Biochemical, biometrical and behavioral changes in male offspring of sleep-deprived mice.
Epidemiological and experimental studies suggest a high prevalence of cognitive impairment and social behavior deficits in adolescents and adults that have experienced prenatal exposure to adverse conditions. This study investigated whether sleep deprivation during the pre-implantation stage of development alters the physiological, behavioral and oxidative metabolic processes in adult male mouse offspring. One group of dams was continuously sleep-deprived using the platform technique from gestational days 0 to 3 (PSD 72). Three additional groups were sleep-deprived by gentle handling for 6h on gestational days 1 (GH 1), 2 (GH 2) or 3 (GH 3). After sleep deprivation, homocysteine, cysteine, corticosterone, estrogen and progesterone concentrations were measured from the experimental mothers and time-matched controls. The sizes and weights of the male pups were measured at various stages throughout the experiment. At PND 90, behavioral (Activity Box and Elevated Plus Maze) and biochemical parameters were assessed. The dams' plasma progesterone concentrations decreased in the PSD 72 group, and the levels of plasma estradiol increased in GH 2. Corticosterone levels were found to increase after all sleep-deprivation procedures. Homocysteine concentrations increased in the GH 2 but decreased in the PSD 72 group. The offspring of GH 1 mothers exhibited decreased superoxide dismutase activity. Exposure to sleep deprivation had a long-lasting impact on tissue weight; in particular, there was a decrease in hemilateral epididymal fat weight in mature animals from the PSD 72 group. Although some of the alterations observed in the mothers (elevated estrogen and corticosterone levels and decreased progesterone) might have played a role in the permanent alterations in the adult offspring, they were not the main cause. The homocysteine changes detected in the sleep-deprived dams may contribute to redox changes, controlling gene expression and shaping epigenetic development.


PestLCI 2.0 sensitivity to soil variations for the evaluation of pesticide distribution in Life Cycle Assessment studies.
Pesticides are commonly applied in conventional agricultural systems, but they can lead to serious environmental contamination. The calculation of on-field pesticide emissions in Life Cycle Assessment (LCA) studies is challenging, because of the difficulty in the calculation of the fate of pesticides and, therefore, several literature approaches based on different dispersion models have been developed. PestLCI 2.0 model can provide simultaneous assessment of the emission fractions of a pesticide to air, surface water and groundwater based on many parameters. The goal of this study is to exploit the extent of PestLCI 2.0 sensitivity to soil variations, with the ultimate goal of increasing the robustness of the modelling of pesticide emissions in LCA studies. The model was applied to maize cultivation in an experimental farm in Northern Italy, considering three tests, which evaluated the distribution of pesticides among environmental compartments obtained considering different soil types. Results show that small variations in soil characteristics lead to great variation of PestLCI 2.0, with a significance that depends on the type of environmental compartment. The compartment most affected by soil variations was groundwater, whereas surface waters were dominated by meteorological conditions, pesticides' physical and chemical properties and wind drift, which are independent from soil characteristics. Therefore, the use of specific soil data in PestLCI 2.0 results in the availability of a comprehensive set of emission data in the different compartments, which represents a relevant input for the inventory phase of LCA studies and can increase their robustness. Nevertheless, PestLCI 2.0 requires a great effort for the data collection and a specific expertise in soil science for interpreting the results. Moreover, characterization factors for pesticide groundwater emissions should be developed, in order to exploit these detailed results in the impact assessment phase, Finally, the study provides further insights into future improvement of PestLCI 2.0.


