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Suppression of hippocampal neurogenesis is associated with developmental stage, number of perinatal seizure episodes, and glucocorticosteroid level.
Seizures increase dentate granule cell proliferation in adult rats but decrease proliferation in young pups. The particular period and number of perinatal seizures required to cause newborn granule cell suppression in development are unknown. Therefore, we examined cell proliferation with bromodeoxyuridine (BrdU) immunohistochemistry during the peak of neurogenesis (e.g., P6 and P9) and at later postnatal ages (e.g., P13, P20, or P30) following single and multiple episodes of perinatal status epilepticus induced by kainate (KA). Because an inverse relationship exists between glucocorticosteroids (CORT) levels and granule cell proliferation, plasma CORT levels and electroencephalographic (EEG) activity were simultaneously monitored to elucidate underlying mechanisms that inhibit cell proliferation. In control animals, the number of BrdU-labeled cells increased then declined with maturation. After 1x KA or 2x KA administered on P6 and P9, the numbers of BrdU-labeled cells were not different from age-matched controls. However, rat pups with 3x KA (on P6, P9, and P13) had marked suppression of BrdU-labeled cells 48-72 h after the last seizure (43 +/- 6.5% of control). Cell proliferation was also significantly inhibited on P20 after 2x KA (to 56 +/- 6.9%) or 3x KA (to 54 +/- 7.9%) and on P30 with 3x KA (to 74.5 +/- 8.2% of age-matched controls). Cell death was not apparent as chromatin stains showed increased basophilia of only inner cells lining the granule cell layers, in the absence of eosinophilia, argyrophilia, or terminal deoxynucleotidyl dUTP nick endlabeling (TUNEL) labeling at times examined. In P13 pups with 3x KA, electron microscopy revealed an increased number of immature granule cells and putative stem cells with irregular shape, condensed cytoplasm, and electron dense nuclei, and they were also BrdU positive. The EEG showed no relationship between neurogenesis and duration of high-synchronous ictal activity. However, endocrine studies showed a correlation with BrdU number and age, sustained increases in circulating CORT levels following 1x KA on P6 (0.7 +/- 0.1 to 2.40 +/- 0.86 microg/dl), and cumulative increases that exceeded 10 microg/dl at 4-8 h after 3x KA on P13 or P20. In conclusion, a history of only one or two perinatal seizure(s) can suppress neurogenesis if a second or third seizure recurs after a critical developmental period associated with a marked surge in CORT. During the first 2 weeks of postnatal life sustained increases in postictal circulating CORT levels but not duration or intensity of ictal activity has long-term consequences on neurogenesis. The occurrence of an increased proportion of immature granule cells and putative stem cells with irregular morphology in the absence of neurodegeneration suggests that progenitors may not differentiate properly and remain in an immature state
Quantum Computing in Molecular Magnets
Shor and Grover demonstrated that a quantum computer can outperform any
classical computer in factoring numbers and in searching a database by
exploiting the parallelism of quantum mechanics. Whereas Shor's algorithm
requires both superposition and entanglement of a many-particle system, the
superposition of single-particle quantum states is sufficient for Grover's
algorithm. Recently, the latter has been successfully implemented using Rydberg
atoms. Here we propose an implementation of Grover's algorithm that uses
molecular magnets, which are solid-state systems with a large spin; their spin
eigenstates make them natural candidates for single-particle systems. We show
theoretically that molecular magnets can be used to build dense and efficient
memory devices based on the Grover algorithm. In particular, one single crystal
can serve as a storage unit of a dynamic random access memory device. Fast
electron spin resonance pulses can be used to decode and read out stored
numbers of up to 10^5, with access times as short as 10^{-10} seconds. We show
that our proposal should be feasible using the molecular magnets Fe8 and Mn12.Comment: 13 pages, 2 figures, PDF, version published in Nature, typos
correcte
Coevolved mutations reveal distinct architectures for two core proteins in the bacterial flagellar motor
Switching of bacterial flagellar rotation is caused by large domain movements of the FliG protein triggered by binding of the signal protein CheY to FliM. FliG and FliM form adjacent multi-subunit arrays within the basal body C-ring. The movements alter the interaction of the FliG C-terminal (FliGC) "torque" helix with the stator complexes. Atomic models based on the Salmonella entrovar C-ring electron microscopy reconstruction have implications for switching, but lack consensus on the relative locations of the FliG armadillo (ARM) domains (amino-terminal (FliGN), middle (FliGM) and FliGC) as well as changes during chemotaxis. The generality of the Salmonella model is challenged by the variation in motor morphology and response between species. We studied coevolved residue mutations to determine the unifying elements of switch architecture. Residue interactions, measured by their coevolution, were formalized as a network, guided by structural data. Our measurements reveal a common design with dedicated switch and motor modules. The FliM middle domain (FliMM) has extensive connectivity most simply explained by conserved intra and inter-subunit contacts. In contrast, FliG has patchy, complex architecture. Conserved structural motifs form interacting nodes in the coevolution network that wire FliMM to the FliGC C-terminal, four-helix motor module (C3-6). FliG C3-6 coevolution is organized around the torque helix, differently from other ARM domains. The nodes form separated, surface-proximal patches that are targeted by deleterious mutations as in other allosteric systems. The dominant node is formed by the EHPQ motif at the FliMMFliGM contact interface and adjacent helix residues at a central location within FliGM. The node interacts with nodes in the N-terminal FliGc α-helix triad (ARM-C) and FliGN. ARM-C, separated from C3-6 by the MFVF motif, has poor intra-network connectivity consistent with its variable orientation revealed by structural data. ARM-C could be the convertor element that provides mechanistic and species diversity.JK was supported by Medical Research Council grant U117581331. SK was supported by seed funds from Lahore University of Managment Sciences (LUMS) and the Molecular Biology Consortium
Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR?
