Plasma luminescence from femtosecond filaments in air: evidence for impact excitation with circularly polarized light pulses.
Filaments produced in air by intense femtosecond laser pulses emit UV luminescence from excited N(2) and N(2)(+) molecules. We report on a strong dependence at high intensities (I≥1.4×10(14) W/cm(2)) of this luminescence with the polarization state of the incident laser pulses. We attribute this effect to the onset of new impact excitation channels from energetic electrons produced with circularly polarized laser pulses above a threshold laser intensity.


Environmental perturbations lead to extensive directional shifts in RNA processing.
Environmental perturbations have large effects on both organismal and cellular traits, including gene expression, but the extent to which the environment affects RNA processing remains largely uncharacterized. Recent studies have identified a large number of genetic variants associated with variation in RNA processing that also have an important role in complex traits; yet we do not know in which contexts the different underlying isoforms are used. Here, we comprehensively characterized changes in RNA processing events across 89 environments in five human cell types and identified 15,300 event shifts (FDR = 15%) comprised of eight event types in over 4,000 genes. Many of these changes occur consistently in the same direction across conditions, indicative of global regulation by trans factors. Accordingly, we demonstrate that environmental modulation of splicing factor binding predicts shifts in intron retention, and that binding of transcription factors predicts shifts in alternative first exon (AFE) usage in response to specific treatments. We validated the mechanism hypothesized for AFE in two independent datasets. Using ATAC-seq, we found altered binding of 64 factors in response to selenium at sites of AFE shift, including ELF2 and other factors in the ETS family. We also performed AFE QTL mapping in 373 individuals and found an enrichment for SNPs predicted to disrupt binding of the ELF2 factor. Together, these results demonstrate that RNA processing is dramatically changed in response to environmental perturbations through specific mechanisms regulated by trans factors.


Matryoshka locally resonant sonic crystal.
The results of numerical modeling of sonic crystals with resonant array elements are reported. The investigated resonant elements include plain slotted cylinders as well as their various combinations, in particular, Russian doll or Matryoshka configurations. The acoustic band structure and transmission characteristics of such systems have been computed with the use of finite element methods. The general concept of a locally resonant sonic crystal is proposed that utilizes acoustic resonances to form additional band gaps that are decoupled from Bragg gaps. An existence of a separate attenuation mechanism associated with the resonant elements that increases performance in the lower frequency regime has been identified. The results show a formation of broad band gaps positioned significantly below the first Bragg frequency. For low frequency broadband attenuation, a most optimal configuration is the Matryoshka sonic crystal, where each scattering unit is composed of multiple concentric slotted cylinders. This system forms numerous gaps in the lower frequency regime, below Bragg bands, while maintaining a reduced crystal size viable for noise barrier technology. The finding opens alternative perspectives for the construction of sound barriers in the low frequency range usually inaccessible by traditional means including conventional sonic crystals.


The duration dilemma in opioid agonist therapy.
Studies dating back to 1964 consistently support the effectiveness of methadone as a maintenance treatment for opioid use disorder (OUD), and since 2003, the effectiveness of buprenorphine. Short-term detoxification has not proven to be an effective treatment, as it results in high relapse rates when compared with maintenance treatment with an opioid agonist therapy (OAT). The question about the duration of maintenance treatment for OUD has been debated with recommendations ranging from a minimum of 1 year, 2 years, to indefinitely. Other factors such as misconceptions, regulations, and insurance barriers also have an impact on the duration dilemma of OAT. There were no a priori criteria for article inclusion and this is not a structured literature review. It is a review of articles of convenience from 1964 to 2018. This paper aims to address the dilemma of the ideal duration of OAT and to discuss the factors that could affect this decision. Sustained OAT has had significantly better long-term outcomes than short-term detoxification or time limited maintenance. Optimal outcomes are dependent on adequate treatment duration. Addiction is a chronic brain disease and its treatment should be similar to the treatment of other chronic medical and psychiatric diseases. Long-term, sometimes lifetime, continuation of OAT for the treatment of OUD results in optimal outcomes when measuring morbidity and mortality. The accumulated evidence does not support any arbitrary limitation to the duration of OAT.


Electrophysiological correlates of reinforcement learning in young people with Tourette syndrome with and without co-occurring ADHD symptoms.
Altered reinforcement learning is implicated in the causes of Tourette syndrome (TS) and attention-deficit/hyperactivity disorder (ADHD). TS and ADHD frequently co-occur but how this affects reinforcement learning has not been investigated. We examined the ability of young people with TS (n=18), TS+ADHD (N=17), ADHD (n=13) and typically developing controls (n=20) to learn and reverse stimulus-response (S-R) associations based on positive and negative reinforcement feedback. We used a 2 (TS-yes, TS-no)×2 (ADHD-yes, ADHD-no) factorial design to assess the effects of TS, ADHD, and their interaction on behavioural (accuracy, RT) and event-related potential (stimulus-locked P3, feedback-locked P2, feedback-related negativity, FRN) indices of learning and reversing the S-R associations. TS was associated with intact learning and reversal performance and largely typical ERP amplitudes. ADHD was associated with lower accuracy during S-R learning and impaired reversal learning (significantly reduced accuracy and a trend for smaller P3 amplitude). The results indicate that co-occurring ADHD symptoms impair reversal learning in TS+ADHD. The implications of these findings for behavioural tic therapies are discussed.


Genomic insights into salt adaptation in a desert poplar.
Despite the high economic and ecological importance of forests, our knowledge of the genomic evolution of trees under salt stress remains very limited. Here we report the genome sequence of the desert poplar, Populus euphratica, which exhibits high tolerance to salt stress. Its genome is very similar and collinear to that of the closely related mesophytic congener, P. trichocarpa. However, we find that several gene families likely to be involved in tolerance to salt stress contain significantly more gene copies within the P. euphratica lineage. Furthermore, genes showing evidence of positive selection are significantly enriched in functional categories related to salt stress. Some of these genes, and others within the same categories, are significantly upregulated under salt stress relative to their expression in another salt-sensitive poplar. Our results provide an important background for understanding tree adaptation to salt stress and facilitating the genetic improvement of cultivated poplars for saline soils.


[High-dosage chemotherapy in primary metastasized and relapsed Ewing's sarcoma. (EI)CESS].
Patients (pts) with primary metastatic Ewing tumours (ET) have a poor prognosis for event free survival (EFS) compared to pts with localised disease. Following relapse the prognosis is extremely poor. Therefore these primary metastatic and relapsed pts were piloted for high dose therapy (HDT) for the last years. Between April 1984 and May 1997, 131 ET pts who underwent HDT were registered in the German CESS/EICESS office: 79 pts with primary metastases and 52 pts with relapsed tumours. After induction therapy, consisting of chemotherapy and local therapy, pts received high dose regimens, mainly based on melphalan and/or etoposide (92%). Stem cell rescue was applied from allogeneic bone marrow (n = 13), autologous bone marrow (n = 17), or peripheral blood stem cells (n = 95). The date of analysis was September 1st, 1998. Outcome was calculated by Kaplan-Meier-analyses. The median time under study since high dose therapy was 3.7 years. 35/131 pts (26.7%) were in continuous complete remission, 80/131 pts (61.1%) had relapsed or progressed, 11/131 pts (8.4%) died of complications and 5/131 pts (3.8%) presented with secondary malignancies. For the total group of primary metastatic pts, EFS five years after diagnosis was 19% for pts with HDT and 27% for those without (p = 0.9209). The subgroup of pts with primary lung and bone metastases seemed to benefit from HDT (EFS five years after diagnosis: 34% versus 5%, p = 0.0001). Outcome of pts with an early ET relapse (< 2 years) was also improved by HDT (EFS four years after relapse: 17% versus 2%, p = 0.0001). The total group of primary metastatic ET pts showed no obvious benefit from HDT, based on melphalan and/or etoposide. Pts with metastases to multiple organ systems, and early relapse seemed to benefit from HDT. The value of HDT should be assessed in prospective clinical trials.


Morbidity of oral mucosa graft harvesting from a single cheek.
The oral mucosa (OM) is a popular substitute for urethroplasty. The aim of this study was to investigate oral morbidity and patient satisfaction in a homogeneous group of patients who underwent OM harvesting. This study is a prospective analysis of 350 patients who underwent OM harvesting from a single cheek. The graft was harvested in an ovoid shape with closure of the wound. Standard graft size was 4 cm in length and 2.5 cm in width. Self-administered, nonvalidated semiquantitative (0, absence of complications or symptoms; 3, the worst complication or symptom) questionnaire consisting of six questions was used to investigate early complications, with 13 questions designed to investigate late complications and patient satisfaction. Early complications included bleeding, which occurred in 15 patients (4.3%); two patients required immediate surgical revision of the harvesting site. The majority of patients (85.2%) showed no pain, and only 3.7% of patients required use of anti-inflammatory drugs. The majority of patients (65.8%) showed slight or moderate swelling. With respect to late complications, most of the patients (73.4%) reported oral numbness for 1 wk, 22.9% for 1 mo, and 3.77% for 3 mo. Numbness resulting from scarring was absent or slight in most of patients. Changes in oral sensitivity occurred in 2.3% of patients. No difficulties opening the mouth or smiling was found in 98.3% and 99.7% of patients, respectively. Slight or moderate dry mouth was found in 97.1% of patients. In response to the question, "Would you undergo oral mucosa graft harvesting using this technique again," 343 patients (98%) replied "yes," and 7 patients (2%) replied "no." The harvesting of an OM ovoid graft from a cheek with closure of the wound is a safe procedure with a high patient satisfaction rate.


A theoretical study of the UV/visible absorption and emission solvatochromic properties of solvent-sensitive dyes.
Using the density-functional vertical self-consistent reaction field (VSCRF) solvation model, incorporated with the conductor-like screening model (COSMO) and the self-consistent reaction field (SCRF) methods, we have studied the solvatochromic shifts of both the absorption and emission bands of four solvent-sensitive dyes in different solutions. The dye molecules studied here are: S-TBA merocyanine, Abdel-Halim's merocyanine, the rigidified amino-coumarin C153, and Nile red. These dyes were selected because they exemplify different structural features likely to impact the solvent-sensitive fluorescence of "push-pull", or merocyanine, fluorophores. All trends of the blue or red shifts were correctly predicted, comparing with the experimental observations. Explict H-bonding interactions were also considered in several protic solutions like H2O, methanol and ethanol, showing that including explicit H-bonding solvent molecule(s) in the calculations is important to obtain the correct order of the excitation and emission energies. The geometries, electronic structures, dipole moments, and intra- and intermolecular charge transfers of the dyes in different solvents are also discussed.


