Forelimb kinematics during hopping and landing in toads.
Coordinated landing in a variety of animals involves the re-positioning of limbs prior to impact to safely decelerate the body. However, limb kinematics strategies for landing vary considerably among species. For example, human legs are increasingly flexed before impact as drop height increases, while turkeys increasingly extend their legs before impact with increasing drop height. In anurans, landing typically involves the use of the forelimbs to decelerate the body after impact. Few detailed, quantitative descriptions of anuran forelimb kinematics during jumping exist and it is not known whether they prepare for larger landing forces by changing forelimb kinematics. In this study, we used high-speed video of 51 hops from five cane toads (Bufo marinus) to test the hypothesis that forelimb kinematics change predictably with distance. We measured excursions of the elbow (flexion/extension) and humerus (protraction/retraction and elevation/depression) throughout every hop. The results indicate that elbow and humeral excursions leading up to impact increase significantly with hop length, but do so without any change in the rate of movement. Instead, because the animal is in the air longer during longer hops, near-constant velocity movements lead to the larger excursions. These larger excursions in elbow extension result in animals hitting the ground with more extended forelimbs in longer hops, which in turn allows animals to decelerate over a greater distance.


Gram-scale synthesis and biofunctionalization of silica-coated silver nanoparticles for fast colorimetric DNA detection.
A direct silica-coating method has been developed for the gram-scale synthesis of well-dispersed Ag@SiO(2) nanoparticles. Subsequent surface functionalization via the well-established silica surface chemistry provided arching points for straightforward bioconjugation with amino-terminated oligonucleotides. Fast hybridization kinetics of the resulting robust oligo-modified Ag@SiO(2) nanoprobes with complementary target oligonucleotides render themselves very useful for the fast colorimetric DNA detection based on the sequence-specific hybridization properties of DNA. Additionally, the reliable protocols developed in this study for preparing and functionalizing Ag@SiO(2) nanoparticles can be readily extended to other silica-coated nanoparticles, which can also provide a specific platform for the covalent attachment of biomolecules such as amino-rich proteins, enzymes, or amino-terminated oligonucleotides for diverse bioapplications.


Oxidative activity of the type 2 isozyme of 17beta-hydroxysteroid dehydrogenase (17beta-HSD) predominates in human sebaceous glands.
Sebum production is regulated by the opposing effects of androgens and estrogens. The intracrine activity of steroid metabolizing enzymes is important in regulating sebum production because these enzymes can convert weak steroids from the serum into potent androgens and estrogens within the sebaceous gland (SG). 17Beta-hydroxysteroid dehydrogenase (17beta-HSD) interconverts weak and potent sex steroids via redox reactions. In this regard, it may function as a gatekeeping enzyme regulating the hormonal milieu of the SG. Six isozymes of 17beta-HSD have been identified that differ in their substrate preference and their preference to produce weak or potent sex steroids via oxidation or reduction, respectively. The goals of this study are: (i) to identify which isozyme (s) of 17beta-HSD is active in SG; (ii) to determine if its activity differs in facial skin compared with nonacne-prone skin that may account for the regional differences in sebum production; (iii) to compare the activity of 17beta-HSD in intact glands and in SG homogenates; and (iv) to determine if 13-cis retinoic acid inhibits 17beta-HSD activity. Human SG were assayed for 17beta-HSD activity using estrogens, androgens, and progestins as substrates. Oxidative activity of the type 2 isozyme predominated in all samples tested. Although transcripts for the types 1, 2, 3, and 4 isozymes were detected using reverse transcriptase-polymerase chain reaction, only mRNA for the predominant type 2 isozyme and the type 4 isozyme were detected in northern analysis. Greater reductive activity of 17beta-HSD was noted in SG from facial areas compared with nonacne-prone areas, suggesting an increased net production of potent androgens in facial areas. Oxidation was more predominant over reduction in intact SG compared with homogenized SG, thus supporting the hypothesis that 17beta-HSD protects against the effects of potent androgens in vivo. Activity of the type 2 17beta-HSD was not inhibited by 13-cis retinoic acid. In conclusion, SG possess the cellular machinery needed to transcribe the genes for the type 1-4 isozymes of 17beta-HSD. At the protein level, however, oxidative activity of the type 2 isozyme predominates, suggesting that 17beta-HSD isozyme activity may be translationally regulated.


Effects of polyamine synthesis inhibitors on primary tumor features and metastatic capacity of human breast cancer cells.
We have previously reported that inhibition of polyamine biosynthesis with alpha-difluoromethylornithine (DFMO) reduces pulmonary metastasis from MDA-MB-435 human breast cancer xenografts without affecting the volume of the primary tumors (Manni et al. Clin Exp Mets 20:321, 2003). In these experiments, we show that DFMO treatment (2% in drinking H(2)O) reduced the growth fraction of the primary tumors by 60%. However, this effect was counter-balanced by a similar reduction in non-apoptotic necrosis, thus accounting for the preservation of tumor volume in DFMO-treated mice. DFMO treatment caused a 4-fold increase in cytoplasmic staining for cleaved caspase-3 (as opposed to the nuclear staining observed in control tonsil tissue) in the absence of histologic evidence of apoptosis. DFMO treatment reduced the number of mice with pulmonary metastasis by approximately 80% and the number of metastasis per mouse by >90% in association with a reduction in invasiveness of the primary tumor in the surrounding dermis and muscle by approximately 30%. DFMO treatment increased ERK phosphorylation in the tumors, an effect that has been found by us in vitro to be causally linked to the anti-invasive effect of the drug (Manni et al. Clin Exp Metast 2004; 21: 461]. DFMO also increased tyrosine phosphorylation of STAT-3 and expression of STAT-1 and JNK proteins. Administration of SAM486A (1 mg/kg/i.p. daily), an inhibitor of S-adenosylmethionine decarboxylase, either individually or in combination with DFMO, was not found to exert any biological or biochemical effects, most likely as a result of its failure to suppress tissue polyamine levels under these experimental conditions.


Biocatalytic conversion of ethylene to ethylene oxide using an engineered toluene monooxygenase.
Mutants of toluene o-xylene monooxygenase are demonstrated to oxidize ethylene to ethylene oxide in vivo at yields of >99%. The best mutant increases ethylene oxidation activity by >5500-fold relative to the native enzyme. This is the first report of a recombinant enzyme capable of carrying out this industrially significant chemical conversion.


Decrease in CD226 expression on CD4+ T cells in patients with endometriosis.
Endometriosis is a chronic inflammatory disease. The immune-checkpoint molecules CD226 and TIGIT play an important role in regulating T cells' function. However, little is known about the proportion and function of CD226 and TIGIT on CD4+ T cells in endometriosis. The current study found no significant differences in the TIGIT percentage on peripheral CD4+ T cells between patients with endometriosis and the control group. However, CD226 was lower in patients with endometriosis than that in the control group (P < 0.01). The cytokines TNF-α, IL10, and IFN-γ were significantly elevated in TIGIT+ CD4+ T cells compared to TIGIT- CD4+ T cells. HLA-DR+ cells were more numerous among TIGIT+ CD4+ T cells than among the TIGIT- subset (P <0.001). Similarly, the cytokines TNF-α, IL10, and IFN-γ were significantly elevated in CD226+ CD4+ T cells compared to levels in CD226- CD4+ T cells. The proportion of HLA-DR+ CD4+ T cells among CD226+ CD4+ T cells was also significantly higher than that among the CD226- subset (P < 0.001). After TIGIT was blocked, the level of IL-10 in TIGIT+ CD4+ T cells was higher than that in cells with unblocked TIGIT. There were no differences in TNF-α and IFN-γ. After CD226 was blocked, TNF-α and IFN-γwere lower while IL-10 was higher. In conclusion, there is a diminution of CD226 in CD4+ T cells in patients with endometriosis. This is correlated with the effector function of CD4+ T cells, and blocking CD226 can suppress this function.


Optimization of energy recovery efficiency from sweet sorghum stems by ethanol and methane fermentation processes coupling.
Taken separately, a single sweet sorghum stem bioconversion process for bioethanol and biomethane production only leads to a partial conversion of organic matter. The direct fermentation of crushed whole stem coupled with the methanization of the subsequent solid residues in a two-stage process was experimented to improve energy bioconversion yield, efficiency, and profitability. The raw stalk calorific value was 17,144.17 kJ/kg DM. Fermentation step performed using Saccharomyces cerevisiae resulted in a bioconversion yield of 261.18 g Eth/kg DM, i.e. an energy recovery efficiency of 6921.27 kJ/kg DM. The methanogenic potentials were 279 and 256 LCH4/kg DM, respectively, for raw stem and fermentation residues, i.e. energy yields of 10,013.31 and 9187.84 kJ/kg DM, respectively. Coupling processes have significantly increased yield and made it possible to reach 13,309.57 kJ/kg DM, i.e. 77.63% of raw stem energy recovery yield, compared to 40.37% and 58.40%, respectively, for single fermentation and methanization processes.


Inter-regulated d-band centers of the Ni3B/Ni heterostructure for boosting hydrogen electrooxidation in alkaline media.
Ni3B/Ni heterostructures have been constructed, which exhibit exceptional catalytic performance toward the hydrogen oxidation reaction (HOR) under alkaline media, with the mass activity being about 10 times greater than that of Ni3B and Ni, respectively, ranking among the most active platinum-group-metal-free electrocatalysts. Experimental results and theoretical calculations confirm electron transfer from Ni3B to Ni at the Ni3B/Ni interface, resulting in inter-regulated d-band centers of these two components. This inter-regulation gives rise to optimized binding energies of intermediates, which together contribute to enhanced alkaline HOR activity.


