From Alpha Diversity to Zzz: Interactions among sleep, the brain, and gut microbiota in the first year of life.

Sleep disorders have been linked to alterations of gut microbiota composition in adult humans and animal models, but it is unclear how this link develops. With longitudinal assessments in 162 healthy infants, we present a so far unrecognized sleep-brain-gut interrelationship. First, we report a link between sleep habits and gut microbiota: daytime sleep is associated with bacterial diversity, and nighttime sleep fragmentation and variability are linked with bacterial maturity and enterotype. Second, we demonstrate a sleep-brain-gut link: bacterial diversity and enterotype are associated with sleep neurophysiology. Third, we show that the sleep-brain-gut link is relevant in development: sleep habits and bacterial markers predict behavioral-developmental outcomes. Our results demonstrate the dynamic interplay between sleep, gut microbiota, and the maturation of brain and behavior during infancy, which aligns with the newly emerging concept of a sleep-brain-gut axis. Importantly, sleep and gut microbiota represent promising health targets since both can be modified non-invasively. As many adult diseases root in early childhood, leveraging protective factors of adequate sleep and age-appropriate gut microbiota in infancy could constitute a health promoting factor across the entire human lifespan.

Transport through correlated systems with density functional theory.

We present recent advances in density functional theory (DFT) for applications in the field of quantum transport, with particular emphasis on transport through strongly correlated systems. We review the foundations of the popular Landauer-Büttiker(LB) + DFT approach. This formalism, when using approximations to the exchange-correlation (xc) potential with steps at integer occupation, correctly captures the Kondo plateau in the zero bias conductance at zero temperature but completely fails to capture the transition to the Coulomb blockade (CB) regime as the temperature increases. To overcome the limitations of LB + DFT, the quantum transport problem is treated from a time-dependent (TD) perspective using TDDFT, an exact framework to deal with nonequilibrium situations. The steady-state limit of TDDFT shows that in addition to an xc potential in the junction, there also exists an xc correction to the applied bias. Open shell molecules in the CB regime provide the most striking examples of the importance of the xc bias correction. Using the Anderson model as guidance we estimate these corrections in the limit of zero bias. For the general case we put forward a steady-state DFT which is based on one-to-one correspondence between the pair of basic variables, steady density on and steady current across the junction and the pair local potential on and bias across the junction. Like TDDFT, this framework also leads to both an xc potential in the junction and an xc correction to the bias. Unlike TDDFT, these potentials are independent of history. We highlight the universal features of both xc potential and xc bias corrections for junctions in the CB regime and provide an accurate parametrization for the Anderson model at arbitrary temperatures and interaction strengths, thus providing a unified DFT description for both Kondo and CB regimes and the transition between them.

Steady-State Density Functional Theory for Finite Bias Conductances.

In the framework of density functional theory, a formalism to describe electronic transport in the steady state is proposed which uses the density on the junction and the steady current as basic variables. We prove that, in a finite window around zero bias, there is a one-to-one map between the basic variables and both local potential on as well as bias across the junction. The resulting Kohn-Sham system features two exchange-correlation (xc) potentials, a local xc potential, and an xc contribution to the bias. For weakly coupled junctions the xc potentials exhibit steps in the density-current plane which are shown to be crucial to describe the Coulomb blockade diamonds. At small currents these steps emerge as the equilibrium xc discontinuity bifurcates. The formalism is applied to a model benzene junction, finding perfect agreement with the orthodox theory of Coulomb blockade.

Dynamical correction to linear Kohn-Sham conductances from static density functional theory.

For molecules weakly coupled to leads the exact linear Kohn-Sham (KS) conductance can be orders of magnitude larger than the true linear conductance due to the lack of dynamical exchange-correlation (xc) corrections. In this work we show how to incorporate dynamical effects in KS transport calculations. The only quantity needed is the static xc potential in the molecular junction. Our scheme provides a comprehensive description of Coulomb blockade without breaking the spin symmetry. This is explicitly demonstrated in single-wall nanotubes where the corrected conductance is in good agreement with experimental data whereas the KS conductance fails dramatically.

Towards a description of the Kondo effect using time-dependent density-functional theory.