Sex determination and disorders of sex development according to the revised nomenclature and classification in 46,XX individuals.
There have been considerable advances concerning understanding of the early and later stages of ovarian development; a number of genes have been implicated and their mutations have been associated with developmental abnormalities. The most important genes controlling the initial phase of gonadal development, identical in females and males, are Wilms' tumor suppressor 1 (WT1) and steroidogenic factor 1 (SF1). Four genes are likely to be involved in the subsequent stages of ovarian development (WNT4, DAX1, FOXL2 and RSPO1), but none is yet proven to be the ovarian determining factor. Changes in nomenclature and classification were recently proposed in order to incorporate genetic advances and substitute gender-based diagnostic labels in terminology. The term "disorders of sex development" (DSD) is proposed to substitute the previous term "intersex disorders". Three main categories have been used to describe DSD in the 46,XX individual: 1) disorders of gonadal (ovarian) development: ovotesticular DSD, previously named true hermaphroditism, testicular DSD, previously named XX males, and gonadal dysgenesis; 2) disorders related to androgen excess (congenital adrenal hyperplasia, aromatase deficiency and P450 oxidoreductase deficiency); and 3) other rare disorders. In this mini-review, recent advances concerning development of the genital system in 46,XX individuals and related abnormalities are discussed. Basic embryology of the ovary and molecular pathways determining ovarian development are reviewed, focusing on mutations disrupting normal ovarian development. Disorders of sex development according to the revised nomenclature and classification in 46,XX individuals are summarized, including genetic progress in the field.


Peat fire effects on some properties of an artificially drained peatland.
The management of artificially drained organic soils is a very important issue, since the accelerated mineralization and sometimes peat fires alter physical and chemical properties of soils and the availability of plant nutrients. This study was performed to determine relatively short- and long-term effects of peat fires on some physical and chemical properties of soils in the artificially drained Gavur Lake Peatland of Turkey. To achieve this objective, measured properties of soils burned in 2001, burned in 1965, and unburned were compared. The results indicated that soil bulk density, pH, amounts of soluble salts, CaCO3, and concentrations of ammonium acetate-extractable (AAE) Ca, Mg, K, and Na were significantly higher for both sampling depths in the burned areas. The areas burned in 2001 had higher pH, soluble salts, and the concentrations of AAE Ca, Mg, and K compared with sites burned in 1965, and this was reasoned with leaching losses and plant uptake of these basic cations for four decades in the latter. Percent saturation and organic carbon contents of soils, however, were significantly lower in the burned areas for both sampling depths. Olsen P levels were not significantly different between the sites. This work clearly shows that alterations in soils properties with peat fires do not recover in the long term.


Atopic dermatitis.
Atopic dermatitis (AD) is a chronic and relapsing disease affecting an increasing number of patients. Usually starting in early childhood, AD can be the initial step of the so-called atopic march, i.e. followed by allergic rhinitis and allergic asthma. AD is a paradigmatic genetically complex disease involving gene-gene and gene-environment interactions. Genetic linkage analysis as well as association studies have identified several candidate genes linked to either the epidermal barrier function or to the immune system. Stress, bacterial or viral infections, the exposure to aero- or food-allergens as well as hygienic factors are discussed to aggravate symptoms of AD. Athough generalized Th2-deviated immune response is closely linked to the condition of AD, the skin disease itself is a biphasic inflammation with an initial Th2 phase and while chronic lesions harbour Th0/Th1 cells. Regulatory T cells have been shown to be altered in AD as well as the innate immune system in the skin. The main treatment-goals include the elimination of inflammation and infection, preserving and restoring the barrier function and controlling exacerbating factors. The overall future strategy in AD will be aimed to control skin inflammation by a more proactive management in order to potentially prevent the emergence of sensitization as well as to design customized management based on genetic and pathophysiologic information.


Thermacetogenium phaeum gen. nov., sp. nov., a strictly anaerobic, thermophilic, syntrophic acetate-oxidizing bacterium.
A novel anaerobic, thermophilic, syntrophic acetate-oxidizing bacterium, strain PB(T), was isolated from a thermophilic (55 degrees C) anaerobic methanogenic reactor which had been treating kraft-pulp waste water. The bacterium oxidized acetate in co-culture with a thermophilic hydrogenotrophic methanogen. Strain PB(T), a gram-positive, spore-forming, rod-shaped bacterium grew optimally at 58 degrees C and pH 6.8. The bacterium grew acetogenically on several alcohols, methoxylated aromatics, pyruvate, glycine, cysteine, formate and hydrogen/CO2. Strain PB(T) also oxidized acetate with reduction of sulfate or thiosulfate as the electron acceptor. The bacterium contained MK-7 as the major quinone. The G+C content of the DNA was 53.5 mol%. Comparative 16S rDNA analysis indicated that strain PB(T) belongs to the Bacillus-Clostridium subphylum. However, it was distant from any known genera or micro-organism. The closest known relative was Thermoterrabacterium ferrireducens with 87.4% similarity. The name Thermacetogenium phaeum gen. nov., sp. nov. is proposed. The type strain is strain PBT (= DSM 12270T).