Utilization of free maternity services among women of child bearing age in Machakos County, Kenya.
globally, the rate of maternal mortality is unacceptably high with Kenya recording a rate of 362 maternal death per 100,000 live births. Even so, only 62% of women deliver under skilled health care. The government of Kenya introduced Free Maternity Services (FMS) to all women delivering in public health facilities as a way of increasing facility-based deliveries. Despite this, intervention, health facility deliveries in Machakos County are still low. This study aimed to identify hindrances and enablers of the FMS program in Machakos County. it was a cross-sectional study conducted among postnatal women who delivered between September 2018 and September 2019 in Machakos County. A total of 394 women were enrolled. Data was collected using questionnaires and focus group discussions. Key informant interviews were conducted using nursing officer in charge of selected health facilities. Qualitative data was analyzed using chi-square and fishers exact. Multivariate logistic regression was used to determine predictors of utilization of FMS. Statistical significance was set at p < 0.05. utilization of FMS in Machakos County was 75.6%. Factors that were associated with utilization of FMS included marital status (p = 0.006), parity (p = 0.038), distance from health facility (p = 0.000), services offered during labour (p = 0.000), treatment of mothers by healthcare workers during labour (p = 0.000), provision of adequate food (p = 0.005), quality of service (p = 0.000) and cleanliness of the maternity ward (p = 0.000). utilization of FMS in Machakos County is optimal. Health facilities should be supported to offer FMS by providing them with necessary supplies.


Identification of a chemotactic sensitivity in a coupled system.
Chemotaxis is the process by which cells behave in a way that follows the chemical gradient. Applications to bacteria growth, tissue inflammation and vascular tumours provide a focus on optimization strategies. Experiments can characterize the form of possible chemotactic sensitivities. This paper addresses the recovery of the chemotactic sensitivity from these experiments while allowing for non-linear dependence of the parameter on the state variables. The existence of solutions to the forward problem is analysed. The identification of a chemotactic parameter is determined by inverse problem techniques. Tikhonov regularization is investigated and appropriate convergence results are obtained. Numerical results of concentration-dependent chemotactic terms are explored.


[Effect of supplementation with a single dose of vitamin D in children with cerebral palsy. Preliminary randomised controlled study].
Children with cerebral palsy (CP) have an increased risk of vitamin D (VD) deficiency. Although there are many studies on VD and CP, there is limited information about VD supplementation in these patients. To evaluate the effect of supplementation with a single dose of VD on the plasma concentrations of 25-hydroxy-vitamin-D (25OHD) in children with CP. Prospective-randomised-controlled-trial, including 30 Chilean children (19 males) with CP, median age 9.9 years (6.2-13.5). Clinical and biochemical variables including 25OHD, were recorded (time 0 and 8 weeks). Patients were allocated to the supplemented (S) group receiving 100,000 IU oral D3 at baseline, and compared with the placebo (P) group. Among clinical features are highlighted: gastrostomy (60%), underweight (30%), bed-ridden (93.3%), antiepileptic drugs (70%), and 43.3% used VD metabolism inducing antiepileptics. Baseline biochemical measurements were normal. The 25OHD was insufficient in 4/30 and deficient in 6/30. 25OHD levels were not associated with the variables studied. Eight patients completed the study in the S group, and 10 in P group. The placebo and supplementation groups had no significant difference in baseline variables. Serum calcium, phosphate, and alkaline phosphatase levels at 8 weeks were normal in both groups, with no statistically significant differences. 25OHD in the P group was normal in 6/10, and insufficient+deficient in 4/10, and the S group was normal in all (8/8) (exact Fisher test P=.07). A single dose of 100,000 IU VD could normalise the concentrations of 25OHD after 8 weeks of supplementation in Children with CP, but more studies are required to confirm these results.


A roadmap to parity in mental health financing: the case of Lebanon.
Inadequate access to mental health (MH) services in Lebanon, where prevalence is noteworthy, is a concern. Although a multitude of factors affects access to services, lack of financial coverage of MH services is one that merits further investigation. This study aims at providing a systematic description of MH financing systems with a special focus on Lebanon, presenting stakeholder viewpoints on best MH financing alternatives/strategies and recommending options for enhancing financial coverage. A comprehensive review of existing literature on MH financing systems was conducted, with a focus on the system in Lebanon. In addition, key stakeholders were interviewed to assess MH organizational and financing arrangements. Finally, a national round table was organized with the aim of discussing findings (from the review and interviews) and developing an action roadmap. Taxation and out-of-pocket payments are the most common MH financing sources worldwide and in the Eastern Mediterranean Region. In Lebanon, all funding entities, except private insurance and mutual funds, cover inpatient and outpatient MH services, albeit with inconsistencies in levels of coverage. The national roundtable recommended two main MH financing enhancements: (i) creating a knowledge-sharing committee between insurers and MH specialists, and (ii) convincing labor unions/representatives to lobby for MH coverage as part of the negotiated benefit package. There are concerns regarding the equity, effectiveness and efficiency of the MH financing system in Lebanon. The fragmented system in Lebanon leads to differences in MH coverage across different financing intermediaries, which is inequitable. The fact that one out of four Lebanese suffer a mental disorder throughout their lives and very low percentages of those obtain treatment signals a problem in effectiveness. As for efficiency, the inefficient fragmentation of MH financing among seven intermediaries is a problematic characteristic of the healthcare financing system as a whole. Moreover, the orientation of the general healthcare system towards curative rather than preventive care is reflected in MH financing as well. Limitations of the study include the lack of access to data about the MH expenditure of every financing intermediary in Lebanon; therefore it was not possible to calculate a total annual MH spending on a country level. Another limitation was the inability to map the sources of funding with the MH service provision sector, as more extensive data about the MH services provided by each of the public, private, voluntary and informal sectors is needed. Providing a clear description of the current MH financing system helps policymakers recognize the disparities present in the coverage of MH, guiding them into making informed decisions on allocation of funds. This study therefore constitutes the first step towards achieving more equitable and socially just coverage, advances knowledge and provides well-needed locally relevant research. Findings are expected to inform policymaking and have already contributed to influencing a change in the policy of the Internal Security Forces Health Fund. As a result of the roundtable discussion and follow up that ensued, the fund has removed the suicide attempt exclusion from its insurance policy.


Total Syntheses of Vancomycin and Eremomycin Aglycons.
Controlling the elements of planar and axial chirality are the principal challenges in the synthesis of the aglycon of vancomycin. Vancomycin is the prototypical member of the glycopeptide family of antibiotics which are effective for the treatment of infections by methicillin-resistant Staphylococcus aureus. The first total syntheses of the vancomycin and eremomycin aglycons provide insight into the influence of structure on kinetic and thermodynamic control of atropselective macrocyclizations.


Inhibitors of Histone Deacetylases Are Weak Activators of the FMR1 Gene in Fragile X Syndrome Cell Lines.
Fragile X syndrome is the most common cause of inherited intellectual disability in humans. It is a result of CGG repeat expansion in the 5' untranslated region (5' UTR) of the FMR1 gene. This gene encodes the FMRP protein that is involved in neuronal development. Repeat expansion leads to heterochromatinization of the promoter, gene silencing, and the subsequent absence of FMRP. To date, there is no specific therapy for the syndrome. All treatments in clinic practice provide symptomatic therapy. The development of drug therapy for Fragile X syndrome treatment is connected with the search for inhibitors of enzymes that are responsible for heterochromatinization. Here, we report a weak transcriptional activity of the FMR1 gene and the absence of FMRP protein after Fragile X syndrome cell lines treatment with two FDA approved inhibitors of histone deacetylases, romidepsin and vorinostat. We demonstrate that romidepsin, an inhibitor of class I histone deacetylases, does not activate FMR1 expression in patient cell cultures, whereas vorinostat, an inhibitor of classes I and II histone deacetylases, activates a low level of FMR1 expression in some patient cell lines.


Selection for superior growth advances the onset of puberty and increases reproductive performance in ewe lambs.
The reproductive efficiency of the entire sheep flock could be improved if ewe lambs go through puberty early and produce their first lamb at 1 year of age. The onset of puberty is linked to the attainment of critical body mass, and therefore we tested whether it would be influenced by genetic selection for growth rate or for rate of accumulation of muscle or fat. We studied 136 Merino ewe lambs with phenotypic values for depth of eye muscle (EMD) and fat (FAT) and Australian Sheep Breeding Values at post-weaning age (200 days) for live weight (PWT), eye muscle depth (PEMD) and fat depth (PFAT). First oestrus was detected with testosterone-treated wethers and then entire rams as the ewes progressed from 6 to 10 months of age. Blood concentrations of leptin and IGF-I were measured to test whether they were related to production traits and reproductive performance (puberty, fertility and reproductive rate). In total, 97% of the lambs reached first oestrus at average weight 39.4 ± 0.4 kg (mean ± s.e.m.) and age 219 days (range 163 to 301). Age at first oestrus decreased with increases in values for PWT (P < 0.001), and concentrations of IGF-I (P < 0.05) and leptin (P < 0.01). The proportion of ewe lambs that achieved puberty was positively related with increases in values for EMD (P < 0.01), FAT (P < 0.05) or PWT (P < 0.01), and 75% of the ewe lambs were pregnant at average weight 44.7 ± 0.5 kg and age 263 days (range 219 to 307). Ewe lambs that were heavier at the start of mating were more fertile (P < 0.001) and had a higher reproductive rate (P < 0.001). Fertility and reproductive rate were positively correlated with increases in values for EMD (P < 0.01), FAT (P < 0.05), PWT (P < 0.01) and leptin concentration (P < 0.01). Fertility, but not reproductive rate, increased as values for PFAT increased (P < 0.05). Leptin concentration increased with increases in values for EMD (P < 0.001), FAT (P < 0.001), PWT (P < 0.001), PEMD (P < 0.05) and PFAT (P < 0.05). Many of these relationships became non-significant when PWT or live weight was added to the statistical model. We conclude that selection for genetic potential for growth can accelerate the onset of puberty and increase fertility and reproductive rate of Merino ewe lambs. The metabolic hormones, IGF-I and leptin, might act as a physiological link between the growing tissues and the reproductive axis.


