake of the peptide-toxin moiety of relevant complex was blocked by anti-T cell receptor-alpha/beta antibody and by excess toxin-free complex. LD50 determinations revealed that cognate MHC II-(peptide-toxin) killed T cells much more effectively than did peptide-toxin conjugate alone. Finally, T cell uptake of peptide-toxin and intracellular release of toxin occurred after incubation with relevant MHC II-(peptide-toxin) containing radiolabeled toxin. These findings, which provide the first evidence that cloned T cells can be deleted with soluble, cognate MHC II-(peptide-toxin) complexes, may have significant clinical relevance for antigen-specific therapy of autoimmune or other T cell-mediated diseases.