Proof-of-concept study of an aerobic vapor migration barrier beneath a building at a petroleum hydrocarbon-impacted site.
A proof-of-concept study was conducted to evaluate an alternative to traditional extraction-based subslab vapor mitigation systems at sites with petroleum hydrocarbon and/or methane vapor impact concerns. The system utilizes the slow delivery of air beneath a foundation to attenuate vapor migration to the building via aerobic biodegradation. The study was conducted at a site having elevated hydrocarbon plus methane and depleted O(2) vapor concentrations (160 mg/L and <1% v/v, respectively) beneath a building having a 195 m(2) footprint and a basement extending 1.5 m below ground surface (BGS). Nonaqueous phase liquid (NAPL)-impacted soils, first encountered at about 7.6 to 9.1 m BGS, were the source of hydrocarbon and methane vapors, with the latter being generated by anaerobic methanagenesis of the former. O(2) concentrations beneath and around the building were monitored prior to and during air injection through a horizontal well installed about 1.5 m beneath the foundation. The air injection rate was increased from 1 to 5 to 10 L/min, with each held steady until the O(2) distribution stabilized (46-60 d). The 10 L/min flow rate achieved >5% v/v soil gas O(2) concentrations beneath the foundation and spanning a 1.5 m vertical interval. It was within 3× of the pretest stoichiometric requirement estimate of 3.8 L/min. This resulted in reductions in subslab hydrocarbon plus methane concentrations from 80 to <0.01 mg/L and benzene, toluene, ethylbenzene, and xylenes (BTEX) reductions to below detection limits (0.5-0.74 ppb(v)). This air injection rate is <1% of flows for typical extraction-based mitigation systems.


Docetaxel in 253 previously treated patients with progressive locally advanced or metastatic breast cancer: results of a compassionate use program in The Netherlands.
The aims of this study were to evaluate the efficacy and safety of docetaxel (Taxotere) in patients with progressive locally advanced or metastatic breast cancer, previously treated with at least one chemotherapy regimen, and the effect of the number of previous chemotherapy lines on response rate, progression-free survival and overall survival. Two-hundred and fifty-three patients from 10 hospitals in The Netherlands received docetaxel as part of a compassionate use program. The majority had received prior anthracycline-containing chemotherapy (84.2%). The recommended starting dose was 100 mg/m2 i.v. every 3 weeks. All patients received corticosteroid premedication. Two-hundred and thirty patients were evaluable for response. The overall response rates (ORR) to docetaxel when used as second-, third- or fourth-line treatment were, respectively, 40.2, 26.0 and 34.6% (p value 0.30). The median progression-free survival for this population was 4.9 months and the median overall survival of the whole group was 8.5 months, and both were not related to the number of previous chemotherapy regimens (p value, respectively, 0.71 and 0.16). The toxicity of docetaxel was manageable and neutropenia was the most frequently noted toxicity. This study confirms that docetaxel is an active cytotoxic agent in pretreated patients with progressive locally advanced or metastatic breast cancer and is still active when used as third- or fourth-line treatment.


Apoptotic mechanisms in Alzheimer neurofibrillary degeneration: cause or effect?
Increasing evidence suggests that selective neuronal loss in neurodegenerative diseases involves activation of cysteine aspartyl proteases (caspases), which initiate and execute apoptosis. In Alzheimer disease both extracellular amyloid deposits and intracellular amyloid beta protein may activate caspases, leading to cleavage of nuclear and cytoskeletal proteins, including tau protein. Proteolysis of tau may be critical to neurofibrillary degeneration, which correlates with dementia.


[Gender-specific predictors of institutionalisation in the elderly--results of the Leipzig longitudinal study of the aged (LEILA 75+)].
Especially given the different socialization and life conditions of men and women, it could not be assumed that factors leading to nursing home admission (NHA) can be equally applied to both genders. We aimed to determine gender-specific predictors of NHA. Data were derived from the Leipzig Longitudinal Study of the Aged, a population-based study of individuals aged 75 years and older. 1,058 older adults were interviewed six times on average every 1.4 years. Sociodemographic, clinical, and psychometric variables were obtained. Cox proportional hazards regression was used to determine predictors of NHA. 10.3 % of men and 19.5 % of women (p < 0.001) were admitted to nursing home during the study period. The mean time to nursing home was 7.2 years for men and 6.8 years for women. Characteristics associated with a shorter time to NHA were increased age for men and women; cognitive impairment, poor self-rated health status, and less than two specialist's visits in the preceding 12 months for women, and being unmarried, moderate educational status, and hospitalization in the preceding 12 months were predictors of NHA for men. Gender differences in prediction of NHA do actually exist. The inclusion of gender-specific factors in design and application of interventions to support individuals at home and delay or prevent NHA appears to be warranted.


Experiences and Translatability of In Vitro and In Vivo Models to Evaluate Caprate as a Permeation Enhancer.
Transient permeation enhancers (PEs) have been widely used to improve the oral absorption of macromolecules. During pharmaceutical development, the correct selection of the macromolecule, PE, and the combination needs to be made to maximize oral bioavailability and ensure successful clinical development. Various in vitro and in vivo methods have been investigated to optimize this selection. In vitro methods are generally preferred by the pharmaceutical industry to reduce the use of animals according to the "replacement, reduction, and refinement" principle commonly termed "3Rs," and in vitro methods typically have a higher throughput. This paper compares two in vitro methods that are commonly used within the pharmaceutical industry, being Caco-2 and an Ussing chamber, to two in vivo models, being in situ intestinal instillation to rats and in vivo administration via an endoscope to pigs. All studies use solution formulation of sodium caprate, which has been widely used as a PE, and two macromolecules, being FITC-dextran 4000 Da and MEDI7219, a GLP-1 receptor agonist peptide. The paper shares our experiences of using these models and the challenges with the in vitro models in mimicking the processes occurring in vivo. The paper highlights the need to consider these differences when translating data generated using these in vitro models for evaluating macromolecules, PE, and combinations thereof for enabling oral delivery.


Energy input from quasars regulates the growth and activity of black holes and their host galaxies.
In the early Universe, while galaxies were still forming, black holes as massive as a billion solar masses powered quasars. Supermassive black holes are found at the centres of most galaxies today, where their masses are related to the velocity dispersions of stars in their host galaxies and hence to the mass of the central bulge of the galaxy. This suggests a link between the growth of the black holes and their host galaxies, which has indeed been assumed for a number of years. But the origin of the observed relation between black hole mass and stellar velocity dispersion, and its connection with the evolution of galaxies, have remained unclear. Here we report simulations that simultaneously follow star formation and the growth of black holes during galaxy-galaxy collisions. We find that, in addition to generating a burst of star formation, a merger leads to strong inflows that feed gas to the supermassive black hole and thereby power the quasar. The energy released by the quasar expels enough gas to quench both star formation and further black hole growth. This determines the lifetime of the quasar phase (approaching 100 million years) and explains the relationship between the black hole mass and the stellar velocity dispersion.


Toxicity of Plant Secondary Metabolites Modulating Detoxification Genes Expression for Natural Red Palm Weevil Pesticide Development.
This study aimed to explore the larvicidal and growth-inhibiting activities, and underlying detoxification mechanism of red palm weevil against phenylpropanoids, an important class of plant secondary metabolites. Toxicity of α-asarone, eugenol, isoeugenol, methyl eugenol, methyl isoeugenol, coumarin, coumarin 6, coniferyl aldehyde, diniconazole, ethyl cinnamate, and rosmarinic acid was evaluated by incorporation into the artificial diet. All of the phenylpropanoids exhibited dose- and time-dependent insecticidal activity. Among all the tested phenylpropanoids, coumarin exhibited the highest toxicity by revealing the least LD50 value (0.672 g/L). In addition, the most toxic compound (coumarin) observed in the current study, deteriorated the growth resulting tremendous reduction (78.39%) in efficacy of conversion of digested food (ECD), and (ECI) efficacy of conversion of ingested food (70.04%) of tenth-instar red palm weevil larvae. The energy-deficient red palm weevil larvae through their intrinsic abilities showed enhanced response to their digestibility resulting 27.78% increase in approximate digestibility (AD) compared to control larvae. The detoxification response of Rhynchophorus ferrugineus larvae determined by the quantitative expression of cytochrome P450, esterases, and glutathione S-transferase revealed enhanced expression among moderately toxic and ineffective compounds. These genes especially cytochrome P450 and GST detoxify the target compounds by enhancing their solubility that leads rapid excretion and degradation resulting low toxicity towards red palm weevil larvae. On the other hand, the most toxic (coumarin) silenced the genes involved in the red palm weevil detoxification mechanism. Based on the toxicity, growth retarding, and masking detoxification activities, coumarin could be a useful future natural red palm weevil-controlling agent.


Quality image metrics for synthetic images based on perceptual color differences.
Due to the improvement of image rendering processes, and the increasing importance of quantitative comparisons among synthetic color images, it is essential to define perceptually based metrics which enable to objectively assess the visual quality of digital simulations. In response to this need, this paper proposes a new methodology for the determination of an objective image quality metric, and gives an answer to this problem through three metrics. This methodology is based on the LLAB color space for perception of color in complex images, a modification of the CIELab1976 color space. The first metric proposed is a pixel by pixel metric which introduces a local distance map between two images. The second metric associates, to a pair of images, a global value. Finally, the third metric uses a recursive subdivision of the images to obtain an adaptative distance map, rougher but less expensive to compute than the first method.


Identification of OmpR: a positive regulatory protein controlling expression of the major outer membrane matrix porin proteins of Escherichia coli K-12.
We report here on the cloning of a gene located within the ompB locus of E. coli K-12. This gene, designated ompR, resides on a 10.9-kilobase EcoRI fragment that we cloned, using a lambda vector and in vitro packaging techniques. By subcloning portions of this fragment into the high-copy-number plasmid pBR322, we have isolated the ompR gene on a 1.4-kilobase EcoRI-AvaI fragment. This fragment has been characterized physically and will facilitate a more detailed study of the role and mechanism of porin regulation by the ompB locus.