Biochemical and immunological analysis of rapidly purified 10-nm filaments from baby hamster kidney (BHK-21) cells.
Juxtanuclear birefringent caps (FC) containing 10-nm filaments form during the early stages of baby hamster kidney (BHK-21) cell spreading. FC are isolated from spreading cells after replating by treatment with 0.6 M KCl, 1% Triton X-100 (Rohm & Haas Co., Philadelphia, Pa.) and DNase I in phosphate-buffered saline. Purified FC are birefringent and retain the pattern of distribution of 10-nm filaments that is seen in situ. Up to 90% of the FC protein is resolved as two polypeptides of approximately 54,000 and 55,000 molecular weight on sodium dodecyl sulfate (SDS) polyacrylamide gels. The protein is immunologically and biochemically distinct from tubulin as determined by indirect immunofluorescence, double immunodiffusion, one-dimensional peptide mapping by limited proteolysis in SDS gels, and amino acid analysis. The BHK-21 FC amino acid composition, however, is very similar to that obtained for 10-nm filament protein derived from other sources including brain and smooth muscle. Partial disassembly of 10-nm filaments has been achieved by treatment of FC with 6 mM sodium-potassium phosphate buffer, pH 7.4. The solubilized components assemble into distinct 10-nm filaments upon the addition of 0.171 M sodium chloride.


Polaron Photoconductivity in the Weak and Strong Light-Matter Coupling Regime.
We investigate the potential for cavity-modified electron transfer in a doped organic semiconductor through the photocurrent that arises from exciting charged molecules (polarons). When the polaron optical transition is strongly coupled to a Fabry-Perot microcavity mode, we observe polaron polaritons in the photoconductivity action spectrum and find that their magnitude depends differently on applied electric field than photocurrent originating from the excitation of uncoupled polarons in the same cavity. Crucially, moving from positive to negative detuning causes the upper and lower polariton photocurrents to swap their field dependence, with the more polaronlike branch resembling that of an uncoupled excitation. These observations are understood on the basis of a phenomenological model in which strong coupling alters the Onsager dissociation of polarons from their dopant counterions by effectively increasing the thermalization length of the photoexcited charge carrier.


Willingness to participate in future HIV prevention studies among gay and bisexual men in Scotland, UK: a challenge for intervention trials.
This article examines willingness to participate in future HIV prevention research among gay and bisexual men in Scotland, UK. Anonymous, self-complete questionnaires and Orasure™ oral fluid samples were collected in commercial gay venues. 1,320 men were eligible for inclusion. 78.2% reported willingness to participate in future HIV prevention research; 64.6% for an HIV vaccine, 57.4% for a behaviour change study, and 53.0% for a rectal microbicide. In multivariate analysis, for HIV vaccine research, greater age, minority ethnicity, and not providing an oral fluid sample were associated with lower willingness; heterosexual orientation and not providing an oral fluid sample were for microbicides; higher education and greater HIV treatment optimism were for behaviour change. STI testing remained associated with being more willing to participate in microbicide research and frequent gay scene use remained associated with being more willing to participate in behaviour change research. Having an STI in the past 12 months remained significantly associated with being willing to participate in all three study types. There were no associations between sexual risk behaviour and willingness. Although most men expressed willingness to participate in future research, recruitment of high-risk men, who have the potential to benefit most, is likely to be more challenging.


[Antibacterial and anti-algal activity if two traditional drugs in the treatment of urinary tract infection and cystitis in Mali].
For the treatment of the urinary infections and the cystitis, the medicinal plants constitute a source of new molecules with an antimicrobial activity and economically accessible to face the apparition of a phenomena of germ resistance to antibiotics. The urinary infections and the cystitis are very spilled and constitute a problem of public health in developing countries. About 50% of women develop a symptomatic urinary tract infection at least once in their life. The urinary infection is, by order of frequency, the first of the non epidemic infectious illnesses. The objective of our survey is to find in Malian Pharmacopoeia, plants with antibacterial and analgesic properties. Five remedies and their plants used in traditional medicine for the treatment of the urinary tract infections and the cystitis have been selected on the basis of ethnobotanic investigations results. Extracts of five remedies and their plants have been tested for their antibacterial activity on the germs responsible for the urinary infections and the cystitis. Extracts containing Stylosanthes erecta P. Beauv (Fabaceae) demonstrated an antibacterial activity against clinical strains of Escherichia coli, responsible of 75 to 80% of the urinary infections. The same extracts demonstrated an analgesic activity against the pain induced by the acetic acid in mice. The antibacterial and analgesic properties can be of great benefit in the treatment of the urinary tract infections and the cystitis.


Performance of an automated real-time ST-segment analysis program to detect coronary occlusion and reperfusion.
Continuously updated ST-segment recovery analysis has been shown to accurately predict infarct-related artery patency. Salient principles were converted into algorithms and incorporated into a portable ST monitor for optimal application. This study tested the automated program's ability to detect occlusion and reperfusion during balloon angioplasty. ST-segment recordings during 78 balloon occlusions in 31 patients were analyzed. The program requires at least one electrocardiogram with ST elevation of 200 microV or greater in the recording, caused by the current occlusion or by a previous occlusion, before it will yield a patency prediction. All 35 inflations causing peak ST elevation of 200 microV or more were indeed detected. All five inflations causing less than 200 microV ST elevation preceded by an inflation causing 200 microV or higher ST elevation were also detected. Occlusion was detected a median of 40 seconds after inflation, and reperfusion a median of 17 seconds after deflation. Peak ST elevation greater than 200 microV occurred in 19 of 26 left anterior descending artery inflations (73%), 1 of 22 left circumflex artery LCX inflations (5%), and 15 of 30 right coronary artery inflations (50%). Five different leads identified peak ST elevation through 12-lead surveillance. In this model of coronary occlusion during angioplasty balloon inflation, the automated patency assessment program appears to detect coronary angioplasty balloon occlusion and reperfusion within seconds in all occlusions causing a peak ST elevation of 200 microV or greater. Testing this automated patency assessment program as a noninvasive triage tool in myocardial infarction patients seems warranted.


Replication of cucumber mosaic virus satellite RNA from negative-sense transcripts produced either in vitro or in transgenic plants.
Both positive [(+)] and negative [(-)] sense versions of two satellite RNA (satRNA) genes from cucumber mosaic virus (CMV), the necrogenic I17N and the nonnecrogenic R, have been introduced into the genome of tobacco plants. On infection with satRNA-free CMV, satRNA was amplified in plants expressing each of the four genes. All four genes confer protection against CMV infection. However, co-inoculation of plants with viral RNA and CMV satRNA transcripts synthesized in vitro showed that (-) sense transcripts were less active than the corresponding (+) sense transcripts. This is the first report that (-) sense CMV satRNA transcripts can serve as a template for satRNA replication.


Localization of low-sulfur keratin proteins in the wool follicle using monoclonal antibodies.
Monoclonal antibodies that recognize components of the low-sulfur keratin proteins extracted from Merino wool have been used to locate these components within the wool follicle. Immunoblotting procedures showed that all of the monoclonal antibodies bound more than one of the eight low-sulfur protein components, indicating that these proteins have antigenic determinants in common. Immunofluorescence studies showed that those antibodies specific for the component 7 family of the low-sulfur proteins bound to the developing wool fiber, whereas those antibodies recognizing the component 8 family bound to areas throughout the wool follicle, particularly the inner and outer root sheaths, but also to the fiber, the cuticle, and the epidermis. One of the monoclonal antibodies also bound to intermediate filament networks of cultured human epithelial cells.


Relaxation dynamics of high-energy excited states of carotenoids studied by UV excitation and pump-repump-probe transient absorption spectroscopy.
The excited states of carotenoids have been a subject of numerous studies. While a majority of these reports target the excited state dynamics initiated by the excitation of the S2 state, the upper excited state(s) absorbing in the UV spectral region (denoted as SUV) has been only scarcely studied. Moreover, the relation between the SUV and Sn, the final state of the well-known S1-Sn transition of carotenoids, remains unknown. To address this yet-unresolved issue, we compared the excited state dynamics of two carotenoids, namely, β-carotene and astaxanthin, after excitation of either the SUV or Sn state. The SUV state was excited directly by UV light, and the excitation of the Sn state was achieved via re-pumping the S1-Sn transition. The results indicated that direct SUV excitation produces an S1-Sn band that is significantly broader than that obtained after S2 excitation, most probably due to the generation of multiple S1 conformations produced by excess energy. No such broadening is observed if the Sn state is excited by the re-pump pulse. This shows that the Sn and SUV states are different, each initializing a specific relaxation pathway. We propose that the Sn state retains the coupled triplet pair character of the S1 state, while the SUV state is the higher state of Bu+ symmetry accessible by one-photon transition.


Angiolymphoid hyperplasia with eosinophilia.
Angiolymphoid hyperplasia with eosinophilia (AHE) is a distinct clinical and pathologic entity that demonstrates proliferation of endothelial cells associated with varying degrees of lymphocytic, histiocytic, and eosinophilic infiltration. Lymphoid hyperplasia with germinal centers often is present in older lesions and the patients may have an associated blood eosinophilia. Multiple deep nodules developed in a young man on the palmar aspect of the left hand, and subsequently the forehead, histologically diagnostic of AHE. Direct immunofluorescence of the tumor removed from the forehead demonstrated granular deposits of IgA, IgM, and C3 associated with small vessels. Cryoglobulins (IgA, IgM, and IgG) were found in the patient's serum. This new information lends support to the hypothesis that AHE is an inflammatory reactive lesion, possibly secondary to an immunologic injury, rather than a true vascular neoplasm with an associated inflammatory reaction.


A systematic review of vertical integration and quality of care, efficiency, and patient-centered outcomes.
Small independent practices are increasingly giving way to more complex affiliations between provider organizations and hospital systems. There are several ways in which vertically integrated health systems could improve quality and lower the costs of care. But there are also concerns that integrated systems may increase the price and costs of care without commensurate improvements in quality and outcomes. Despite a growing body of research on vertically integrated health systems, no systematic review that we know of compares vertically integrated health systems (defined as shared ownership or joint management of hospitals and physician practices) to nonintegrated hospitals or physician practices. We conducted a systematic search of the literature published from January 1996 to November 2016. We considered articles for review if they compared the performance of a vertically integrated health system and examined an outcome related to quality of care, efficiency, or patient-centered outcomes. Database searches generated 7,559 articles, with 29 articles included in this review. Vertical integration was associated with better quality, often measured as optimal care for specific conditions, but showed either no differences or lower efficiency as measured by utilization, spending, and prices. Few studies evaluated a patient-centered outcome; among those, most examined mortality and did not identify any effects. Across domains, most studies were observational and did not address the issue of selection bias. Recent evidence suggests the trend toward vertical integration will likely continue as providers respond to changing payment models and market factors. A growing body of research on comparative health system performance suggests that integration of physician practices with hospitals might not be enough to achieve higher-value care. More information is needed to identify the health system attributes that contribute to improved outcomes, as well as which policy levers can minimize anticompetitive effects and maximize the benefits of these affiliations.