We demonstrate that the zero-temperature conductance of the Anderson model can be calculated within the Landauer formalism combined with static density-functional theory. The proposed approximate functional is based on finite-temperature density-functional theory and yields the exact Kohn-Sham potential at the particle-hole symmetric point. Furthermore, in the limit of zero temperature it correctly exhibits a derivative discontinuity which is shown to be essential to reproduce the conductance plateau. On the other hand, at the Kondo temperature the exact Kohn-Sham conductance overestimates the real one by an order of magnitude. To understand the failure of density-functional theory, we resort to its time-dependent version and conclude that the suppression of the Kondo resonance must be attributed to dynamical exchange-correlation corrections.

Surgical hip dislocation in symptomatic cam femoroacetabular impingement: what matters in early good results?

In order to assess outcome and possible predictors of early good results, a prospective study on 22 patients who were treated with save surgical hip dislocation for symptomatic isolated cam-type femoroacetabular impingement (FAI) was performed. After a follow-up of 6 and 12 months, standard clinical and radiographic parameters were recorded. A statistically significant improvement of the clinical status according to the Harris hip score could be assessed at six months (p-value = 0.003) and 12 months (p-value = 0.001) post-surgery. By comparing standard clinical and radiographic preoperative parameters with various follow-up outcomes, we revealed no specific parameter with predictive value. These findings are important for centers that have just started to use this surgical technique and are still identifying their learning curve.

Dynamical Coulomb blockade and the derivative discontinuity of time-dependent density functional theory.

The role of the discontinuity of the exchange-correlation potential of density functional theory is studied in the context of electron transport and shown to be intimately related to Coulomb blockade. By following the time evolution of an interacting nanojunction attached to biased leads, we find that, instead of evolving to a steady state, the system reaches a dynamical state characterized by correlation-induced current oscillations. Our results establish a dynamical picture of Coulomb blockade manifesting itself as a periodic sequence of charging and discharging of the nanostructure.

Bound states in time-dependent quantum transport: oscillations and memory effects in current and density.

The presence of bound states in a nanoscale electronic system attached to two biased, macroscopic electrodes is shown to give rise to persistent, non-decaying, localized current oscillations which can be much larger than the steady part of the current. The amplitude of these current oscillations and of the corresponding density oscillations depends on the entire history of the applied potential. The bound-state contribution to the time-averaged density turns out to be history-dependent as well and leads to a natural definition of the bound-state occupations out of equilibrium.

Dependence of Response Functions and Orbital Functionals on Occupation Numbers.

Explicitly orbital-dependent approximations to the exchange-correlation energy functional of density functional theory typically not only depend on the single-particle Kohn-Sham orbitals but also on their occupation numbers in the ground-state Slater determinant. The variational calculation of the corresponding exchange-correlation potentials with the optimized effective potential (OEP) method therefore also requires a variation of the occupation numbers with respect to a variation in the effective single-particle potential, which is usually not taken into account. Here it is shown under which circumstances this procedure is justified.

Orbital currents in the Colle-Salvetti correlation energy functional and the degeneracy problem.

Popular density functionals for the exchange-correlation energy typically fail to reproduce the degeneracy of different ground states of open-shell atoms. As a remedy, functionals which explicitly depend on the current density have been suggested. We present an analysis of this problem by investigating functionals that explicitly depend on the Kohn-Sham orbitals. Going beyond the exact-exchange approximation by adding correlation in the form of the Colle-Salvetti functional, we show how current-dependent terms enter the Colle-Salvetti expression and their relevance is evaluated. A very good description of the degeneracy of ground states for atoms of the first and second rows of the Periodic Table is obtained.

First-principles approach to noncollinear magnetism: towards spin dynamics.

A description of noncollinear magnetism in the framework of spin-density functional theory is presented for the exact exchange energy functional which depends explicitly on two-component spinor orbitals. The equations for the effective Kohn-Sham scalar potential and magnetic field are derived within the optimized effective potential (OEP) framework. With the example of a magnetically frustrated Cr monolayer it is shown that the resulting magnetization density exhibits much more noncollinear structure than standard calculations. Furthermore, a time-dependent generalization of the noncollinear OEP method is well suited for an ab initio description of spin dynamics. We also show that the magnetic moments of solids Fe, Co, and Ni are well reproduced.