Preliminary evaluation of sensititre system for identifying gram-negative bacilli.
The automated microdilution Sensititre System (Sensititre, LtD.) was evaluated for the identification of 120 clinically isolated fermenter and non-fermenter Gram negative bacilli and of 12 ATCC reference strains (American Type Culture Collection). Daily and overnight (5 and 18 hours) identifications were performed according to the manufacturer. In both cases, the results were compared with those obtained with the overnight API 20E (API System, La Balme les Grottes, Montalieu Vercieu) used as reference method. Concordance between the results obtained after 5 hrs of incubation and those obtained with API 20E was found in 65% of cases (acceptable identification criteria with probability over 80%). When results were determined after 18 hrs of incubation (identification criteria with probably over 80%) concordance was found in 82.5%. Reproducibility obtained by repeated (10 times) identification with four different strains was 100% both at 5 hrs and 18 hrs. Identification accuracy of the 12 ATCC strains was 8/12 (66.6%) after 5 hrs and 12/12 (100%) after 18 hrs.


Home-based cardiac rehabilitation: development, implementation and outcome evaluation in patients with coronary artery diseases in Lahore, Pakistan - a mixed-methods study protocol.
Cardiac rehabilitation (CR) is an important strategy to bring cardiac patients back to a normal life after a cardiac event. The benefits of CR as part of secondary prevention are widely known among people who have undergone myocardial infarction or revascularisation. As evidenced by several systematic reviews and meta-analyses, home-based CR (HBCR) has similar or greater effects on health-related quality of life, health outcomes, physical activity, anxiety and unplanned visits to the emergency department as compared with centre-based CR. The purpose of this study is to develop a contextual HBCR intervention and evaluate its effects on quality of life, health behaviours, bio-physiological parameters and emergency hospital visits of patients with coronary artery diseases in Lahore, Pakistan. This study will employ a mixed-method exploratory sequential research design. The researchers will invite 15-20 cardiac patients and 12-15 healthcare providers for semi-structured interviews in the qualitative phase of the study. Once the intervention is developed and validated through the qualitative phase, the outcomes will be evaluated through a single-blinded randomised control trial in the quantitative phase. A total of 118 patients with acute coronary syndrome will be recruited through a screening checklist and randomly allocated into the control and intervention groups (59 patients in each group). The inductive coding approach will be used for the thematic analysis of qualitative data, whereas the quantitative data will be analysed through descriptive and inferential statistics using SPSS to see the difference within the groups, between groups and between three intervals. The Ethical Review Committee of Aga Khan University and Mayo Hospital Lahore under the registration number 2023-8282-24191 and No/75749MH have approved this study protocol, respectively. The results of this study will be disseminated to participating patients (in the Urdu language), healthcare professionals and the public by publishing the manuscript in an open-access peer-reviewed journal and presenting it at different conferences. Australian New Zealand Clinical Trial Registry (ACTRN12623000049673p).


Dissociation in response to methylphenidate on response variability in a group of medication naïve children with ADHD.
Increased variability in reaction time (RT) has been proposed as a cardinal feature of attention deficit hyperactivity disorder (ADHD). Increased variability during sustained attention tasks may reflect inefficient fronto-striatal and fronto-parietal circuitry; activity within these circuits is modulated by the catecholamines. A disruption to dopamine signaling is suggested in ADHD that may be ameliorated by methylphenidate (MPH). This study investigated the effects of MPH administration on the variability in RT and error performance on a sustained attention task of a group of 31 medication naïve children with ADHD, compared with 22 non-ADHD, non-medicated, control children. All children performed the fixed-sequence sustained attention to response task (SART) at two time-points: at baseline and after six weeks. The children with ADHD were tested when medication naive at baseline and after six weeks of treatment with MPH and whilst on medication. The medication naïve children with ADHD performed the SART with greater errors of commission and omission when compared with the control group. They demonstrated greater standard deviation of RT and fast moment-to-moment variability. They did not differ significantly from the control group in terms of slow variability in RT. MPH administration resulted in reduced and normalised levels of commission errors and fast, moment-to-moment variability in RT. MPH did not affect the rate of omission errors, standard deviation of RT or slow frequency variability in RT. MPH administration may have a specific effect on those performance components that reflect sustained attention and top-down control rather than arousal.


Prediction of inherited portosystemic shunts in Irish Wolfhounds on the basis of pedigree analysis.
To test validity of prediction for inherited portosystemic shunts (PSS) in Irish Wolfhounds, using nonselective clinical findings and a computerized database containing 5-generation pedigrees. 613 dogs in the first and 396 dogs in the second cohort. Preprandial venous ammonia concentration was measured at 6 to 8 weeks in all pups born between Jan 1, 1988 and Jan 1, 1997 Portosystemic shunts were confirmed in hyperammonemic pups, using radioisotope shunt index measurement, and diagnosis of shunting was confirmed at abdominal surgery or necropsy. Findings in dogs of the first cohort (born before Jan 1, 1992) were used to predict shunting in their offspring of the second cohort. Common ancestors of first-cohort dogs with shunts were tested for positive associations with the disease. Risk for a shunt in all second-cohort dogs was predicted on the basis of relatedness with founders and was compared with outcome of clinical screening. Prevalence of shunts in first and second cohorts was 3.1 and 2.3%, respectively. Fifteen highly related associated founders could be identified. Second-cohort dogs were classified into 6 groups of increasing predicted risk. Mean number of dogs per class was 60; number of clinically diagnosed cases ranged from 0 in the class with the lowest risk to 4 in the highest risk class. Genetic risk for reproducing a PSS in Irish Wolfhounds was accurate, using the described method. Risk estimation provides a tool for genetic counseling, does not require knowledge of the mode of inheritance, and may be valid for any inherited disease.


Antenatal steroid therapy for fetal lung maturation: is there an association with childhood asthma?
This study was designed to test the hypothesis that fetal exposure to corticosteroids in the antenatal period is an independent risk factor for the development of asthma in childhood. A population-based cohort study was conducted of all pregnant women who resided in Nova Scotia, Canada, and gave birth to a singleton fetus between January 1989 and December 1998 and lived to discharge. After exclusions, 79,395 infants were available for analysis. Using linked health care utilization records, incident asthma cases between 36 to 72 months of age were identified. Generalized Estimating Equations were used to estimate the odds ratio of the association between exposure to corticosteroids and asthma while controlling for confounders. Over the 10 years of the study corticosteroid therapy increased by threefold. Exposure to corticosteroids during pregnancy was associated with a risk of asthma in childhood: adjusted odds ratio of 1.23 (95% confidence interval: 1.06, 1.44). Antenatal steroid therapy appears to be an independent risk factor for the development of asthma between 36 and 72 months of age. Further research into the smallest possible steroid dose required to achieve the desired post-natal effect is needed to reduce the risk of developing childhood asthma.


Exposure of the extracellular matrix and colonization of the ovary in metastasis of fallopian-tube-derived cancer.
High-grade serous ovarian cancer (HGSOC) can originate in the fallopian tube epithelium (FTE), but the role of the ovary in these tumors is unclear. Tumorigenic murine oviductal epithelial (MOE) cells allografted in the ovarian bursa resulted in aggressive tumors that spread throughout the peritoneum whereas intraperitoneal xenografting the same number of cells did not form tumors, indicating that colonization of the ovary may play a role in metastasis. Physical tearing of the ovarian surface to mimic rupture of the ovary during ovulation (independent of hormonal changes) resulted in more MOE and HGSOC cells adhering to the ovary compared with intact ovaries. More MOE cells also adhered to three-dimensional (3D) collagen and primary ovarian stromal cells than to ovarian surface epithelia, indicating that FTE cells adhered to the extracellular matrix exposed during ovulation. However, plating cells on 3D collagen reduced the viability of normal FTE but not cancer cells. Mutation of p53 (R273H or R248W) and activation of Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) (G12V) did not increase the viability of MOE cells on 3D collagen. In contrast, loss of phosphatase and tensin homolog (PTEN) allowed MOE cells to retain normal viability on 3D collagen. Loss of PTEN activated AKT and RAC1/c-jun N-terminal kinase signaling that each contributed to the increased viability, invasion and attachment in the collagen rich ovarian microenvironment. These results show that loss of PTEN activates multiple pathways that together enhance colonization of the ovary due to access to 3D collagen, which is a critical organ in the colonization of FTE-derived HGSOC.


Carotid Atherosclerosis and Cerebral Microbleeds: The Framingham Heart Study.
Carotid atherosclerosis is associated with subclinical ischemic cerebrovascular disease, but its role in hemorrhage-prone small vessel disease-represented by cerebral microbleed (CMB)-is unclear, although vascular risk factors underlie both conditions. We hypothesized that persons with carotid atherosclerosis would have higher risk of CMB, particularly in deep regions. We studied 1243 participants in the Framingham Offspring Study (aged 56.9±8.8 years; 53% women) with carotid ultrasound available on 2 occasions (1995-1998 and 2005-2008) prior to brain magnetic resonance imaging. Using multivariable logistic regression, we related baseline carotid stenosis, baseline intima-media thickness, and site-specific carotid intima-media thickness progression (at internal and common carotid locations) to the prevalence and location (lobar or deep plus mixed) of CMB. In addition, we assessed effect modification by lipid levels and use of statin and antithrombotic medications. Carotid stenosis ≥25% (a marker of cerebrovascular atherosclerosis) was associated with presence of CMB overall (Odds Ratio 2.20, 95% CI 1.10-4.40) and at deep and mixed locations (odds ratio 3.60, 95% CI 1.23-10.5). Baseline carotid intima-media thickness was not associated with CMB. Progression of common carotid artery intima-media thickness among persons on hypertension treatment was associated with lower risk of deep and mixed CMB (odds ratio per SD 0.41, 95% CI 0.18-0.96). Cumulative vascular risk factor exposure may increase the risk of CMB, especially in deep regions. The apparent paradoxical association of carotid intima-media thickness progression with lower risk of CMB may reflect benefits of intensive vascular risk factor treatment among persons with higher cardiovascular risk and deserves further investigation. If replicated, the results may have potential implications for assessment of preventive and therapeutic interventions for subclinical cerebral hemorrhage.