A statistical method for detecting differentially expressed SNVs based on next-generation RNA-seq data.
In this article, we propose a new statistical method-MutRSeq-for detecting differentially expressed single nucleotide variants (SNVs) based on RNA-seq data. Specifically, we focus on nonsynonymous mutations and employ a hierarchical likelihood approach to jointly model observed mutation events as well as read count measurements from RNA-seq experiments. We then introduce a likelihood ratio-based test statistic, which detects changes not only in overall expression levels, but also in allele-specific expression patterns. In addition, this method can jointly test multiple mutations in one gene/pathway. The simulation studies suggest that the proposed method achieves better power than a few competitors under a range of different settings. In the end, we apply this method to a breast cancer data set and identify genes with nonsynonymous mutations differentially expressed between the triple negative breast cancer tumors and other subtypes of breast cancer tumors.


Assessment of Immature Granulocytes Percentage to Predict Severe Bacterial Infection in Latvian Children: An Analysis of Secondary Data.
Background: Detection of small proportion of serious bacterial infections (SBI) with a potentially life threating course in a large group of children with fever admitted to emergency department (ED) is still complicated. Measurement of immature granulocytes (IG) percentage may be used as a marker of bacterial infections. The aim of the study was to evaluate whether the IG percentage is a useful additional predictive marker of SBI. Methods: This study included 258 children with febrile infections that were admitted to the ED. Clinical follow-up, microbiological and radiological tests were used as reference standards for the definition of SBI. Study population was categorized into two groups: (1) infected patients with no suspicion of SBI (n = 75); (2) patients with suspicion of SBI (n = 183). IG percentage, white blood cell count (WBC), and C-reactive protein (CRP) levels were analyzed from the first routine blood samples at hospital admission. Results: A statistically significant difference in IG percentage levels was observed in children with SBI and those without-the mean IG percentage was 1.2% for the SBI group, 0.3% for those without SBI. The cutoff level of IG percentage to predict SBI was 0.45 (84% specificity, 66% sensitivity, 90% positive predictive value). We combine variables and evaluate their additive values. The sensitivity of WBC to detected SBI improved from 74% to 85% when IG percentage was added to the prediction models. When CRP, WBC, and IG percentage were combined, the sensitivity to predict SBI increased to 93%, the specificity to 86% (95% CI 77%⁻93%). Receiver operator characteristic analysis to predict SBI showed an area under the curve (AUC) of 0.80 for IG percentage. Conclusion: Addition of IG percentage to traditionally used markers of SBI as WBC and CRP may help to identify children with serious bacterial infections. Furthermore, IG percentage can be rapidly obtained from the traditional full blood count without any extra sampling and costs.


The exposome--exciting opportunities for discoveries in reproductive and perinatal epidemiology.
Understanding the mechanisms that underlie successful human reproduction and development is an ambitious goal, given the many unique methodological challenges surrounding such study. These challenges are well understood by reproductive and perinatal epidemiologists and include its conditional nature, unobservable yet informative outcomes such as conception, multi-scale missing data, correlated or non-independent outcomes, interval censoring and a hierarchical data structure. Novel methodologies for overcoming these challenges and for answering critical data gaps are needed if we are to better understand the inefficiency that currently characterises human reproduction with the goal of improving population health. The exposome is an emerging paradigm that offers promise for understanding the natural history of human reproduction and development, and its many associated impairments that develop later in child- or adulthood. This novel paradigm recognises the need to identify and measure the totality of environmental (non-genetic) exposures from preconception through sensitive windows, and to identify patterns associated with healthy and adverse outcomes. The exposome accommodates research focusing on unique subpopulations, such as couples undergoing assisted reproductive technologies, so that methodological limitations such as unobservable and conditional outcomes can be better addressed. Reproductive and perinatal epidemiology is uniquely suited for proof-of-concept exposome research, given the intricate relations between fecundity, gravid health and later onset disease and the narrow and interrelated sensitive windows that characterise the conditional nature of human reproduction and development. Bold new conceptual frameworks such as the exposome are needed for designing research that may lead to discovery and improve population health.


Microencapsulated islet allografts in diabetic NOD mice and nonhuman primates.
Our goal was to assess the efficacy of encapsulated allogeneic islets transplanted in diabetic NOD mice and streptozotocin (STZ)-diabetic nonhuman primates (NHPs). Murine or NHP islets were microencapsulated and transplanted in non-immunosuppressed mice or NHPs given clinically-acceptable immunosuppressive regimens, respectively. Two NHPs were treated with autologous mesenchymal stem cells (MSCs) and peri-transplant oxygen therapy. Different transplant sites (intraperitoneal [i.p.], omental pouch, omental surface, and bursa omentalis) were tested in separate NHPs. Graft function was monitored by exogenous insulin requirements, fasting blood glucose levels, glucose tolerance tests, percent hemoglobin A1c (% HbA1c), and C-peptide levels. In vitro assessment of grafts included histology, immunohistochemistry, and viability staining; host immune responses were characterized by flow cytometry and cytokine/chemokine multiplex ELISAS. Microencapsulated islet allografts functioned long-term i.p. in diabetic NOD mice without immunosuppression, but for a relatively short time in immunosuppressed NHPs. In the NHPs, encapsulated allo-islets initially reduced hyperglycemia, decreased exogenous insulin requirements, elevated C-peptide levels, and lowered % HbA1c in plasma, but graft function diminished with time, regardless of transplant site. At necropsy, microcapsules were intact and non-fibrotic, but many islets exhibited volume loss, central necrosis and endogenous markers of hypoxia. Animals receiving supplemental oxygen and autologous MSCs showed improved graft function for a longer post-transplant period. In diabetic NHPs and mice, cell-free microcapsules did not elicit a fibrotic response. The evidence suggested that hypoxia was a major factor for damage to encapsulated islets in vivo. To achieve long-term function, new approaches must be developed to increase the oxygen supply to microencapsulated islets and/or identify donor insulin-secreting cells which can tolerate hypoxia.


Primary structure and morphine-like activity of human beta-endorphin.
The complete amino acid sequence of human beta-endorphin was obtained by automatic sequencing of a sulfonyl isothiocyanate derivative of this peptide, in combination with peptide mapping of a tryptic digest of the native molecule. It was found to be identical with the carboxy-terminal portion 61-91 of human beta-lipotropin (beta-LPH). The morphine-like activity of beta-endorphin is comparable both in the mouse vas deferens bioassay and in the opiate receptor binding assay. However, beta-LPH is not active up to concentrations of 10(-6) M.


Zerumbone Restores Gut Microbiota Composition in ETBF Colonized AOM/DSS Mice.
Colorectal cancer (CRC) is the leading cause of common malignant neoplasm worldwide. Many studies have analyzed compositions of gut microbiota associated with various diseases such as inflammatory bowel diseases (IBD) and colon cancer. One of the most representative bacteria involved in CRC is enterotoxigenic Bacteroides fragilis (ETBF), a species belonging to phylum Bacteroidetes. We used ETBF colonized mice with azoxymethane (AOM)/dextran sulphate sodium (DSS) and zerumbone, a compound with anti-bacterial effect, to determine whether zerumbone could restore intestinal microbiota composition. Four experimental groups of mice were used: sham, ETBF colonized AOM/DSS group, ETBF colonized AOM/DSS group zerumbone 60 mg kg-1 (ETBF/AOM/ DSS + Z (60)), and only zerumbone (60 mg kg-1)-treated group. We performed reversible dye terminators-based analysis of 16S rRNA gene region V3-V4 for group comparison. Microbiota compositions of ETBF/AOM/DSS + Z (60) group and ETBF colonized AOM/DSS group not given zerumbone were significantly different. There were more Bacteroides in ETBF/AOM/DSS + Z (60) group than those in ETBF colonized AOM/DSS group, suggesting that B. fragilis could be a normal flora activated by zerumbone. In addition, based on linear discriminant analysis of effect size (LEfSe) analysis, microbial diversity decreased significantly in the ETBF colonized AOM/DSS group. However, after given zerumbone, the taxonomic relative abundance was increased. These findings suggest that zerumbone not only influenced the microbial diversity and richness, but also could be helpful for enhancing the balance of gut microbial composition. In this work, we demonstrate that zerumbone could restore the composition of intestinal microbiota.


Transcranial magnetic stimulation of deep brain regions: evidence for efficacy of the H-coil.
Standard coils used in research and the clinic for noninvasive magnetic stimulation of the human brain are not capable of stimulating deep brain regions directly. As the fields induced by these coils decrease rapidly as a function of depth, only very high intensities would allow functional stimulation of deep brain regions and such intensities would lead to undesirable side effects. We have designed a coil based on numerical simulations and phantom brain measurements that allows stimulation of deeper brain regions, termed the Hesed coil (H-coil). In the present study we tested the efficacy and some safety aspects of the H-coil on healthy volunteers. The H-coil was compared to a regular figure-8 coil in 6 healthy volunteers by measuring thresholds for activation of the abductor pollicis brevis (APB) representation in the motor cortex as a function of distance from each of the coils. The rate of decrease in the coil intensity as a function of distance is markedly slower for the H-coil. The motor cortex could be activated by the H-coil at a distance of 5.5 cm compared to 2 cm with the figure-8 coil. The present study indicate that the H-coil is likely to have the ability of deep brain stimulation and without the need of increasing the intensity to extreme levels that would cause a much greater stimulation in cortical regions. The ability of non-invasive deep brain stimulation potentially opens a wide range of both research and therapeutic applications.