The increase in numbers of adults with cystic fibrosis (CF) has allowed us to identify previously unrecognized chronic complications of CF, as well as appreciate unique presentations of cystic fibrosis-related diseases. Do these chronic complications and unique presentations provide us with new insight into cystic fibrosis transmembrane conductance regulator (CFTR) function? Current data suggest that the 'chronic complications' reveal mainly the effect of a long-term absence of previously recognized CFTR functions. In contrast, the 'unique presentations' provide new insight into the role of CFTR in different tissues
Collagen concentration and biomechanical properties of samples from the lower uterine cervix in relation to age and parity in non-pregnant women
<p>Abstract</p> <p>Background</p> <p>During normal pregnancy the cervix has a load bearing function. The cervical tissue consists mainly of an extracellular matrix (ECM) rich in collagen; important for the biomechanical properties. The aim of the present study was to evaluate how the biomechanical strength of samples from the distal cervix is associated with collagen content in relation to age and parity. This study demonstrates a method to investigate cervical tissue from women who still have their uterus in situ.</p> <p>Methods</p> <p>Cervical punch biopsies (2 × 15 mm) were obtained from 57 healthy women (median age: 39 years, range: 29-49 years). Biomechanical tensile testing was performed, and collagen concentration (as % of dry defatted weight (DDW)) and content (mg of collagen per mm of specimen length) was determined. Histomorphometry was used to determine the volume densities of extracellular matrix and smooth muscle cells. Smooth muscle cells were identified by immunohistochemistry. Finally, orientation of collagen fibers was estimated. Data are given as mean +/- SD.</p> <p>Results</p> <p>The mean collagen concentration (62.2 +/- 6.6%) increased with age (0.5% per year, r = 0.45, p = 0.003) and decreased with parity (1.7% per birth, r = -0.45, p = 0.033). Maximum load was positively correlated with collagen content (mg of collagen per mm of specimen length) (r = 0.76, p < 0.001). Normalized maximum stiffness was increased with age (r = 0.32, p = 0.017), whereas no correlation was found with regard to parity. In tissue samples with a length of approximately one cm, volume density of smooth muscle cells increased gradually from 8.9% in the distal part near the epithelium, to 15.5% in the proximal part (p < 0.001).</p> <p>Conclusions</p> <p>The present study shows that cervical collagen concentration increases with age and decreases with parity in non-pregnant women. In addition, collagen stiffness increased with age, whereas no change in collagen tensile strength with respect to age and parity was found. These results show that collagen contributes to cervical tissue tensile strength and age and parity should be considered confounding factors.</p
A primary care, multi-disciplinary disease management program for opioid-treated patients with chronic non-cancer pain and a high burden of psychiatric comorbidity
BACKGROUND: Chronic non-cancer pain is a common problem that is often accompanied by psychiatric comorbidity and disability. The effectiveness of a multi-disciplinary pain management program was tested in a 3 month before and after trial. METHODS: Providers in an academic general medicine clinic referred patients with chronic non-cancer pain for participation in a program that combined the skills of internists, clinical pharmacists, and a psychiatrist. Patients were either receiving opioids or being considered for opioid therapy. The intervention consisted of structured clinical assessments, monthly follow-up, pain contracts, medication titration, and psychiatric consultation. Pain, mood, and function were assessed at baseline and 3 months using the Brief Pain Inventory (BPI), the Center for Epidemiological Studies-Depression Scale scale (CESD) and the Pain Disability Index (PDI). Patients were monitored for substance misuse. RESULTS: Eighty-five patients were enrolled. Mean age was 51 years, 60% were male, 78% were Caucasian, and 93% were receiving opioids. Baseline average pain was 6.5 on an 11 point scale. The average CESD score was 24.0, and the mean PDI score was 47.0. Sixty-three patients (73%) completed 3 month follow-up. Fifteen withdrew from the program after identification of substance misuse. Among those completing 3 month follow-up, the average pain score improved to 5.5 (p = 0.003). The mean PDI score improved to 39.3 (p < 0.001). Mean CESD score was reduced to 18.0 (p < 0.001), and the proportion of depressed patients fell from 79% to 54% (p = 0.003). Substance misuse was identified in 27 patients (32%). CONCLUSIONS: A primary care disease management program improved pain, depression, and disability scores over three months in a cohort of opioid-treated patients with chronic non-cancer pain. Substance misuse and depression were common, and many patients who had substance misuse identified left the program when they were no longer prescribed opioids. Effective care of patients with chronic pain should include rigorous assessment and treatment of these comorbid disorders and intensive efforts to insure follow up