In Vitro Differentiation of Mature Myofibers for Live Imaging.
Skeletal muscles are composed of myofibers, the biggest cells in the mammalian body and one of the few syncytia. How the complex and evolutionarily conserved structures that compose it are assembled remains under investigation. Their size and physiological features often constrain manipulation and imaging applications. The culture of immortalized cell lines is widely used, but it can only replicate the early steps of differentiation. Here, we describe a protocol that enables easy genetic manipulation of myofibers originating from primary mouse myoblasts. After one week of differentiation, the myofibers display contractility, aligned sarcomeres and triads, as well as peripheral nuclei. The entire differentiation process can be followed by live imaging or immunofluorescence. This system combines the advantages of the existing ex vivo and in vitro protocols. The possibility of easy and efficient transfection as well as the ease of access to all differentiation stages broadens the potential applications. Myofibers can subsequently be used not only to address relevant developmental and cell biology questions, but also to reproduce muscle disease phenotypes for clinical applications.


What safety measures need to be taken in oral food challenges in children?
Food allergens are often accused of causing numerous ailments. This is particularly true for the pediatric population, where the incidence of food allergy is four times as high as in adults. As food challenges may provoke life-threatening reactions, intensive safety measures need to be taken during provocation, and prompt medical intervention may become necessary. We retrospectively evaluated 349 oral challenges in 204 children with atopic dermatitis, looking for criteria to help the physician decide which patients need medical intervention. A total of 178 (51%) oral food challenges with the four allergens (cow's milk [CM], hen's egg [HE], wheat, and soy) showed a positive clinical reaction. Of these, 120 (67%) needed medical intervention. In 42 (35%) cases, intervention was parenteral, and oral medication was given in 78 (65%) cases. There was a strong positive correlation (90%) between the level of specific IgE and the need for medical intervention (> or = 17.50 kU/l for CM, wheat, and soy; > or = 3.50 kU/l for HE). Patient history of food allergy was an indicator of the need for medical intervention (P = 0.01). A positive patient history and a high level of specific IgE were significantly (P=0.003) associated with parenteral medication in HE. Patient history of food allergy is a reliable indicator of the need for medical intervention in the cases of CM, wheat, and soy regardless of the level of specific IgE. With HE, a positive patient history plus a high level of specific IgE significantly indicates the need for parenteral medication. On the basis of our results, we recommend establishing intravenous access in children with a level of specific IgE of > or = 17.50 kU/l (CAP class 4) to CM and wheat, or with specific IgE of > or =3.50 kU/l (CAP class 3) to HE.


An altered beta-adrenoreceptor-mediated modulation of noradrenaline-induced vasoconstriction in spontaneously hypertensive rat mesenteric arteries.
Pressor responses to bolus injections of noradrenaline (NA) were analysed, in the isolated perfused spontaneously hypertensive (SHR) rat mesenteric arterial bed, in an attempt to investigate the beta-adrenoreceptor-mediated modulation of catecholamine-induced vasoconstriction. NA-induced responses were potentiated in the presence of timolol (10(-7) M) and suppressed by (-)isoprenaline (10(-4) M), indicating the presence of a vasodilator beta-adrenoreceptor population. The suppressant effect of (-)isoprenaline (10(-4) M) was antagonised by timolol (10(-7) M). Lower doses of (-)isoprenaline (10(-7) M - 10(-5) M) potentiated the NA-induced pressor responses, while (+)isoprenaline (10(-5) M - 10(-4) M) suppressed the NA-induced responses. It is concluded that although a vasodilator beta-adrenoreceptor population exists in the SHR mesenteric vasculature, its vasodilator function is compromised when compared to that found in normotensive rats.


Predominant emphysema phenotype in chronic obstructive pulmonary.
Patients with fixed airflow limitation are grouped under the heading of chronic obstructive pulmonary disease (COPD). The authors investigated whether COPD patients have distinct functional, radiological and sputum cells characteristics depending on the presence or absence of emphysema. Twenty-four COPD outpatients, 12 with and 12 without emphysema on high-resolution computed tomography scan of the chest, were examined. Patients underwent chest radiography, pulmonary function tests and sputum induction and analysis. Subjects with documented emphysema had lower forced expiratory volume in one second (FEV1), FEV1/forced vital capacity ratio, and lower carbon monoxide diffusion constant (K(CO)), compared with subjects without emphysema. Chest radiograph score of emphysema was higher, chest radiograph score of chronic bronchitis was lower, and the number of sputum lymphocytes was increased in patients with emphysema, who also showed a negative correlation between K(CO) and pack-yrs. Chronic obstructive pulmonary disease patients with emphysema, documented by high-resolution computed tomography scan, have a different disease phenotype compared with patients without emphysema. Identification of chronic obstructive pulmonary disease-related phenotypes may improve understanding of the natural history and treatment of the disease.


Effects of a myotoxic phospholipase A2 isolated from Bothrops asper venom on skeletal muscle sarcoplasmic reticulum.
The myotoxin from B. asper snake venom inhibited Ca-ATPase activity of rabbit sarcoplasmic reticulum after incubation in vitro. Inhibition was non-competitive and albumin enhanced the effect of the toxin. Furthermore, B. asper myotoxin hydrolyzed sarcoplasmic reticulum phospholipids and induced a dose-dependent release of horseradish peroxidase that had been trapped in sarcoplasmic reticulum vesicles. Binding studies indicated that myotoxin does not bind to any particular protein of this membrane, suggesting that the toxin might interact with phospholipids. Inhibition of Ca-ATPase is probably a consequence of an alteration in sarcoplasmic reticulum phospholipids.


Hyperhomocysteinemia and B-vitamin deficiencies in infants and children.
Measurement of total homocysteine (tHcy) in healthy and diseased children has documented the utility of this marker in pediatric research and diagnostics. This article focuses on novel data obtained in infants, children and adolescents, with emphasis on cobalamin status in infants. In children, determinants of plasma tHcy are similar to those established in adults, and include age, gender, nutrition, B-vitamin status, and some drugs interfering with B-vitamin function. In infants (age < 1 year), tHcy is moderately elevated and related to serum cobalamin, whereas in older children and throughout childhood, plasma tHcy is low (about 60% of adult levels), and folate status becomes a strong tHcy determinant. As in adults, hyperhomocysteinemia in childhood is a risk factor for stroke, and folate-responsive hyperhomocysteinemia has been detected in children with renal failure. tHcy seems to be a sensitive indicator of folate deficiency in children on a poor diet, in HIV-infected children, and in children treated with anti-folate drugs. In children at increased risk of cobalamin deficiency, which includes children born to vegetarian mothers or children in developing countries on a poor diet, tHcy and methylmalonic acid are responsive indicators of a deficiency state. In newborns and infants born to mothers with an adequate nutrition, there are consistent observations of low cobalamin, elevated tHcy and methylmalonic acid, and reduction of both metabolites by cobalamin supplementation. These data have raised the question whether cobalamin deficiency may be widespread and undetected in babies born to non-vegetarian women on a Westernized diet.


Children With Type 1 Spinal Muscular Atrophy Are at Increased Risk for Nephrolithiasis.
Nephrolithiasis is not a well-documented condition in children with spinal muscular atrophy (SMA). It is possible that this condition was underestimated before the era of nusinersen because of a much shorter life expectancy. We present our observational data on nephrolithiasis and its possible risk factors in children with type 1 SMA. We retrospectively reviewed the charts of 20 children with genetically confirmed type 1 SMA. Thirteen patients (aged 9 to 55 months) who underwent urinary tract ultrasonography were included in the study. Medical records were retrospectively reviewed for demographic and clinical characteristics, ultrasound results, and metabolic abnormalities. Seven children (54%) had nephrolithiasis; 5 had multiple stones and two had a single stone. Two patients had microlithiasis (<3 mm), three had a stone in the size of 3 to 5 mm, and one had a stone in the size of more than 8 mm. Two patients with nephrolithiasis had urinary tract abnormalities. Patients with nephrolithiasis were more likely to have a history of urinary tract infections (UTIs) (P = 0.048) and higher urine specific gravity (P = 0.014) than patients without nephrolithiasis. Five of seven children with nephrolithiasis had a urine metabolic evaluation; all had hypercalciuria, three had hyperuricosuria, but none had hyperoxaluria, hypocitraturia, or hypomagnesemia. Children with SMA type 1 are at an increased risk for nephrolithiasis. Hypercalciuria and high urine specific gravity appear to be the most common risk factors for the occurrence of nephrolithiasis. In addition, UTI is more common in patients with type 1 SMA with nephrolithiasis.


Combination therapy with trastuzumab (Herceptin) and cisplatin for chemoresistant metastatic breast cancer: evidence for receptor-enhanced chemosensitivity.
The anti-HER-2/neu antibody trastuzumab (Herceptin; Genentech, San Francisco, CA) interferes with DNA repair induced by cisplatin and, as a result, promotes cytotoxicity in HER-2/neu-overexpressing tumor target cells in a synergistic fashion. This effect of trastuzumab, termed receptor-enhanced chemosensitivity, is specific for HER-2/neu-overexpressing cells, having no effect on cells without overexpression. Based on these findings, we conducted phase I and II clinical trials of trastuzumab plus cisplatin to determine the toxicity, pharmacokinetics, response rate, and response duration of this combination in patients with HER-2/neu-overexpressing metastatic breast cancer who had demonstrated disease progression (chemoresistance) while on active chemotherapy just prior to study entry. In phase I, four of 15 patients had objective clinical responses, including one complete response of several years' duration. Of 37 assessable patients enrolled in phase II, nine (24.3%) had objective clinical responses and an additional nine had minor responses or stable disease. The median time to progression among the responders was 8.4 months. The toxicity profile reflected that expected from cisplatin alone, with no apparent increase in toxicity caused by the addition of trastuzumab. Moreover, the pharmacokinetics of trastuzumab were unaltered by coadministration of cisplatin. We conclude that the combination of trastuzumab and cisplatin results in response rates higher than that reported for either single agent alone. Such receptor-enhanced chemosensitivity offers a new approach to target overexpressed growth factor receptors in a variety of cancers, which will lead to new, biologically based therapeutic strategies for clinical intervention.


Primary care and health. A cross-national comparison.
Ten Western industrialized nations were compared on the basis of three characteristics: the extent of their primary health service, their levels of 12 health indicators (eg, infant mortality, life expectancy, and age-adjusted death rates), and the satisfaction of their populations in relation to overall costs of the systems. Information was derived primarily from published sources. Indices were developed to characterize the extent of primary care in each country and the standing of each country relative to the others on the health indicators. There was general concordance for primary care, the health indicators, and the satisfaction-expense ratio in nine of the 10 countries. Ratings for the United States were low on all three measures. West Germany also had low ratings. In contrast, Canada, Sweden, and the Netherlands had generally high ratings for all three measures. The lack of concordance in the ratings in the United Kingdom may be a result of relatively low expenditures for other social services and public education in that country. The findings may add to the debate and deliberations concerning modifications in organization and financing of care that are currently being considered in the United States.