Nephronophthisis.
Nephronophthisis (NPHP) is an autosomal recessive kidney disorder characterized by chronic tubulointerstitial nephritis and leading to end-stage renal failure. NPHP as a renal entity is often part of a multisystem disorder and has been associated with many syndromes including Joubert syndrome (and related disorders) and Senior-Loken syndrome. Recent molecular genetic advances have allowed identification of several genes underlying NPHP. Most of these genes express their protein products, named nephrocystins, in primary cilial/basal body structures. Some nephrocystins are part of adherens junction and focal adhesion kinase protein complexes. This shared localization suggests that common pathogenic mechanisms within the kidney underlie this disease. Functional studies implicate nephrocystins in planar cell polarity pathways, which may be crucial for renal development and maintenance of tubular architecture.


Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: blockade by MK-801 but not naloxone.
Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.


The expressed support needs of families of adults who have survived critical illness: A thematic synthesis.
Surviving critical illness can result in ongoing psychological, physical and cognitive impairments for both survivors and families. During the time from the critical illness through to the period of adaptation back to community living, families, alongside survivors, have support needs. This systematic review aimed to provide an in-depth insight into the expressed support needs of families of adults who survived an admission to an intensive care unit and returned to a home environment. It also aimed to explore how these needs change over time, and what support provisions families perceived to be helpful. This was a systematic review using thematic synthesis methodology. Predefined searches were conducted in CINAHL, Medline, PsychINFO, SocIndex, EMbase, Academic Search Complete, EThOS and OpenGrey to locate studies published in English from 2000. Two reviewers screened each study against the inclusion criteria. Quality appraisal was undertaken using Joanna Briggs Institute tools. Extracted data were managed in Nvivo12® and analysed to identify descriptive and analytical themes. The Timing it Right Framework was used to frame changes in need across the recovery continuum. Thirty-nine studies were included, 30 qualitative, eight quantitative and one mixed methods. Five key family needs were identified across the recovery continuum: for security; to make sense of the situation; finding a balance; holding everything together; and for trust. Families found the following interventions helpful: written information; care coordination and navigation; input from intensive care staff after discharge to support continuity; and provision of family support groups. Although there are similarities between the needs of families and survivors, there are sufficient differences to warrant the development of processes to identify and address family need throughout the recovery continuum. More research is required to develop a tool to better identify the needs of families across the recovery continuum, identify gaps in current service provision, and design interventions to meet these needs. CRD42019136883 (PROSPERO).


Interaction of beta-lactam antibiotics with H+/peptide cotransporters in rat renal brush-border membranes.
Two H+/peptide cotransporters, PEPT1 and PEPT2, are expressed in the kidney, mediating the renal tubular reabsorption of oligopeptides and beta-lactam antibiotics. We examined the interactions of beta-lactam antibiotics with peptide transporters in rat renal brush-border membranes by evaluating the inhibitory potencies of the antibiotics against glycylsarcosine transport. Western blot analysis revealed that PEPT1 and PEPT2 were expressed in the renal brush-border membranes with the apparent molecular masses of 75 and 105 kDa, respectively. Using renal brush-border membrane vesicles, the uphill transport of glycylsarcosine was observed in the presence of an inward H+ gradient and an inside-negative membrane potential. Two transport systems with high affinity (Km of 50 microM) and low affinity (Km of 1.2 mM) appeared kinetically to mediate the glycylsarcosine uptake. The inhibition constants of the antibiotics for glycylsarcosine transport were more closely correlated with those in stable LLC-PK1 cells transfected with rat PEPT2 rather than PEPT1 cDNA. The beta-lactam antibiotics with an alpha-amino group showed trans-stimulation effects on the glycylsarcosine uptake, suggesting that these antibiotics and glycylsarcosine share a common peptide transporter. However, the antibiotics lacking an alpha-amino group failed to show the trans-stimulation effect. It is concluded that amino-beta-lactam antibiotics at therapeutic concentrations interact predominantly with PEPT2 localized in the brush-border membranes of rat kidney.


Spinal neurite reabsorption and regrowth in vitro depend on the polarity of an applied electric field.
Retraction and regrowth of frog neural tube neurites have been studied in vitro in control cultures and in the presence of a small, continuously applied electrical field. In control cultures, some degree of retraction was seen in 39% of neurites while 7% were reabsorbed completely. Reabsorption of anodal-facing neurites was at least twice as common, with 67% showing some retraction and 17% almost totally reabsorbed. Cathodal-facing neurites were spared from retraction. Following extreme reabsorption of anodal-facing neurites, reversal of the electric field promoted regeneration in 47% (9/19) of cases studied. growth cone morphology also was determined by the polarity of the applied field. Anodal-facing growth cones had fewer filopodia than cathodal-facing growth cones sharing the same cell body. Field reversal induced a polarity-specific change in filopodia number on individual growth cones: a shift from anodal to cathodal increased filopodia numbers and vice versa. Some possible mechanisms involved and the significance of these results are discussed.


[Membrane phospholipids of the rat liver endoplasmic reticulum normally and in the early stage of carcinogenesis].
There were found certain changes in the total content of phospholipids as well as in the content of their separate fractions in the membranes of endoplasmic reticulum in the rat liver at early stages of carcinogenesis. In the first week under the carcinogen DENA exposure a considerable reduction of the total phospholipids content was noted in the fraction of granular endoplasmic reticulum, while in agranular reticulum during this period of embryogenesis the total content of phospholipids is not changed, but subsequently the former increases as compared with normal values. During the whole period of carcinogenesis under study changes in the phospholipid content are observed in both fractions of endoplasmic reticulum membranes, the greatest changes being noted in the fractions of lysophosphatidicholines, phosphatidilcholines, and phosphatidilinosites.


MicroRNA-mediated loss of ADAR1 in metastatic melanoma promotes tumor growth.
Some solid tumors have reduced posttranscriptional RNA editing by adenosine deaminase acting on RNA (ADAR) enzymes, but the functional significance of this alteration has been unclear. Here, we found the primary RNA-editing enzyme ADAR1 is frequently reduced in metastatic melanomas. In situ analysis of melanoma samples using progression tissue microarrays indicated a substantial downregulation of ADAR1 during the metastatic transition. Further, ADAR1 knockdown altered cell morphology, promoted in vitro proliferation, and markedly enhanced the tumorigenicity in vivo. A comparative whole genome expression microarray analysis revealed that ADAR1 controls the expression of more than 100 microRNAs (miRNAs) that regulate many genes associated with the observed phenotypes. Importantly, we discovered that ADAR1 fundamentally regulates miRNA processing in an RNA binding–dependent, yet RNA editing–independent manner by regulating Dicer expression at the translational level via let-7. In addition, ADAR1 formed a complex with DGCR8 that was mutually exclusive with the DGCR8-Drosha complex that processes pri-miRNAs in the nucleus. We found that cancer cells silence ADAR1 by overexpressing miR-17 and miR-432, which both directly target the ADAR1 transcript. We further demonstrated that the genes encoding miR-17 and miR-432 are frequently amplified in melanoma and that aberrant hypomethylation of the imprinted DLK1-DIO3 region in chromosome 14 can also drive miR-432 overexpression.


Interaction of polypeptide hormones with lipid monolayers.
1. The interaction between lipid monolayers spread on the surface of water and oxytocin, [8-arginine]-vasotocin and [1-asparagine-5-valine]-angiotensin II in the subphase was investigated in a Langmuir surface trough by studying the changes in pressure produced on injection of various quantities of the polypeptide solution under the film. 2. The effect of 2m- and 4m-urea on the character of the adsorption is reported. 3. Structures for the adsorbed films formed in this way are suggested. 4. If the lipid monolayer is taken as a suitable model of cell membranes, then it may be supposed that the effect of such structures forming in cell membranes would be to provide effective ;pores' to facilitate the movement of water and other small molecules across the membrane.


Anti-atherosclerotic effects of sitagliptin in patients with type 2 diabetes mellitus.
Advanced glycation end products, selectins, and adiponectin play important roles in the development of atherosclerosis in individuals with diabetes. Sitagliptin has been shown to reduce the concentration of glycated hemoglobin in diabetic patients. However, its effects on soluble receptor for advanced glycation end products (sRAGEs), selectins, and adiponectin in these patients are poorly understood. This study was conducted to assess the effects of sitagliptin on the circulating levels of sRAGEs, monocyte chemoattractant protein-1 (MCP-1), selectins, and adiponectin in patients with type 2 diabetes. Diabetic patients eligible for sitagliptin monotherapy or combination therapy (eg, sitagliptin plus a sulfonylurea) were administered sitagliptin (50 mg/day) for 6 months. Levels of soluble P-selectin (sP-selectin), soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule-1 (sVCAM-1), MCP-1, sRAGEs, and adiponectin were measured by ELISA at baseline and after 3 and 6 months of treatment. At baseline, the levels of MCP-1, sP-selectin, sE-selectin, and sVCAM-1 were higher and the level of adiponectin was lower in diabetic patients than in nondiabetic patients. Sitagliptin therapy for 3 and 6 months significantly reduced plasma levels of sP-selectin, sE-selectin, sVCAM-1, and MCP-1 relative to baseline, while significantly increasing adiponectin levels. sRAGEs did not exhibit a statistical significance, although there was an increasing tendency. Furthermore, the reductions in sP-selectin, sE-selectin, sVCAM-1, and MCP-1 during sitagliptin therapy were significantly greater in responders, defined as patients with a significant increase in adiponectin levels, than in nonresponders. In contrast, responders showed a significant increase in the plasma concentration of sRAGEs. Sitagliptin shows an adiponectin-dependent anti-atherothrombotic effect, which may be beneficial for primary prevention of atherothrombosis, in patients with type 2 diabetes.