On the degeneracy of atomic states within exact-exchange (spin-) density functional theory.

The problem of degenerate ground states of open-shell atoms is investigated in spin-restricted and spin-unrestricted density functional theories using the exact-exchange energy functional. For the spin-unrestricted case, spurious energy splittings of the order of 2-3 kcal/mol are found for atoms of the second and third periods which are larger than the splittings obtained from recently proposed approximate exchange functionals depending explicitly on the current density. In remarkable contrast, for spin-restricted calculations the degeneracy of different atomic ground states is recovered to within less than 0.6 kcal/mol.

Simulation of all-order density-functional perturbation theory, using the second order and the strong-correlation limit

To boost the accuracy of electronic structure calculations, the exchange-correlation energy may be constructed from the Kohn-Sham orbitals. A formally exact construction is the density-functional perturbation series, which appears to diverge for many real systems. We predict the radius of convergence and resum this series, using only exact exchange and second-order correlation plus explicit density functionals for the strong-interaction limit. Our new correlation functional, along with exact exchange, predicts atomization energies with competitive accuracy and without the usual error cancellation.

Significance of serum creatinine values in new end-stage renal disease patients.

The appropriate use of serum creatinine level as a surrogate for time in the course of renal failure when dialysis commences requires it to be a significant predictor of mortality in incident patients with end-stage renal disease (ESRD). This study evaluated factors that account for variations in creatinine level before the initiation of dialysis and whether incident creatinine level after controlling for these factors was a risk factor for mortality. This is a retrospective cohort study of patients from Maryland and Virginia who initiated dialysis between April 1, 1995, and December 31, 1996, with data ascertained from the Health Care Financing Administration Form 2728. Multivariate models were used to evaluate both the factors that predict incident serum creatinine level and the association between creatinine level and mortality. There were 5, 388 patients followed up for an average of 23.6 +/- 0.2 months. Mean creatinine level was 9.2 +/- 0.1 mg/dL, with case-mix factors most predictive of serum creatinine level and accounting for 9% of its variance. Hematocrit and blood urea nitrogen levels as additional surrogates for progression of renal disease accounted for 7.4% of the variance, whereas the nutritional parameters, body mass index, and albumin level only explained an additional 1% of the total variance in creatinine level. Creatinine level was inversely correlated with mortality risk, and this relationship was sustained both with transformation into an estimated glomerular filtration rate and multivariate adjustment for confounders (relative risk = 0. 96; P < 0.0001). Creatinine values from an incident ESRD population have a weak relationship with the timing of dialysis initiation but represent a strong measure of health status.

Combined schedule of 7-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal vaccine in children and young adults with sickle cell disease.

We compared the immunogenicity of 7-valent pneumococcal-conjugate vaccine plus 23-valent pneumococcal vaccine to immunization with 23-valent vaccine only in individuals > or = 2 years of age with sickle cell disease. IgG pneumococcal antibody concentrations were higher in the combined schedule group with no increase in side effects observed after immunization with 23-valent vaccine.

Rod and rod mediated function in patients with beta-thalassemia major.

An electroretinographic (ERG) study was undertaken to test the hypothesis that scotopic retinal function is altered in transfused thalassemics on chronic Deferoxamine (DFO). ERG a- and b-wave responses and dark adapted visual thresholds were obtained from 11 patients with beta-thalassemia major, ages 7 to 38 (median 17) years. A quantitative model of the activation of phototransduction was fitted to the a-waves to estimate the gain of the transduction processes and the saturated amplitude of the rod photoresponse. From b-wave stimulus/response functions. the saturated b-wave amplitude and an index of b-wave sensitivity (log sigma ) were calculated. The patients' data were compared to those of normal subjects. The relations of the ERG parameters to age. average ferritin level, and duration of transfusion without DFO as well as other clinical parameters were examined. Longitudinal measures of b-wave responses and dark adapted visual thresholds. available for nine of the patients, were examined for significant change over time. For all patients both the gain and saturated amplitude of the rod response are normal. In two patients log sigma is below the 99% prediction interval for normal. One has low scotopic visual sensitivity. The duration of transfusion therapy unprotected by DFO chelation therapy was correlated with log a. These results suggest iron accumulation rather than DFO toxicity underlies scotopic dysfunction in older thalassemics. some of whom may have had extended periods of transfusion without the protection of chelation. Thus, monitoring of retinal function is recommended in such patients.