Histopathologic analysis of intraocular allogeneic tumors in mice.
The authors have studied histopathologically the growth, invasion, and regression of allogeneic P815 mastocytoma cells placed in the anterior chambers of eyes of three different strains of inbred mice. Previous clinical observations had suggested that the degree of immunogenetic disparity between tumor and recipient governed the intensity and specificity of the host's immune response to the intraocular neoplasm. Our histopathologic studies confirm this conclusion. BALB/c mice, which are H-2 syngeneic with P815 cells, develop progressively growing tumors around which no evidence of host immune or inflammatory response can be found. P815 cells confront A/J mice with a single class I MHC disparity; early intraocular tumor growth is vigorous in this strain, and when the tumor rejection takes place, it is followed by marked fibrovascular scar tissue formation which destroys intraocular structures, resulting in atrophia bulbi. C57BL/6 mice recognize immunologically three categories of allogeneic class I antigens on P815 cells. In these hosts, early tumor growth within the anterior chamber is feeble and rejection is attended by only minimal inflammation; as a consequence, scar formation is trivial and the eye remains anatomically intact. Based on certain histopathologic features, the authors suggest that two distinctly different immune effector mechanisms are involved in intraocular tumor rejection in A/J and C57BL/6 hosts. One immune rejection process results in extensive innocent bystander destruction of normal host tissues (A/J mice) while the other immune mechanism is more precise and does not damage host ocular structures (C57BL/6 mice).


Postpartum contraceptive use in Gondar town, Northwest Ethiopia: a community based cross-sectional study.
Addressing family planning in the postpartum period is crucial for better maternal, neonatal and child survival because it enables women to achieve healthy interval between births. The contraceptive behavior of women in the postpartum period is usually different from other times in a woman's life cycle due to the additional roles and presence of emotional changes. Therefore, this study is conducted with the aim of assessing the contraceptive behavior of women in the postpartum period. A community-based cross-sectional study was conducted in August 2013 among women who gave birth one year before the study period in Gondar town, Northwest Ethiopia. Multistage cluster sampling technique was employed to recruit a total of 703 study participants. For data collection, a structured and pretested questionnaire was used. Descriptive statistics were done to characterize the study population using different variables. Bivariate and multiple logistic regression models were fitted. Odds ratios with 95% confidence intervals were computed to identify factors associated with contraceptive use. Nearly half (48.4%) of the postpartum women were using different types of contraceptives. The most commonly used method was injectable (68.5%). Resumption of mensus [Adjusted Odds Ratio (AOR) = 8.32 95% Confidence Interval (CI): (5.27, 13.14)], age ≤24 years [AOR = 2.36, 95% CI: (1.19, 4.69), duration of 7-9 months after delivery [AOR = 2.26 95% CI: (1.12, 4.54)], and having antenatal care [AOR = 5.76, 95% CI: (2.18, 15.2)] were the factors positively associated with contraceptive use in the extended postpartum period. Postpartum contraceptive practice was lower as compared to the Ethiopian demographic and health survey 2011 report for urban areas. Strengthening family planning counseling during antenatal care visit and postnatal care would improve contraceptive use in the postpartum period.


Synergistic growth inhibition mediated by dual PI3K/mTOR pathway targeting and genetic or direct pharmacological AKT inhibition in human glioblastoma models.
Molecular genetic aberrations in the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway are common in human cancers including glioblastoma, yet, novel therapeutic approaches targeting this pathway in glioblastoma have not been successful. We hypothesized that molecular profiling in combination with in vitro drug sensitivity testing allows to identify signatures associated with sensitivity or resistance to PI3K/mTOR pathway inhibition. We analyzed the molecular mechanisms determining sensitivity to PI3K/mTOR inhibition using gene silencing or pharmacological target inhibition and proliferation, clonogenicity, or spherogenicity as readouts, in human long-term glioma cell (LTC) lines and glioma-initiating cells (GIC). Cultured glioma cells were universally sensitive to growth inhibition induced by PQR309, a novel, dual pan-PI3K/mTOR antagonist. Cells exhibited profound growth arrest, but little apoptotic or necrotic cell death as confirmed by electron microscopy; yet, there was evidence of senescence. Cell lines with high basal levels of phosphorylated (active) AKT, low levels of phosphorylated (inactive) protein translation repressor eukaryotic initiation factor (eIF) 4E-binding protein 1 (p4E-BP1), and high levels of Ser9-phosphorylated (inactive) glycogen synthase kinase 3 beta (pGSK3β) were more sensitive to PQR309. Accordingly, the activity of PQR309 was synergistically enhanced by AKT gene silencing or direct pharmacological AKT inhibition. In vivo studies confirmed the anti-glioma activity of PQR309 alone or in combination with AKT inhibition in the orthotopic LN-229 glioma xenograft model in nude mice. These data justify to explore combined targeted therapy approaches in glioblastoma that aim at down-regulating AKT function to enhance the therapeutic potential of dual PI3K/mTOR inhibitors.


Malignant transformation of hpv-immortalized human oral keratinocytes by chemical carcinogens.
We previously immortalized primary human oral keratinocytes by transfection with cloned human papillomavirus type 16 (HPV-16) DNA and established a cell line, human oral keratinocytes-16B (HOK-16B). This line contained intact HPV-16 DNA in an integrated form, expressed viral genes, and demonstrated an indefinite life span. However, the cells proliferated only in keratinocyte growth medium containing a low level of calcium and were not tumorigenic in nude mice. To develop an in vitro multistage model suitable for the study of human oral carcinogenesis and to investigate the molecular mechanisms of cell transformation, the HOK-16B cells were exposed to either benzo(a)pyrene [B(a)P] or 7,12-dimethylbenz(a)anthracene (DMBA). Two chemically transformed cell colonies, one from B(a)P exposure and the other from DMBA treatment, were isolated. These cell lines proliferated well in Dulbecco's minimum essential medium containing a physiological level of calcium, demonstrated anchorage-independent growth, and developed tumors in nude mice. They contained integrated HPV-16 sequences and expressed higher levels of epidermal growth factor receptor (EGFR) and c-myc transcripts compared to the parental cells. Similar to their immortalized parental cells, the chemically transformed cells also contained lower levels of p53 protein and transforming growth factor-beta (TGF-beta) transcripts than normal human oral keratinocytes. These results indicate that malignant transformation of oral keratinocytes can be caused by a sequential combined effect of high-risk HPV and chemical carcinogens. It also demonstrates that overexpression of viral E6/E7, EGFR and c-myc messages, together with the down-regulation of TGF-beta mRNA and the inactivation of p53 gene, may be associated with the malignant conversion of HPV-immortalized cells.


Nobiletin, a citrus flavonoid with neurotrophic action, augments protein kinase A-mediated phosphorylation of the AMPA receptor subunit, GluR1, and the postsynaptic receptor response to glutamate in murine hippocampus.
Nobiletin isolated from citrus peels prevents bulbectomy- and amyloid-beta protein-induced memory impairment in rodents. In the present study, using combined methods of biochemistry and electrophysiology, we examined the effects of nobiletin on phosphorylation of GluR1 receptor, the subunit of alpha-amino-3-hydroxy-5-methyl-D-aspartate (AMPA) receptors, and the receptor-mediated synaptic transmission in the hippocampus, a region implicated in memory formation, in culture and/or in slices. Western blot analysis showed that nobiletin-stimulated phosphorylation of multiple protein kinase A (PKA) substrates at 10 min following the treatment in cultured hippocampal neurons. In the cultured neurons, this natural compound also increased not only PKA activity, but also phosphorylation of GluR1 receptor at a PKA phosphorylation site, Ser 845, which has been demonstrated to be critical for synaptic plasticity, including enhancement of postsynaptic glutamate response, and important for spatial memory in vivo. The increased phosphorylation of GluR1 receptor at Ser 845 was abolished by H89 (N-(2-[p-bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride), the PKA inhibitor, but not U0126 (1,4-diamino-2,3-dicyano-1,4-bis (2-aminophenylthio) butadiene), the mitogen-activated protein kinase/ERK kinase (MEK) inhibitor, in the cultured neurons. An increment of the phosphorylation of GluR1 receptor at Ser 845 was induced by nobiletin in the hippocampal slices as well. Furthermore, our electrophysiological analysis showed that nobiletin potentiated the AMPA receptor-mediated synaptic transmission at Schaffer collateral-CA1 pyramidal cell synapses in the hippocampal slices. This potentiation induced by the natural compound was not accompanied by the changes in paired-pulse ratio, and partially occluded the long-term potentiation, indicating the possible involvement of the postsynaptic mechanism. These findings suggest that nobiletin probably up-regulates synaptic transmission via the postsynaptic AMPA receptors at least partially by stimulation of PKA-mediated phosphorylation of GluR1 receptor in the hippocampus.


Effects of dentin disinfectants on the shear bond strength of all-ceramics to dentin.
This study investigated the effect of dentin disinfectants on the shear bond strength of all-ceramic restorations luted with two different dual-polymerizing systems to dentin. Dentin disinfectants chlorhexidine gluconate-based Concepsis and benzalkonium chloride-based Tubulicid Red were applied in combination with Variolink 2 and Resilute. The buccal surfaces of non-carious extracted human premolars were flattened to expose dentin and subsequently polished with 600-grit wet silicon carbide paper. Each dual-polymerizing luting system had two test groups and a control group. Dentin from the test groups was first treated with dentin disinfectants, then the all-ceramic restorations were luted with dual polymerizing systems. The dentin without disinfectant application and ceramic restoration was used as a control. After the all-ceramic samples were luted to all treated surfaces, the specimens were thermocycled and tested for shear bond strength until failure. Analysis of the fractured dentin surfaces was performed using Optical Microscope-Nikon ECLIPSE ME 600 (Nikon Co, Tokyo, Japan) at between 10x and 1000x magnifications and the images were analyzed with Image Analyzer LUCIA 4.21 (Nikon Co). The data were analyzed with one-way ANOVA and Duncan test at a significance level of p<0.05. Application of the two dentin disinfectants increased the shear bond strength of both the Variolink 2 and Resilute systems, but this increase was statistically significant only in Tubulicid Red treated specimens (p<0.05). Surface analysis showed that all the specimens showed the adhesive failure mode between the dentin and composite luting agent interface.