Placental Regulation of Energy Homeostasis During Human Pregnancy.
Successful pregnancies rely on sufficient energy and nutrient supply, which require the mother to metabolically adapt to support fetal needs. The placenta has a critical role in this process, as this specialized organ produces hormones and peptides that regulate fetal and maternal metabolism. The ability for the mother to metabolically adapt to support the fetus depends on maternal prepregnancy health. Two-thirds of pregnancies in the United States involve obese or overweight women at the time of conception. This poses significant risks for the infant and mother by disrupting metabolic changes that would normally occur during pregnancy. Despite well characterized functions of placental hormones, there is scarce knowledge surrounding placental endocrine regulation of maternal metabolic trends in pathological pregnancies. In this review, we discuss current efforts to close this gap of knowledge and highlight areas where more research is needed. As the intrauterine environment predetermines the health and wellbeing of the offspring in later life, adequate metabolic control is essential for a successful pregnancy outcome. Understanding how placental hormones contribute to aberrant metabolic adaptations in pathological pregnancies may unveil disease mechanisms and provide methods for better identification and treatment. Studies discussed in this review were identified through PubMed searches between the years of 1966 to the present. We investigated studies of normal pregnancy and metabolic disorders in pregnancy that focused on energy requirements during pregnancy, endocrine regulation of glucose metabolism and insulin resistance, cholesterol and lipid metabolism, and placental hormone regulation.


The role of type II deiodinase polymorphisms in clinical management of hypothyroid patients treated with levothyroxine.
Several factors can affect achieving the goals with levothyroxine (L-T4) therapy. This study investigates the clinical and biochemical response to L-T4 replacement therapy in hypothyroid patients in correlation with genetic variation in Deiodinase type || (DIO2) gene. This is a cross-sectional correlation study. The setting was the diabetes and endocrinology clinics at 2 Jordanian Hospitals. Patients with primary hypothyroidism who are controlled on stable L-T4 replacement therapy were recruited and thyroid function test was performed. Genetic analysis to detect 4 single nucleotide polymorphisms (SNPs) rs225011, rs7140952, rs225012 and rs2839858 in DIO2 gene was carried out using the polymerase chain reaction-based restriction fragment length polymorphism assay (PCR-RFLP). There was no correlation between the 4 SNPs in DIO2 gene and replacement doses of L-T4, whereas a statistical significance was found between rs7140952 and central obesity (P<0.05), and systolic and diastolic blood pressure (P<0.05). The dose of L-T4 was associated with lower levels of TSH, fT4, central obesity, body mass index and waist circumference. While L-T4 dose is associated with several positive effects on hypothyroid patients, none of the examined SNPs in DIO2 is correlated with replacement doses of the drug. However, rs7140952 polymorphism is associated with components of metabolic syndrome including blood pressure and central obesity.


Characteristics of a short incubation model of scrapie in the golden hamster.
Repeated passage of the "Chandler" strain of scrapie in female golden hamsters using the intracerebral route of inoculation reduces the minimum incubation period to 60 days, about half of the minimum incubation period so far found in any of the mouse models of scrapie. The infectivity titres in brain in the clinical stage of the disease are considerably higher (greater than 8-0 -log10 LD50 i.c. units/0-05 g) than those found in mouse scrapie. The biological characteristics of this model of hamster scrapie are reported, including the effects on incubation period of route of inoculation, dose of agent, sex of hamster, ambient temperature (hibernation) and splenectomy. Some general and specific applications of this experimental model of scrapie are discussed.


Proliferation-associated differences in the spatial and temporal expression of gap junction genes in rat liver.
After a 70% partial hepatectomy (PH), the steady-state levels of Connexin (Cx)32, Cx26, and Cx43 messenger RNA (mRNA) transcripts each displayed unique patterns of temporal expression. Within 1 hour after surgical resection, increased expression of all three Cx mRNAs was observed. Subsequently, the level of Cx32 mRNA transcripts transiently decreased to a nadir at 12 hours. Comparisons of the spatial changes with previously reported hepatocyte proliferation kinetics induced by PH demonstrated that hepatocytes before S-phase "remodel" their GJs. Within 1 to 5 hours post-PH, midzonal hepatocytes exhibited diffuse membrane staining different from the normal punctate distribution. Subsequently, midzonal hepatocytes expressed colocalized punctate Cx32 and Cx26 immunostaining. Because the changes occurred in midzonal hepatocytes before 24 hours post-PH, near the peak of hepatocyte DNA synthesis, these findings indicate that Cx26 is enhanced in hepatocytes before the onset of S-phase. In contrast to the restricted expression of Cx43 in Glisson's capsule in adult liver, Cx43 protein and mRNA were enhanced specifically in proliferating bile duct and perisinusoidal cells post-PH. PH performed during continuous administration of 2-acetylaminofluorene (AAF) prevented changes in Cx32 and Cx26 staining observed in the absence of AAF. Proliferating oval cells were found to express diffuse Cx43 immunoreactivity. On day 11 post-PH and AAF, basophilic hepatocytes displayed both punctate Cx32 and Cx26 staining, whereas bile ducts and perisinusoidal cells expressed Cx43. These findings indicate that alterations in Cx32 and Cx26 expression occur rapidly in hepatocytes stimulated to proliferate and that several nonparenchymal liver cell types upregulate Cx43 expression when induced to proliferate. Differentiation of oval cells into basophilic hepatocytes resulted in their expression of Cx32 and Cx26.


Leucocytoclastic vasculitis associated with hepatitis C virus antibodies.
The actiopathogenesis of leucocytoclastic vasculitis is still unknown, but recently hepatitis C virus (HCV) has been suggested as trigger of autoimmunity. We report a case of a 26-yr-old patient with purpura due to leucocytoclastic vasculitis associated with hepatitis C virus infection. Laboratory findings showed AST, ALT, gamma GT within normal limits, positive antibodies to HCV (IIF and Riba II) and polymerase chain reaction for HCV RNA. Anti-nuclear antibodies, IgG and IgM anti-cardiolipin antibodies, anti-platelet antibodies and anti-neutrophil cytoplasmic antibodies with perinuclear pattern were also present. A skin biopsy specimen of a purpuric lesion showed leucocytoclastic vasculitis with small vessel thrombosis and perivascular deposition of IgM and fibrinogen on immunofluorescence study. This case shows a role of HCV in leucocytoclastic vasculitis; it is possible that this HCV can induce autoimmunity independently of cryoglobulins and liver involvement.


[The growth of Rhodotorula rubra yeasts and their synthesis of ergosterol on media with lovastatin].
The effect of lovastatin, a competing inhibitor of 3-hydroxy-3-methylglutaryl-CoA-reductase (HMG-CoA-reductase) of the fungal origin on the growth of and ergosterol biosynthesis by Rh. rubra VKPM Y 1337 was studied. It was shown that the yeast growth was inhibited by lovastatin in concentrations of 0.25 to 5.0 micrograms/ml when the inhibitor was added to the cultivation medium either with the inoculum or at later periods of the yeast cultivation. In concentrations of 2.0 to 5.0 micrograms/ml lovastatin almost completely inhibited the yeast growth. In the concentrations tested the inhibitor did not decrease the ergosterol level in the yeast cells below 40 per cent of the control. When lovastatin was added in concentrations of 1.0 to 5.0 micrograms/ml the maximum inhibition of the ergosterol biosynthesis was observed at the end of the growth log phase. Further cultivation of the yeast in the presence of the inhibitor resulted in an increase of the ergosterol biosynthesis. It is believed that the increase in the quantity of ergosterol may be due either to the HMG-CoA-reductase induction under the action of the inhibitor or to its inactivation as a result of the hydroxylation.


SREBP1, PPARG and AMPK pathways mediated the Cu-induced change in intestinal lipogenesis and lipid transport of yellow catfish Pelteobagrus fulvidraco.
Cu could act as a modifier and influence lipid metabolism, but the potential mechanism was not explored. Juvenile yellow catfish were fed diet containing 0.71 (low Cu), 3.93 (intermediate Cu) and 88.81 (high Cu) mg Cu kg-1, for 8 weeks to explore the modulation of intestinal lipid metabolism following dietary Cu addition. Using specific pathway inhibitors (Fatostatin for SREBP1, T0070907 for PPARG and Compound C for AMPK), primary enterocytes of yellow catfish were used to explore the molecular mechanisms of Cu reducing intestinal lipid deposition. Dietary Cu addition triggered Cu accumulation but suppressed lipid deposition in the fore- and mid-intestine. The reduced lipid deposition was attributable to the suppressed lipogenesis and lipid absorption, and accelerated lipid transport. The PPARG, SREBP1 and AMPK signaling pathways mediated the Cu-induced changes in lipogenesis, lipid uptake and lipid transport in the intestine of yellow catfish.


Application of the consolidated species concept to Cercospora spp. from Iran.
The genus Cercospora includes many important plant pathogenic fungi associated with leaf spot diseases on a wide range of hosts. The mainland of Iran covers various climatic regions with a great biodiversity of vascular plants, and a correspondingly high diversity of cercosporoid fungi. However, most of the cercosporoid species found to date have been identified on the basis of morphological characteristics and there are no cultures that support these identifications. In this study the Consolidated Species Concept was applied to differentiate Cercospora species collected from Iran. A total of 161 Cercospora isolates recovered from 74 host species in northern Iran were studied by molecular phylogenetic analysis. Our results revealed a rich diversity of Cercospora species in northern Iran. Twenty species were identified based on sequence data of five genomic loci (ITS, TEF1-α, actin, calmodulin and histone H3), host, cultural and morphological data. Six novel species, viz. C. convolvulicola, C. conyzae-canadensis, C. cylindracea, C. iranica, C. pseudochenopodii and C. sorghicola, are introduced. The most common taxon was Cercospora cf. flagellaris, which remains an unresolved species complex with a wide host range. New hosts were recorded for previously known Cercospora species, including C. apii, C. armoraciae, C. beticola, C. cf. richardiicola, C. rumicis, Cercospora sp. G and C. zebrina.


The acute effect of methylphenidate on cerebral blood flow in boys with attention-deficit/hyperactivity disorder.
Methylphenidate (MPH) is the most commonly prescribed treatment for attention-deficit/hyperactivity disorder (ADHD). The therapeutic mechanisms of MPH are not, however, fully understood. We studied the effects of MPH on brain activity in male children and adolescents with ADHD, using the blood flow radiotracer technetium-99m ethyl cysteinate dimer ((99m)Tc-ECD) and single-photon emission tomography (SPET). The study was randomized, double blind, and placebo controlled (MPH group, n=19; placebo group, n=17), Radiotracer was administered during the performance of the Continuous Performance Test and before and after 4 days of MPH treatment. Statistical parametric mapping (SPM99) analysis showed a significant reduction in regional cerebral blood flow in the left parietal region in the MPH group compared with the placebo group (P<0.05, corrected for multiple comparisons). Our findings suggest that the posterior attentional system, which includes the parietal cortex, may have a role in the mediation of the therapeutic effects of MPH in ADHD.