The Decline of University Patenting and the End of the Bayh-Dole Effect
University patenting has been heralded as a symbol of changing relations
between universities and their social environments. The Bayh-Dole Act of 1980
in the USA was eagerly promoted by the OECD as a recipe for the
commercialization of university research, and the law was imitated by a number
of national governments. However, since the 2000s university patenting in the
most advanced economies has been on the decline both as a percentage and in
absolute terms. We suggest that the institutional incentives for university
patenting have disappeared with the new regime of university ranking. Patents
and spin-offs are not counted in university rankings. In the new arrangements
of university-industry-government relations, universities have become very
responsive to changes in their relevant environments
Asthma prevalence and risk factors in schoolchildren of the city of São Paulo, Brazil
OBJETIVO: Analisar a prevalência de asma e possÃveis fatores de risco associados. MÉTODOS: Estudo transversal, integrante do International Study of Asthma and Allergies in Childhood. Participaram 561 escolares de seis a sete anos de idade, provenientes de 35 escolas públicas da cidade de São Paulo, escolhidas por sorteio, em 2002. A amostra incluiu 168 asmáticos e 393 não asmáticos, que responderam questionário constituÃdo por 33 questões referentes a dados pessoais, familiares e ambientais. A associação entre asma e fatores de risco foi avaliada pela análise de regressão logÃstica, considerando-se nÃvel de significância estatÃstica de 5%. RESULTADOS: Entre os escolares, 31,2% referiam sibilos nos 12 meses anteriores à entrevista. Os fatores de risco significativamente associados à asma foram: sexo masculino (OR=2,4;IC 95%: 1,4;4,2), mãe fumante no primeiro ano de vida (OR=2,0; IC 95%: 1,1;3,8), presença de eczema em locais caracterÃsticos (OR=3,0; IC 95%:1,2; 7,6) e rinoconjuntivite (OR=2,4;IC 95%: 1,2; 4,8). CONCLUSÕES: A prevalência de asma na região estudada foi elevada e os fatores de risco relacionados foram: sexo masculino, sintomas de rinoconjuntivite no último ano, mãe fumante no primeiro ano de vida e presença de eczema em locais caracterÃsticos.OBJECTIVE: To assess asthma prevalence and potential risk factors associated. METHODS: Cross-sectional study part of the International Study of Asthma and Allergies in Childhood. A total of 561 schoolchildren aged 6-7 years from 35 public schools in the city of São Paulo (Southeastern Brazil) were drawn to participate in the study, in 2002. The sample consisted of 168 asthmatic and 393 non-asthmatic children who answered a questionnaire comprising 33 questions on personal, family and environmental information. The association between asthma and the risk factors studied was assessed by logistic regression analysis at a 5% statistical significance. RESULTS: Among the schoolchildren studied, 31.2% reported wheezing in the 12 months preceding the interview. The following risk factors were significantly associated with asthma: male gender (OR=2.4; 95% CI: 1.4;4.2), maternal smoking in the child's first year of life (OR=2.0; 95% CI: 1.1;3.8), eczema on characteristic body areas (OR=3.0; 95% CI: 1.2;7.6) and rhinoconjunctivitis (OR=2.4; 95% CI: 1.2;4.8). CONCLUSIONS: Asthma prevalence in the study area was high and the risk factors identified were male gender, rhinoconjunctivitis in last year, maternal smoking in the child's first year of life and eczema on characteristic body areas
Optimal error estimation for H(curl)-conforming p-interpolation in two dimensions
In this paper we prove an optimal error estimate for the H(curl)-conforming
projection based p-interpolation operator introduced in [L. Demkowicz and I.
Babuska, p interpolation error estimates for edge finite elements of variable
order in two dimensions, SIAM J. Numer. Anal., 41 (2003), pp. 1195-1208]. This
result is proved on the reference element (either triangle or square) K for
regular vector fields in H^r(curl,K) with arbitrary r>0. The formulation of the
result in the H(div)-conforming setting, which is relevant for the analysis of
high-order boundary element approximations for Maxwell's equations, is provided
as well
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