Activation of spinal dorsal horn astrocytes by noxious stimuli involves descending noradrenergic signaling.
Astrocytes are critical regulators of neuronal function in the central nervous system (CNS). We have previously shown that astrocytes in the spinal dorsal horn (SDH) have increased intracellular Ca2+ levels following intraplantar injection of the noxious irritant, formalin. However, the underlying mechanisms remain unknown. We investigated these mechanisms by focusing on the role of descending noradrenergic (NAergic) signaling because our recent study revealed the essential role of the astrocytic Ca2+ responses evoked by intraplantar capsaicin. Using in vivo SDH imaging, we found that the Ca2+ level increase in SDH astrocytes induced by intraplantar formalin injection was suppressed by ablation of SDH-projecting locus coeruleus (LC)-NAergic neurons. Furthermore, the formalin-induced Ca2+ response was dramatically decreased by the loss of α1A-adrenaline receptors (ARs) in astrocytes located in the superficial laminae of the SDH. Moreover, similar inhibition was observed in mice pretreated intrathecally with an α1A-AR-specific antagonist. Therefore, activation of α1A-ARs via descending LC-NAergic signals may be a common mechanism underlying astrocytic Ca2+ responses in the SDH evoked by noxious stimuli, including chemical irritants.


Regulated delivery of therapeutic proteins after in vivo somatic cell gene transfer.
Stable delivery of a therapeutic protein under pharmacologic control was achieved through in vivo somatic gene transfer. This system was based on the expression of two chimeric, human-derived proteins that were reconstituted by rapamycin into a transcription factor complex. A mixture of two adeno-associated virus vectors, one expressing the transcription factor chimeras and one containing erythropoietin (Epo) under the control of a promoter responsive to the transcription factor, was injected into skeletal muscle of immune-competent mice. Administration of rapamycin resulted in 200-fold induction of plasma Epo. Stable engraftment of this humanized system in immune-competent mice was achieved for 6 months with similar results for at least 3 months in a rhesus monkey.


[Early results of autologous mononuclear bone marrow cell implantation in nontraumatic avascular necrosis of the femoral head].
We evaluated early clinical and radiologic results of core decompression combined with autologous mononuclear bone marrow cell implantation for early stage nontraumatic avascular necrosis of the femoral head. The study included nine patients (1 female, 8 males, mean age 46.5 years; range 33 to 59 years) with stage I-II nontraumatic avascular necrosis of the femoral head, according to the Steinberg classification. Bone marrow-derived CD34 cells were injected through a core decompression channel into the femoral head. Clinical assessment included a visual analog scale (VAS), Harris hip score, and the WOMAC Osteoarthritis Index. Radiologically, femoral head collapse, narrowing of the coxofemoral joint space, and the size of the osteonecrotic area were assessed. The mean follow-up was 27.2 months (range 24 to 38 months). Pre- and postoperative (24th month) evaluations showed that the mean VAS score and the WOMAC Osteoarthritis Index decreased from 3.4+/-0.4 to 1.2+/-0.6, and from 33+/-3 to 11+/-6, respectively, with an increase in the Harris hip score (from 54 to 92). Preoperatively, two patients were Steinberg I-B, four were I-C, and three were II-A. Finally, all the patients were stage 0 except for one patient who regressed to I-A. None of the patients exhibited femoral head collapse or narrowing of the coxofemoral joint space. Autologous mononuclear bone marrow cell implantation relieves articular pain, prevents the progression of osteonecrosis, and hence subchondral fractures. Therefore, it may be treatment of choice particularly in stage I-II avascular necrosis of the femoral head.


Heart rate variability as a measure of autonomic regulation of cardiac activity for assessing stress and welfare in farm animals -- a review.
Measurement of heart rate variability (HRV) is a non-invasive technique that can be used to investigate the functioning of the autonomic nervous system, especially the balance between sympathetic and vagal activity. It has been proven to be very useful in humans for both research and clinical studies concerned with cardiovascular diseases, diabetic autonomic dysfunction, hypertension and psychiatric and psychological disorders. Over the past decade, HRV has been used increasingly in animal research to analyse changes in sympathovagal balance related to diseases, psychological and environmental stressors or individual characteristics such as temperament and coping strategies. This paper discusses current and past HRV research in farm animals. First, it describes how cardiac activity is regulated and the relationships between HRV, sympathovagal balance and stress and animal welfare. Then it proceeds to outline the types of equipment and methodological approaches that have been adapted and developed to measure inter-beats intervals (IBI) and estimate HRV in farm animals. Finally, it discusses experiments and conclusions derived from the measurement of HRV in pigs, cattle, horses, sheep, goats and poultry. Emphasis has been placed on deriving recommendations for future research investigating HRV, including approaches for measuring and analysing IBI data. Data from earlier research demonstrate that HRV is a promising approach for evaluating stress and emotional states in animals. It has the potential to contribute much to our understanding and assessment of the underlying neurophysiological processes of stress responses and different welfare states in farm animals.


Smoking is Associated With Extra-intestinal Manifestations in Inflammatory Bowel Disease.
Smoking affects the course of disease in patients with ulcerative colitis (UC) and Crohn's disease (CD). We aimed to study the association between smoking and extra-intestinal manifestations (EIMs) in inflammatory bowel disease (IBD). We cross-sectionally explored the association between smoking and EIMs in IBD in three cohort studies: (1) the COIN study, designed to estimate healthcare expenditures in IBD; (2) the Groningen study, focused on cigarette smoke exposure and disease behaviour in IBD; and (3) the JOINT study, evaluating joint and back manifestations in IBD. In the COIN, Groningen and JOINT cohorts, 3030, 797 and 225 patients were enrolled, of whom 16, 24 and 23.5% were current smokers, respectively. Chronic skin disorders and joint manifestations were more prevalent in smoking IBD patients than in non-smokers (COIN, 39.1 vs 29.8%, p <0.01; Groningen, 41.7 vs 30.0%, p <0.01) in both CD and UC. In the JOINT cohort, smoking was more prevalent in IBD patients with joint manifestations than in those without (30.3 vs 13.0%, p <0.01). EIMs appeared to be more prevalent in high- than in low-exposure smokers (56.0 vs 37.1%, p = 0.10). After smoking cessation, the prevalence of EIMs in IBD patients rapidly decreased towards levels found in never smokers (lag time: COIN cohort, 1-2 years; Groningen cohort, within 1 year). There is a robust dose-dependent association between active smoking and EIMs in both CD and UC patients. Smoking cessation was found to result in a rapid reduction of EIM prevalence to levels encountered in never smokers.


Treatment of presumed prolactinoma by transsphenoidal operation: early and late results.
Seventy seven patients who were presumed to have a prolactinoma on the basis of biochemical findings underwent transsphenoidal operation between October 1977 and September 1983. Sixty one patients were found to have a microadenoma, and hyperprolactinaemia was cured in 46 of these, amenorrhoea in 39 (80% of those with the symptom), galactorrhoea in 32 (80%), and infertility in 31 (82%). Four of eight patients found to have a macroadenoma were also satisfactorily treated with surgery. Two patients had a lesion other than a prolactinoma, and in six a tumour could not be found at operation; four of these last eight patients had a normal serum prolactin concentration after operation. Recurrent hyperprolactinaemia was rare, occurring in only three patients in the series overall; among the 32 patients followed up for more than five years only two of the 22 whose operation had initially been successful developed recurrent hyperprolactinaemia.


Non-pharmacological management of gestational diabetes: The role of myo-inositol.
Gestational diabetes mellitus (GDM) is the most common metabolic disorder occurring in pregnancy. GDM plays an important role in the current diabetes epidemic: exposure to a high glycemic environment during the early stages of development increases the risk of the fetus to develop type two diabetes mellitus (T2DM) in adult life. Various cardiometabolic risk factors are linked to GDM. A thorough knowledge of the risk factors and genes involved in the development of GDM, along with an understanding of the underlying pathophysiological mechanisms are crucial to properly identify patients at risk of developing this condition. There is growing evidence showing that myo-inositol, combined with an appropriate therapeutic regimen for GDM, can provide additional benefits to the patient. The aim of this review is to analyze the role of inositol isomers - especially myo-inositol (MYO-INS) - in the treatment of patients with GDM.


Cloning of adipose triglyceride lipase complementary deoxyribonucleic acid in poultry and expression of adipose triglyceride lipase during development of adipose in chickens.
Increasing the breakdown of stored fat in adipose tissue leads to reducing fat content, enhancing feed efficiency and, consequently, decreasing the production cost of poultry. The processes of lipolysis are not completely understood, and the proteins involved in this process need to be identified. An adipose triglyceride lipase (ATGL), recently identified in several species, has not been studied in avian species. We have cloned the full-length coding sequences of ATGL cDNA for the chicken, turkey, and quail. Sequence comparisons among mammals and these avian species showed that the avian ATGL have 2 conserved domains, the patatin domain and the hydrophobic domain. The patatin domain contains lipase activity, and the hydrophobic domain exhibits lipid droplet binding. The high levels of chicken, turkey, and quail ATGL mRNA and protein are exclusively found in subcutaneous and abdominal adipose tissues. In addition, chicken ATGL (gATGL) is mainly expressed in the fractionated adipocytes compared with stromal-vascular cells that mostly contain preadipocytes (P < 0.001). Furthermore, ontogeny of gATGL mRNA and protein expression in adipose tissue showed induction of gATGL immediately after hatching before access to food (P < 0.05), suggesting that an energy deficit due to posthatching starvation may increase breakdown of stored fat via increasing gATGL expression in adipose tissue. Our studies showed that expression of the chicken ATGL is adipose specific and regulated developmentally, suggesting that a possible modulation of ATGL expression would regulate fat deposition in avian species.


Harmonic surface mapping algorithm for molecular dynamics simulations of particle systems with planar dielectric interfaces.
We have developed an accurate and efficient method for molecular dynamics simulations of charged particles confined by planar dielectric interfaces. The algorithm combines the image-charge method for near field with the harmonic surface mapping, which converts the contribution of infinite far-field charges into a finite number of charges on an auxiliary spherical surface. We approximate the electrostatic potential of far-field charges via spherical harmonic expansion and determine the coefficients by fitting the Dirichlet-to-Neumann boundary condition, which only requires the potential within the simulation cell. Instead of performing the direct evaluation of spherical harmonic series expansion, we use Green's second identity to transform the series expansion into a spherical integral, which can be accurately represented by discrete charges on the sphere. Therefore, the fast multipole method can be readily employed to sum over all charges within and on the sphere, achieving truly linear O(N) complexity. Our algorithm can be applied to a broad range of charged complex fluids under dielectric confinement.