Activation status of cord blood gamma delta T cells reflects in utero exposure to Plasmodium falciparum antigen.
Placental Plasmodium falciparum infection modulates neonatal cell-mediated immune responses and is associated with increased susceptibility of infants to malaria. By flow-cytometric analysis of maternal peripheral and cord blood samples collected at delivery, we measured and compared the activation status and proinflammatory cytokine activity of T cells from women segregated into groups according to malaria status. Stimulation with phorbol myristate acetate/ionomycin resulted in the highest percentages of tumor necrosis factor-alpha- and interferon-gamma-positive gamma delta T cells in peripheral blood samples and in corresponding cord blood samples from those treated for malaria during pregnancy. Cord blood samples from this group also contained significantly higher percentages of CD69(+) and CD25(+) gamma delta T cells and CD3(+) T cells, compared with samples from either the group with active placental P. falciparum infection at delivery or the group with no infection. Proinflammatory cytokine activity of cells from the group with placental P. falciparum infection at delivery was either similar to or lower than that of cells from the group with no infection. The findings imply that treatment of P. falciparum malaria during pregnancy leads to enhanced innate immune T cell activation and proinflammatory cytokine responses in both maternal and fetal compartments. Ongoing placental P. falciparum infection, conversely, is associated with an absence of such activity.


The "Forgotten" Treatment of Alcohol Withdrawal Delirium With Electroconvulsive Therapy: Successful Use in a Very Prolonged and Severe Case.
Alcohol withdrawal delirium (AWD) is a notorious complication in alcohol withdrawal. Usually, the symptomatic treatment is efficacious; however, some patients show treatment resistance or a prolonged course of AWD. We report the case of a patient with a prolonged and severest form of AWD. Even 11 weeks after admission, he received approximately 100 mg diazepam per week to manage the symptoms of withdrawal delirium. A treatment course of electroconvulsive therapy was initiated, which allowed a complete tapering off of benzodiazepines during electroconvulsive therapy without adverse effects. The reported case might contribute to alternative approaches reserved for severest forms of prolonged AWD.


Spinopelvic pathways to bipedality: why no hominids ever relied on a bent-hip-bent-knee gait.
Until recently, the last common ancestor of African apes and humans was presumed to resemble living chimpanzees and bonobos. This was frequently extended to their locomotor pattern leading to the presumption that knuckle-walking was a likely ancestral pattern, requiring bipedality to have emerged as a modification of their bent-hip-bent-knee gait used during erect walking. Research on the development and anatomy of the vertebral column, coupled with new revelations from the fossil record (in particular, Ardipithecus ramidus), now demonstrate that these presumptions have been in error. Reassessment of the potential pathway to early hominid bipedality now reveals an entirely novel sequence of likely morphological events leading to the emergence of upright walking.


Assessing the Electronic Evidence System Needs of Canadian Public Health Professionals: Cross-sectional Study.
True evidence-informed decision-making in public health relies on incorporating evidence from a number of sources in addition to traditional scientific evidence. Lack of access to these types of data as well as ease of use and interpretability of scientific evidence contribute to limited uptake of evidence-informed decision-making in practice. An electronic evidence system that includes multiple sources of evidence and potentially novel computational processing approaches or artificial intelligence holds promise as a solution to overcoming barriers to evidence-informed decision-making in public health. This study aims to understand the needs and preferences for an electronic evidence system among public health professionals in Canada. An invitation to participate in an anonymous web-based survey was distributed via listservs of 2 Canadian public health organizations in February 2019. Eligible participants were English- or French-speaking individuals currently working in public health. The survey contained both multiple-choice and open-ended questions about the needs and preferences relevant to an electronic evidence system. Quantitative responses were analyzed to explore differences by public health role. Inductive and deductive analysis methods were used to code and interpret the qualitative data. Ethics review was not required by the host institution. Respondents (N=371) were heterogeneous, spanning organizations, positions, and areas of practice within public health. Nearly all (364/371, 98.1%) respondents indicated that an electronic evidence system would support their work. Respondents had high preferences for local contextual data, research and intervention evidence, and information about human and financial resources. Qualitative analyses identified several concerns, needs, and suggestions for the development of such a system. Concerns ranged from the personal use of such a system to the ability of their organization to use such a system. Recognized needs spanned the different sources of evidence, including local context, research and intervention evidence, and resources and tools. Additional suggestions were identified to improve system usability. Canadian public health professionals have positive perceptions toward an electronic evidence system that would bring together evidence from the local context, scientific research, and resources. Elements were also identified to increase the usability of an electronic evidence system.


Matching glass-forming ability with the density of the amorphous phase.
The density of the amorphous phase of metals is generally thought to be related to glass formation, but this correlation has not been demonstrated experimentally to date. In this work, systematic deflection measurements using microcantilevers and a combinatorial deposition method show a correlation between glass-forming ability and the density change upon crystallization over a broad compositional range in the copper-zirconium binary system. Distinct peaks in the density of the amorphous phase were found to correlate with specific maxima in the critical thickness for glass formation. Our findings provide quantitative data for the development of structural models of liquids that are readily quenched to the amorphous state. The experimental method developed in this work can facilitate the search for new glass-forming alloys.


Widespread disruption of genomic imprinting in adult interspecies mouse (Mus) hybrids.
Mammalian interspecies hybrids exhibit parent-of-origin effects in that offspring of reciprocal matings, even though genetically identical, frequently exhibit opposite phenotypes, especially in growth. This was also observed in hybridization with the genus Mus. These parent-of-origin effects suggested that imbalance in the expression of imprinted genes, which are expressed differentially, depending on their transmission through the maternal or paternal germline, and/or differential loss-of-imprinting (LOI) could underlie these opposite growth phenotypes in reciprocal mammalian hybrids. Here we report that tissue-specific LOI occurs in adult Mus hybrids. Contrary to expectations, LOI patterns were not consistent with a direct influence of altered expression levels of imprinted genes on growth. Bisulfite sequencing revealed that reactivation of maternal alleles of Peg3 and Snrpn in specific tissues was accompanied by partial demethylation at their potential imprinting control regions. We propose that abnormal reprogramming after fertilization and during preimplantation development is in part responsible for hybrid dysgenesis, for which a strong epigenetic basis has been demonstrated.


A qualitative study of interference with communicative participation across communication disorders in adults.
To explore the similarities and differences in self-reported restrictions in communicative participation across different communication disorders in community-dwelling adults. Interviews were conducted with 44 adults representing 7 different medical conditions: spasmodic dysphonia, multiple sclerosis, stroke, stuttering, Parkinson's disease, amyotrophic lateral sclerosis, and laryngectomy. This article represents a secondary analysis of qualitative data collected in cognitive interviews during development of the Communicative Participation Item Bank. The data were analyzed to identify themes in participants' experiences related to communicative participation. Participants described many situations in which they experienced interference in communicative participation. Two themes emerged from the data. The first theme was Interference is both "functional" and "emotional," in which participants defined interference as limitations in accomplishing tasks and emotional consequences. The second theme was "It depends"-sources of interference, in which participants described many variables that contribute to interference in participation. Participants had limited control of some variables such as symptoms and environmental contexts, but personal decisions and priorities also influenced participation. Despite different impairments and activity limitations, participants described similar communicative participation restrictions. These similarities may have theoretical and clinical implications in terms of how we assess, treat, and study the participation restrictions associated with communication disorders.


Cardiac transplantation outcomes in patients with amyloid cardiomyopathy.
Amyloid cardiomyopathy (ACM) is a progressive and life-threatening disease caused by abnormal protein deposits within cardiac tissue. The most common forms of ACM are caused by immunoglobulin derived light chains (AL) and transthyretin (TTR). Orthotopic heart transplantation (OHT) remains the definitive treatment for patients with end stage heart failure. In this study, we perform a contemporary multicenter analysis evaluating post OHT survival in patients with ACM. We conducted a multicenter analysis of 40,044 adult OHT recipients captured in the United Network for Organ Sharing (UNOS) registry from 1987-2018. Patients were characterized as ACM or non-ACM. Baseline characteristics were obtained, and summary characteristics were calculated. Outcomes of interest included post-transplant survival, infection, treated rejection, and the ability to return to work. Racial differences in OHT survival were also analyzed. Unadjusted associations between ACM and non-ACM survival were determined using the Kaplan-Meier estimations and confounding was addressed using multivariable Cox proportional hazards models. Three hundred ninety-eight patients with a diagnosis of ACM were identified of which 313 underwent heart only OHT. ACM patients were older (61 vs 53; P < .0001) and had a higher proportion of African Americans (30.7% vs 17.6%; P < .0001). Median survival for ACM was 10.2 years vs 12.5 years in non-ACM (P = .01). After adjusting for confounding, ACM patients had a higher likelihood of death post-OHT (HR 1.39 CI: 1.14, 1.70; P = .001). African American ACM patients had a higher likelihood of survival compared to White ACM patients (HR 0.51 CI 0.31-0.85; P = .01). No difference was observed in episodes of treated rejection (OR 0.63 CI 0.23, 1.78; P = .39), hospitalizations for infections (OR 1.24 CI: 0.85, 1.81; P = .26), or likelihood of returning to work for income (OR 1.23 CI: 0.84, 1.80; P = .30). In this analysis of OHT in ACM, ACM was associated with a higher likelihood of post-OHT mortality. Racial differences in post-OHT were observed with African American patients with ACM having higher likelihood of survival compared to White patients with ACM. No differences were observed in episodes of treated rejection, hospitalization for infection, or likelihood to return to work for income.