Therapy with oral clotrimazole induces inhibition of the Gardos channel and reduction of erythrocyte dehydration in patients with sickle cell disease.

Pathologic water loss from sickle erythrocytes concentrates the abnormal hemoglobin and promotes sickling. The Ca2+-activated K+ channel (Gardos channel) contributes to this deleterious dehydration in vitro, and blockade of K+ and water loss via this channel could be a potential therapy in vivo. We treated five subjects who have sickle cell anemia with oral clotrimazole, a specific Gardos channel inhibitor. Patients were started on a dose of 10 mg clotrimazole/kg/d for one week. Protocol design allowed the daily dose to be escalated by 10 mg/kg each week until significant changes in erythrocyte density and K+ transport were achieved. Blood was sampled three times a week for hematological and chemical assays, erythrocyte density, cation content, and K+ transport. At dosages of 20 mg clotrimazole/kg/d, all subjects showed Gardos channel inhibition, reduced erythrocyte dehydration, increased cell K+ content, and somewhat increased hemoglobin levels. Adverse effects were limited to mild/moderate dysuria in all subjects, and a reversible increase in plasma alanine transaminase and aspartic transaminase levels in two subjects treated with 30 mg clotrimazole/kg/d. This is the first in vivo evidence that the Gardos channel causes dehydration of sickle erythrocytes, and that its pharmacologic inhibition provides a realistic antisickling strategy.

Intraarterial hepatic chemotherapy with fluorouracil, fluorodeoxyuridine, mitomycin C, cisplatin or methotrexate as single-agent anticancer drugs for a transplanted experimental liver tumor in rats.

A prospective, controlled and standardized animal experiment was performed to study the influence of various anticancer drugs. The Novikoff hepatoma transplanted into male Sprague-Dawley rats was treated with fluorouracil (FUra), mitomycin C, methotrexate, cisplatin and fluorodeoxyuridine (FdUrd) at equi-effective dosage, in terms of side effects (weight loss), in comparison to a control group (0.9% saline solution) by locoregional application via the hepatic artery. The tumor multiplication factor (TMF = tumor volume day 12/tumor volume day 5) served as the parameter to compare the tumor growth of the various groups. All drugs showed a significant (P < 0.05) effect on the tumor growth. In comparison to the control group (mean TMF 9.66), FdUrd (3.78) and FUra (3.03) only limited the tumor growth, mitomycin C (0.96) produced stable tumor, cisplatin (0.64) and methotrexate (0.15) significantly reduced (P < 0.01) the tumor size. We suggest that, in addition to the established (FUra, FdUrd, mitomycin C) drugs, methotrexate and cisplatin should be considered in further studies of the treatment of primary and secondary liver malignancies.

Quantitative volumetric analysis of brain MR: normative database spanning 5 decades of life.

PURPOSE: To present a normative volumetric database, spanning 5 decades of life, of cerebrospinal fluid, subarachnoid cerebrospinal fluid, total brain volume, total ventricular volume (component ventricular volumes of lateral, temporal horn, and third and fourth ventricles) and estimates of white and gray matter, based on a multispectral segmentation of brain MR. This database is presented as a reference for future studies comparing pathologic states. METHOD: One hundred ninety-four healthy subjects, ranging in age from 16 to 65 years, received standard axial intermediate- and T2-weighted spin-echo MR images. Multispectral segmentation and volume analysis were performed using ANALYZE. RESULTS: Normative volumetric estimates, both uncorrected and corrected for differences in total intracranial volume, were obtained for all subjects and presented by decade and sex. Age-related cerebrospinal fluid changes were evident for both male and female subjects. Most gender differences were eliminated by correction for differences in total intracranial volume. Standard and fast spin-echo acquisition methods gave comparable volume estimates. Total brain volume measurements from MR compare favorably with data from large autopsy series. CONCLUSION: Although there may be limitations to generalizations, these normative data tables can provide a comparison index for contrasting pathologic groups with a normative sample.