Ultrasonic inspection of studs (bolts) using dynamic predictive deconvolution and wave shaping.
Bolt degradation has become a major issue in the nuclear industry since the 1980's. If small cracks in stud bolts are not detected early enough, they grow rapidly and cause catastrophic disasters. Their detection, despite its importance, is known to be a very difficult problem due to the complicated structures of the stud bolts. This paper presents a method of detecting and sizing a small crack in the root between two adjacent crests in threads. The key idea is from the fact that the mode-converted Rayleigh wave travels slowly down the face of the crack and turns from the intersection of the crack and the root of thread to the transducer. Thus, when a crack exists, a small delayed pulse due to the Rayleigh wave is detected between large regularly spaced pulses from the thread. The delay time is the same as the propagation delay time of the slow Rayleigh wave and is proportional to the site of the crack. To efficiently detect the slow Rayleigh wave, three methods based on digital signal processing are proposed: wave shaping, dynamic predictive deconvolution, and dynamic predictive deconvolution combined with wave shaping.


Impact of Circadian Disruption on Cardiovascular Function and Disease.
The circadian system, that is ubiquitous across species, generates ∼24 h rhythms in virtually all biological processes, and allows them to anticipate and adapt to the 24 h day/night cycle, thus ensuring optimal physiological function. Epidemiological studies show time-of-day variations in adverse cardiovascular (CV) events, and controlled laboratory studies demonstrate a circadian influence on key markers of CV function and risk. Furthermore, circadian misalignment, that is typically experienced by shift workers as well as by individuals who experience late eating, (social) jet lag, or circadian rhythm sleep-wake disturbances, increases CV risk factors. Therefore, understanding the mechanisms by which the circadian system regulates CV function, and which of these are affected by circadian disruption, may help to develop intervention strategies to mitigate CV risk.


Intracluster correlation coefficients from the 2005 WHO Global Survey on Maternal and Perinatal Health: implications for implementation research.
Cluster-based studies involving aggregate units such as hospitals or medical practices are increasingly being used in healthcare evaluation. An important characteristic of such studies is the presence of intracluster correlation, typically quantified by the intracluster correlation coefficient (ICC). Sample size calculations for cluster-based studies need to account for the ICC, or risk underestimating the sample size required to yield the desired levels of power and significance. In this article, we present values for ICCs that were obtained from data on 97,095 pregnancies and 98,072 births taking place in a representative sample of 120 hospitals in eight Latin American countries. We present ICCs for 86 variables measured on mothers and newborns from pregnancy to the time of hospital discharge, including 'process variables' representing actual medical care received for each mother and newborn. Process variables are of primary interest in the field of implementation research. We found that overall, ICCs ranged from a minimum of 0.0003 to a maximum of 0.563 (median 0.067). For maternal and newborn outcome variables, the median ICCs were 0.011 (interquartile range 0.007-0.037) and 0.054 (interquartile range 0.013-0.075) respectively; however, for process variables, the median was 0.161 (interquartile range 0.072-0.328). Thus, we confirm previous findings that process variables tend to have higher ICCs than outcome variables. We demonstrate that ICCs generally tend to increase with higher prevalences (close to 0.5). These results can help researchers calculate the required sample size for future research studies in maternal and perinatal health.


Augmented P2X response and immunolabeling in dorsal root ganglion neurons innervating skeletal muscle following femoral artery occlusion.
The responsiveness of sensory neurons to muscle metabolites is altered under the conditions of insufficient limb blood supply in some diseases, such as peripheral artery disease. The purpose of this study was to examine ATP-induced current with activation of purinergic P2X subtypes P2X₃ and P2X₂/₃ in dorsal root ganglion (DRG) neurons of control limbs and limbs with 24 h of femoral artery occlusion using whole cell patch-clamp methods. Also, dual-labeling immunohistochemistry was employed to determine existence of P2X₃ expression in DRG neurons of thin-fiber afferents. DRG neurons from 4- to 6-wk-old rats were labeled by injecting the fluorescence tracer DiI into the hindlimb muscles 4-5 days before the recording experiments. Transient (P2X₃), mixed (P2X₃ and P2X₂/₃), and sustained (P2X₂/₃) current responses to α,β-methylene ATP (a P2X receptor agonist) are observed in small and medium DRG neurons, and size distribution of DRG neurons is similar in control and occluded limbs. However, the peak current amplitude of DRG neuron induced by stimulation of P2X₃ and/or P2X₂/₃ is larger in occluded limbs than that in control limbs. Moreover, the percentage of DRG neurons with P2X₃ transient currents is greater after arterial occlusion compared with control. In addition, a rapid desensitization was observed in DRG neurons with transient currents, but not with sustained currents in control and occluded groups. Furthermore, results from immunofluorescence experiments show that femoral artery occlusion primarily augments P2X₃ expression within DRG neurons projecting C-fiber afferents. Overall, these findings suggest that 1) greater ATP-induced currents with activation of P2X₃ and P2X₂/₃ are developed when hindlimb arterial blood supply is deficient under ischemic conditions and 2) increased P2X₃ expression is largely observed in C-fibers of DRG neurons after hindlimb vascular insufficiency.


Osteoporosis case finding in the general practice: phalangeal radiographic absorptiometry with and without risk factors for osteoporosis to select postmenopausal women eligible for lumbar spine and hip densitometry.
Mass screening for osteoporosis using DXA measurements at the spine and hip is presently not recommended by health authorities. Instead, risk factor questionnaires and peripheral bone measurements may facilitate the selection of women eligible for axial bone densitometry. The aim of this study was to validate a case finding strategy for postmenopausal women who would benefit most from subsequent DXA measurement by using phalangeal radiographic absorptiometry (RA) alone or in combination with risk factors in a general practice setting. The sensitivity and specificity of this strategy in detecting osteoporosis (T-score < or =2.5 SD at the spine and/or the hip) were compared with those of the current reimbursement criteria for DXA measurements in Switzerland. Four hundred and twenty-three postmenopausal women with one or more risk factors for osteoporosis were recruited by 90 primary care physicians who also performed the phalangeal RA measurements. All women underwent subsequent DXA measurement of the spine and the hip at the Osteoporosis Policlinic of the University Hospital of Berne. They were allocated to one of two groups depending on whether they matched with the Swiss reimbursement conditions for DXA measurement or not. Logistic regression models were used to predict the likelihood of osteoporosis versus "no osteoporosis" and to derive ROC curves for the various strategies. Differences in the areas under the ROC curves (AUC) were tested for significance. In women lacking reimbursement criteria, RA achieved a significantly larger AUC (0.81; 95% CI 0.72-0.89) than the risk factors associated with patients' age, height and weight (0.71; 95% C.I. 0.62-0.80). Furthermore, in this study, RA provided a better sensitivity and specificity in identifying women with underlying osteoporosis than the currently accepted criteria for reimbursement of DXA measurement. In the Swiss environment, RA is a valid case finding tool for patients with risk factors for osteoporosis, especially for those who do not qualify for DXA reimbursement.


A Typology for the Application of Team Coordination Dynamics Across Increasing Levels of Dynamic Complexity.
This review and synthesis examines approaches for measuring and assessing team coordination dynamics (TCD). The authors advance a system typology for classifying TCD approaches and their applications for increasing levels of dynamic complexity. There is an increasing focus on how teams adapt their coordination in response to changing and uncertain operational conditions. Understanding coordination is significant because poor coordination is associated with maladaptive responses, whereas adaptive coordination is associated with effective responses. This issue has been met with TCD approaches that handle increasing complexity in the types of TCD teams exhibit. A three-level system typology of TCD approaches for increasing dynamic complexity is provided, with examples of research at each level. For System I TCD, team states converge toward a stable, fixed-point attractor. For System II TCD, team states are periodic, which can appear complex, yet are regular and relatively stable. In System III TCD, teams can exhibit periodic patterns, but those patterns change continuously to maintain effectiveness. System I and System II are applicable to TCD with known or discoverable behavioral attractors that are stationary across mid-to long-range timescales. System III TCD is the most generalizable to dynamic environments with high requirements for adaptive coordination across a range of timescales. We outline current challenges for TCD and next steps in this burgeoning field of research. System III approaches are becoming widespread, as they are generalizable to time- and/or scale-varying TCD and multimodal analyses. Recommendations for deploying TCD in team settings are provided.


Transport and removal of spores of Bacillus subtilis in an alluvial gravel aquifer at varying flow rates and implications for setback distances.
To guarantee proper protection from fecally transmitted pathogen infections, drinking water wells should have a sufficiently large setback distance from potential sources of contamination, e.g. a nearby river. The aim of this study was to provide insight in regards to microbial contamination of groundwater under different flow velocities, which can vary over time due to changes in river stage, season or pumping rate. The effects of these changes, and how they affect removal parameters, are not completely understood. In this study, field tracer tests were carried out in a sandy gravel aquifer near Vienna, Austria to evaluate the ability of subsurface media to attenuate Bacillus subtilis spores, used as a surrogate for Cryptosporidium and Campylobacter. The hydraulic gradient between injection and extraction was controlled by changing the pumping rate (1, 10 l/s) of a pumping well at the test site, building upon previously published work in which tracer tests with a 5 l/s pumping rate were carried out. Attachment and detachment rate coefficients were determined using a HYDRUS-3D model and ranged from 0.12 to 0.76 and 0-0.0013 h-1, respectively. Setback distances were calculated based on the 60-day travel time, as well as a quantitative microbial risk assessment (QMRA) approach, which showed similar results at this site; around 700 m at the highest pumping rate. Removal rates (λ) in the field tests ranged from 0.2 to 0.3 log/m, with lower pumping rates leading to higher removal. It was shown that scale must be taken into consideration when determining λ for the calculation of safe setback distances.