A framework for studying transient dynamics of population projection matrix models.
Empirical models are central to effective conservation and population management, and should be predictive of real-world dynamics. Available modelling methods are diverse, but analysis usually focuses on long-term dynamics that are unable to describe the complicated short-term time series that can arise even from simple models following ecological disturbances or perturbations. Recent interest in such transient dynamics has led to diverse methodologies for their quantification in density-independent, time-invariant population projection matrix (PPM) models, but the fragmented nature of this literature has stifled the widespread analysis of transients. We review the literature on transient analyses of linear PPM models and synthesise a coherent framework. We promote the use of standardised indices, and categorise indices according to their focus on either convergence times or transient population density, and on either transient bounds or case-specific transient dynamics. We use a large database of empirical PPM models to explore relationships between indices of transient dynamics. This analysis promotes the use of population inertia as a simple, versatile and informative predictor of transient population density, but criticises the utility of established indices of convergence times. Our findings should guide further development of analyses of transient population dynamics using PPMs or other empirical modelling techniques.


Chromatin remodeling at the Ig loci prior to V(D)J recombination.
Rearrangement of Ig H and L chain genes is highly regulated and takes place sequentially during B cell development. Several lines of evidence indicate that chromatin may modulate accessibility of the Ig loci for V(D)J recombination. In this study, we show that remodeling of V and J segment chromatin occurs before V(D)J recombination at the endogenous H and kappa L chain loci. In recombination-activating gene-deficient pro-B cells, there is a reorganization of nucleosomal structure over the H chain J(H) cluster and increased DNase I sensitivity of V(H) and J(H) segments. The pro-B/pre-B cell transition is marked by a decrease in the DNase I sensitivity of V(H) segments and a reciprocal increase in the nuclease sensitivity of Vkappa and Jkappa segments. In contrast, J(H) segments remain DNase I sensitive, and their nucleosomal organization is maintained in mu(+) recombination-activating gene-deficient pre-B cells. These results indicate that initiation of rearrangement is associated with changes in the chromatin structure of both V and J segments, whereas stopping recombination involves changes in only V segment chromatin. We further find an increase in histone H4 acetylation at both the H and kappa L chain loci at the pro-B cell stage. Although histone H4 acetylation appears to be an early change associated with B cell commitment, acetylation alone is not sufficient to promote subsequent modifications in Ig chromatin.


Real-time mobile monitoring of bipolar disorder: a review of evidence and future directions.
Rapidly accumulating data from mobile assessments are facilitating our ability to track patterns of emotions, behaviors, biologic rhythms, and their contextual influences in real time. These approaches have been widely applied to study the core features, traits, changes in states, and the impact of treatments in bipolar disorder (BD). This paper reviews recent evidence on the application of both passive and active mobile technologies to gain insight into the role of the circadian system and patterns of sleep and motor activity in people with BD. Findings of more than two dozen studies converge in demonstrating a broad range of sleep disturbances, particularly longer duration and variability of sleep patterns, lower average and greater variability of motor activity, and a shift to later peak activity and sleep midpoint, indicative of greater evening orientation among people with BD. The strong associations across the domains tapped by real-time monitoring suggest that future research should shift focus on sleep, physical/motor activity, or circadian patterns to identify common biologic pathways that influence their interrelations. The development of novel data-driven functional analytic tools has enabled the derivation of individualized multilevel dynamic representations of rhythms of multiple homeostatic regulatory systems. These multimodal tools can inform clinical research through identifying heterogeneity of the manifestations of BD and provide more objective indices of treatment response in real-world settings. Collaborative efforts with common protocols for the application of multimodal sensor technology will facilitate our ability to gain deeper insight into mechanisms and multisystem dynamics, as well as environmental, physiologic, and genetic correlates of BD.


Patterning the embryonic pulmonary mesenchyme.
Smooth muscle guides the morphogenesis of several epithelia during organogenesis, including the mammalian airways. However, it remains unclear how airway smooth muscle differentiation is spatiotemporally patterned and whether it originates from transcriptionally distinct mesenchymal progenitors. Using single-cell RNA-sequencing of embryonic mouse lungs, we show that the pulmonary mesenchyme contains a continuum of cell identities, but no transcriptionally distinct progenitors. Transcriptional variability correlates with spatially distinct sub-epithelial and sub-mesothelial mesenchymal compartments that are regulated by Wnt signaling. Live-imaging and tension-sensors reveal compartment-specific migratory behaviors and cortical forces and show that sub-epithelial mesenchyme contributes to airway smooth muscle. Reconstructing differentiation trajectories reveals early activation of cytoskeletal and Wnt signaling genes. Consistently, Wnt activation induces the earliest stages of smooth muscle differentiation and local accumulation of mesenchymal F-actin, which influences epithelial morphology. Our single-cell approach uncovers the principles of pulmonary mesenchymal patterning and identifies a morphogenetically active mesenchymal layer that sculpts the airway epithelium.


Disparities in Access to Preemptive Repeat Kidney Transplant: Still Missing the Mark?
The need for repeat transplant due to failing kidney allografts is increasing over time. The benefit of preemptive kidney retransplant (PKre-T) is controversial. Marginalized populations are less likely to undergo their first transplant preemptively; however, whether inequities exist for those undergoing PKre-T is unknown. We performed a cohort study of adult patients undergoing live and deceased kidney transplant in the United States from 2000 to 2018 identified using the Scientific Registry of Transplant Recipients, and we identified patients with first preemptive kidney transplant (PKT) and PKre-T. In the primary analysis, a multivariable logistic regression was used to identify independent predictors of PKre-T. In secondary analyses, multivariable Cox models were used to determine the association of PKre-T with death-censored and all-cause graft loss. In total, 4910 (15.5%) patients underwent PKre-T, and 43,293 (19.1%) underwent first PKT. Inequities in access to PKre-T persisted (OR, 0.49; 95% CI, 0.44 to 0.55 for unemployed versus full time; OR, 1.61; 95% CI, 1.14 to 2.25 for graduate school versus not completing high school; OR, 0.61; 95% CI, 0.52 to 0.70 for Black versus White race); 7.1% of all transplanted Black patients received PKre-T versus 17.4% of White patients. Women were more likely to undergo PKre-T than men (OR, 1.42; 95% CI, 1.29 to 1.57). PKre-T was associated with superior graft survival relative to retransplant after a period of dialysis (HR, 0.73; 95% CI, 0.67 to 0.80 for all-cause graft failure; HR, 0.72; 95% CI, 0.65 to 0.81 for death-censored graft loss). Despite improved patient and graft survival, inequities in access to PKre-T persist. Patients with lower education, patients with reduced employment status, patients of Black race, and men are less likely to receive PKre-T.


Intestinal Microbiome in Irritable Bowel Syndrome before and after Gut-Directed Hypnotherapy.
Irritable bowel syndrome (IBS) is a disorder with brain-gut-microbiome alterations. Gut-directed hypnotherapy (GHT) has been shown to improve quality of life and symptoms in IBS. This therapy targets psychological coping, central nervous processing and brain-gut interaction. Studies have also demonstrated effects of hypnosis on intestinal transit and the mucosal immune system. So far, no study has examined the effect of GHT on the intestinal microbiome. This study aimed at examining microbial composition, IBS symptoms, and psychological distress before and after GHT. Fecal samples were collected from 38 IBS patients (Rome-III criteria, mean age 44 years, 27 female, 11 male, 22 diarrhea-dominant, 12 alternating-type and 4 constipation-dominant IBS) before and after 10 weekly group sessions of GHT. Assessments in psychological (perceived stress, PSQ; psychological distress, HADS-D; quality of life, visual analogue scales) and IBS symptom-related variables (IBS severity, IBS-SSS; single symptoms, visual analogue scales) were performed with validated questionnaires. Fecal samples underwent microbial 16S rRNA analyses (regions V1⁻2). Microbial alpha diversity was stable before and after GHT (chao1 2591 ± 548 vs. 2581 ± 539, p = 0.92). No significant differences were found in relative bacterial abundances but trends of reduced abundance of Lachnospiraceae 32.18 (4.14⁻39.89) Median (Q1⁻Q3) vs. 28.11 (22.85; 35.55) and Firmicutes: Bacteroidetes ratio after GHT were observable. Significant reductions in symptom severity (323 (266⁻371) vs. 264 (191⁻331), p = 0.001) and psychological distress 17.0 (12.6⁻21.8) vs. 12.0 (8.3⁻18.0), p = 0.001, and increased well-being were found after GHT. Adequate relief after therapy was reported by 32 (84%) patients. Reductions in IBS symptoms and psychological burden were observed after gut-directed hypnotherapy, but only small changes were found in intestinal microbiota composition. The findings suggest that hypnosis may act by central nervous impact and other factors largely independent from microbiota composition modulating the brain-gut axis, possibly alterations in vagus nerve functioning and microbiota metabolism.


pH gradients in the developing teeth of young mice from autoradiography of [14C]DMO.
The distribution of the weak acid [14C]DMO was studied in mice, 10-19 days old, by an autoradiographic technique that does not translocate or remove the compound. Calculations of pH values in areas of the developing teeth of these animals were made by comparing the photometric density of the distribution of [14C]DMO, as an indicator of pH, with that of 14C]NAAP, as an indicator of water content, which was reported in the companion paper. The cellular layers, i.e., odontoblasts, ameloblasts, etc., had pH values of 7.1 +/- 0.1; the pH values in enamel, predentine, and dentine ranged from 7.3 to 8.5. It is suggested that an alkaline matrix promotes nucleation and growth of hydroxyapatite.


Spatial and temporal features of afferent inhibition of thalamocortical relay cells.
1. The temporal and spatial features of the afferent inhibition of thalamocortical relay (TCR) cells in the ventrobasal complex of the thalamus have been examined using paired conditioning and test air jets. 2. The response of TCR units to air jets may be divided into three parts: a) an early response of 1--6 impulses, which begins after a latency of 8--10 ms and lasts for 10--25 ms; b) a period of 70--80 ms following the early response, during which the spontaneous activity is inhibited; and c) a period of late activity, which follows the inhibitory period. 3. The inhibition of TCR units generated by an air jet lasts about 80 ms. The time course of inhibition is the same in hair units and in units activated by Pacinian corpuscles. Evidence is presented that suggests that inhibition decays at the same rate throughout the inhibitory receptive field. 4. The spatial features of inhibition demonstrated in this study are: a) that the excitatory and inhibitory receptive-field centers coincide; b) that these fields have different shape; and c) that there is a significant area in which the inhibitory receptive field surrounds the excitatory receptive field.