Crystal structures and kinetic properties of enoyl-acyl carrier protein reductase I from Candidatus Liberibacter asiaticus.
Huanglongbing (HLB) is a destructive citrus disease. The leading cause of HLB is Candidatus Liberibacter asiaticus. Fatty acid biosynthesis is essential for bacterial viability and has been validated as a target for the discovery of novel antibacterial agents. Enoyl-acyl carrier protein reductase (also called ENR or FabI and a product of the fabI gene) is an enzyme required in a critical step of bacterial fatty acid biosynthesis and has attracted attention as a target of novel antimicrobial agents. We determined the crystal structures of FabI from Ca. L. asiaticus in its apoform as well as in complex with b-nicotinamide adenine dinucleotide (NAD) at 1.7 and 2.7 Å resolution, respectively, to facilitate the design and screening of small molecule inhibitors of FabI. The monomeric ClFabI is highly similar to other known FabI structures as expected; however, unlike the typical tetramer, ClFabI exists as a hexamer in crystal, whereas as dimer in solution, on the other hand, the substrate binding loop which always disordered in apoform FabI structures is ordered in apo-ClFabI. Interestingly, the structure of ClFabI undergoes remarkable conformational change in the substrate-binding loop in the presence of NAD. We conclude that the signature sequence motif of FabI can be considered as Gly-(Xaa)5-Ser-(Xaa)n-Val-Tyr-(Xaa)6-Lys-(Xaa)n-Thr instead of Tyr-(Xaa)6-Lys. We have further identified isoniazid as a competitive inhibitor with NADH.


Human adipose-derived mesenchymal stem cells seeded into a collagen-hydroxyapatite scaffold promote bone augmentation after implantation in the mouse.
Traumatic injury or surgical excision of diseased bone tissue usually require the reconstruction of large bone defects unable to heal spontaneously, especially in older individuals. This is a big challenge requiring the development of biomaterials mimicking the bone structure and capable of inducing the right commitment of cells seeded within the scaffold. In particular, given their properties and large availability, the human adipose-derived stem cells are considered as the better candidate for autologous cell transplantation. In order to evaluate the regenerative potential of these cells along with an osteoinductive biomaterial, we have used collagen/hydroxyapatite scaffolds to test ectopic bone formation after subcutaneous implantation in mice. The process was analysed both in vivo, by Fluorescent Molecular Tomography (FMT), and ex vivo, to evaluate the formation of bone and vascular structures. The results have shown that the biomaterial could itself be able of promoting differentiation of host cells and bone formation, probably by means of its intrinsic chemical and structural properties, namely the microenvironment. However, when charged with human mesenchymal stem cells, the ectopic bone formation within the scaffold was increased. We believe that these results represent an important advancement in the field of bone physiology, as well as in regenerative medicine.


Dual impacts of Medicare payment reform and the COVID-19 pandemic on therapy staffing in skilled nursing facilities.
Implementation of new skilled nursing facility (SNF) Medicare payment policy, the Patient Driven Payment Model (PDPM), resulted in immediate declines in physical and occupational therapy staffing. This study characterizes continuing impacts of PDPM in conjunction with COVID-19 on SNF therapy staffing and examines variability in staffing changes based on SNF organizational characteristics. We analyzed Medicare administrative data from a national cohort of SNFs between January 2019 and March 2022. Interrupted time series mixed effects regression examined changes in level and trend of total therapy staffing minutes/patient-day during PDPM and COVID-19 and by type of staff (therapists, assistants, contractors, and in-house staff). Secondary analyses examined the variability in staffing by organizational characteristics. PDPM resulted in a -6.54% level change in total therapy staffing, with larger declines for assistants and contractors. Per-patient staffing fluctuated during COVID-19 as the census changed. PDPM-related staffing declines were larger in SNFs that were: Rural, for-profit, chain-affiliated, provided more intensive therapy, employed more therapy assistants, and admitted more Medicare patients before PDPM. COVID-19 resulted in larger staffing declines in rural SNFs but smaller early declines in SNFs that were hospital-based, for-profit, or received more relief funding. SNFs that historically engaged in profit-maximizing behaviors (e.g., providing more therapy via lower-paid assistants) had larger staffing declines during PDPM compared to other SNFs. Therapy staffing fluctuated during COVID-19, but PDPM-related reductions persisted 2 years into the pandemic, especially in rural SNFs. Results suggest specific organizational characteristics that should be targeted for staffing and quality improvement initiatives.


[Prophylaxis of gastrointestinal hemorrhage in patients with noninflammatory pancreatic disease complicated by jaundice].
Frequency, severity of clinical course, pathophysiological mechanisms of occurrence and consequences of gastroduodenal erosion and ulcer, complicated by hemorrhage, were analyzed in patients with noninflammatory diseases of pancreas, complicated by jaundice, by cancer, in particular. Basing on investigations done there was elaborated complex programme of prophylaxis of gastrointestinal hemorrhage occurrence in such patients.


Physicochemical properties and photodynamic activity of novel derivatives of triarylmethane and thiazine.
Triarylmethane and thiazine dyes have attracted attention as anticancer and antimicrobial agents, due to their structural features and selective localizations. Although these dyes have been initially explored in the context of photodynamic therapy, some of these such as New Fuchsin and Azure B have still not been extensively investigated. For this reason, we evaluated the chemical stability, aggregation effect, and lipophilicity, as well as the photodynamic activity against LM-2 murine mammary carcinoma cells of five new brominated dyes of triarylmethane and thiazine. These cationic compounds were obtained at high purities and unequivocally characterized by conventional techniques. The introduction of bromine atoms into the chromophoric system of New Fuchsin and Azure B dyes gave rise to a moderate bathochromic shift and increased the lipophilicity, thereby improving their photophysical and photochemical properties for biomedical applications. Moreover, the in vitro photodynamic activity demonstrated that, as the degree of bromination increased, the phototoxicity remained unchanged or decreased. The lower efficiency to inactivate cultured tumor cells may be attributed to the formation of the colorless carbinol pseudobase and aggregation effects for triarylmethane and thiazine dyes, respectively. A promising strategy to reverse the biological activity decrease observed might be the design of third-generation photosensitizers.


Reversal of paraparesis after thoracic aneurysm repair by cerebrospinal fluid drainage.
To describe a case of reversal of delayed paraparesis, after an elective type I thoracoabdominal aortic aneurysm (TAAA) repair, via cerebrospinal fluid (CSF) drainage. A 75-yr-old woman developed paraparesis 13 hr after type I TAAA repair. The patient had been given combined regional and general anesthesia. There was no cerebrospinal fluid drain inserted at the time of surgery. The patient was hemodynamically stable throughout the procedure and was transported to the intensive care unit with trachea intubated and lungs ventilated. She demonstrated some initial lower limb paraparesis but had good recovery of limb function three hours after cessation of the epidural infusion. However, five hours and forty-five minutes after stopping the epidural, she was again paraparetic. Peripheral nerve injury, prolonged effects of epidural local anesthetic, and epidural hematoma were ruled out as precipitating factors. Cord ischemia was considered possible and a CSF catheter was inserted. Immediate improvement was seen upon catheter insertion and commencement of drainage, beginning with movement in the left toes and foot. Drainage was performed when the CFS pressure became > 15 mmHg. Motor function in the lower limbs continued to improve with each drainage extending to complete recovery after 40 hr. She was discharged home 11 days after surgery with no neurological deficit. Drainage of CSF was useful in treating a case of post-TAAA neurologic deficit.


Interactions between chromium and sulfur metabolism in Brassica juncea.
The effects of chromate on sulfate uptake and assimilation were investigated in the accumulator Brassica juncea (L.) Czern. Seven-day-old plants were grown for 2 d under the following combination of sulfate and chromate concentration: (i) no sulfate and no chromate (-S), (ii) no sulfate and 0.2 mmol L(-1) chromate (-S +Cr), (iii) 1 mmol L(-1) sulfate and no chromate (+S), or (iv) 1 mmol L(-1) sulfate and 0.2 mmol L(-1) chromate (+S +Cr). Despite the toxic effects exerted by chromate as indicated by altered level of reducing sugars and proteins in leaves, the growth of B. juncea was only weakly reduced by chromate, and no variation in chlorophyll a and b was measured, regardless of S availability. Chromium (Cr) was stored more in roots than in leaves, and the maximum Cr accumulation was measured in -S +Cr plants. The significant decrease of the sulfate uptake rates observed in Cr-treated plants was accompanied by a repression of the root low-affinity sulfate transporter (BjST1), suggesting that the transport of chromate in B. juncea may involve sulfate carriers. Once absorbed, chromate induced genes involved in sulfate assimilation (ATP-sulfurylase: atps6; APS-reductase: apsr2; Glutathione synthethase: gsh2) and accumulation of cysteine and glutathione, which may suggest that these reduced S compounds play a role in Cr tolerance. Together, our findings indicate that when phytoremediation technologies are used to recover Cr-contaminated areas, the concentration of sulfate in the plant growth medium must be considered because it may influence the ability of plants to accumulate and tolerate Cr.


Stem cell therapy: pieces of the puzzle.
Acute ischemic injury and chronic cardiomyopathies can cause irreversible loss of cardiac tissue leading to heart failure. Cellular therapy offers a new paradigm for treatment of heart disease. Stem cell therapies in animal models show that transplantation of various cell preparations improves ventricular function after injury. The first clinical trials in patients produced some encouraging results, despite limited evidence for the long-term survival of transplanted cells. Ongoing research at the bench and the bedside aims to compare sources of donor cells, test methods of cell delivery, improve myocardial homing, bolster cell survival, and promote cardiomyocyte differentiation. This article reviews progress toward these goals.


Perceptions of the nursing role in spinal cord injury rehabilitation.
In the UK, over the last 50 years there have been many developments in the rehabilitation of spinal cord-injured people leading to improvements in outcomes. In spinal cord injury rehabilitation nurses work as members of a multiprofessional team but their role is not clearly defined and, unlike other professionals, they have a 24-hour relationship with patients. This article presents some findings from a larger ongoing ethnographic research study. The aim of this section of the study was to identify how nurses and patients perceive the nursing role in spinal cord injury rehabilitation. Semistructured interviews were carried out with 14 spinal cord-injured patients and 14 registered nurses. The findings suggest that patients value the nursing contribution as a means of emotional and physical support but that they do not necessarily see nursing input as rehabilitation. Nurses see their role as multifaceted but identify difficulties in crossing over from an acute care philosophy to a rehabilitation philosophy. The 24-hours close relationship with patients may be a source of imbalanced power relationships between nurses and patients and this causes distress to some patients. It is suggested that nurses need to develop their bedrock role in a way that empowers patients in spinal cord rehabilitation.