Two-dimensional overdamped fluctuations of the soft perovskite lattice in CsPbBr3.
Lead halide perovskites exhibit structural instabilities and large atomic fluctuations thought to impact their optical and thermal properties, yet detailed structural and temporal correlations of their atomic motions remain poorly understood. Here, these correlations are resolved in CsPbBr3 crystals using momentum-resolved neutron and X-ray scattering measurements as a function of temperature, complemented with first-principles simulations. We uncover a striking network of diffuse scattering rods, arising from the liquid-like damping of low-energy Br-dominated phonons, reproduced in our simulations of the anharmonic phonon self-energy. These overdamped modes cover a continuum of wave vectors along the edges of the cubic Brillouin zone, corresponding to two-dimensional sheets of correlated rotations in real space, and could represent precursors to proposed two-dimensional polarons. Further, these motions directly impact the electronic gap edge states, linking soft anharmonic lattice dynamics and optoelectronic properties. These results provide insights into the highly unusual atomic dynamics of halide perovskites, relevant to further optimization of their optical and thermal properties.


Spinal changes in patients with ankylosing spondylitis on MRI: case series.
Magnetic Resonance Imaging appearances are described in three cases of Ankylosing Spondylitis (AS). The different appearances of AS on magnetic resonance imaging are described and their significance in relation to the pathology of this condition is discussed. MRI is increasingly used to detect changes in the spine of patients with AS. Spinal changes associated with spondyloarthritis are florid anterior spondylitis (Romanus lesion), florid discitis (Andersson lesion), ankylosis, insufficiency fractures of the ankylosed spine, syndesmophytes, arthritis of the apophyseal and costovertebral joints and enthesitis of the interspinal ligaments.


Defense system by mesenchyme cells in bipinnaria larvae of the starfish, Asterina pectinifera.
Here we characterize starfish larval mesenchyme cells, in terms of not only their phagocytic behavior, but also their structural and functional properties as a defense system. Our study reveals the following: (1) most mesenchyme cells construct a dynamic network structure beneath the body wall; (2) mesenchyme cells phagocytically respond to almost all foreign materials and form syncytial aggregates to conceal relatively large amounts and large sizes of foreign material; (3) the morphologies of the syncytial aggregates differ from one another depending on the species and the surface configuration of the cellular foreign material; (4) no mesenchyme cells respond to live mesenchyme cells even though they phagocytose chemically fixed cells; (5) mesenchyme cells phagocytose both cellular constituents effluxed from the ectodermal cells and foreign materials taken into the blastocoel through the body wall. Together, these results suggest that mesenchyme cells are equipped with a spectrum of abilities to engage in a defense system in starfish larva.


Understanding the pharmacological properties of a metabolic PET tracer in prostate cancer.
Generally, solid tumors (>400 mm(3)) are inherently acidic, with more aggressive growth producing greater acidity. If the acidity could be targeted as a biomarker, it would provide a means to gauge the pace of tumor growth and degree of invasiveness, as well as providing a basis for predicting responses to pH-dependent chemotherapies. We have developed a (64)Cu pH (low) insertion peptide (pHLIP) for targeting, imaging, and quantifying acidic tumors by PET, and our findings reveal utility in assessing prostate tumors. The new pHLIP version limits indiscriminate healthy tissue binding, and we demonstrate its targeting of extracellular acidification in three different prostate cancer models, each with different vascularization and acid-extruding protein carbonic anhydrase IX (CAIX) expression. We then describe the tumor distribution of this radiotracer ex vivo, in association with blood perfusion and known biomarkers of acidity, such as hypoxia, lactate dehydrogenase A, and CAIX. We find that the probe reveals metabolic variations between and within tumors, and discriminates between necrotic and living tumor areas.


The effects of background television on the toy play behavior of very young children.
This experiment tests the hypothesis that background, adult television is a disruptive influence on very young children's behavior. Fifty 12-, 24-, and 36-month-olds played with a variety of toys for 1 hr. For half of the hour, a game show played in the background on a monaural TV set. During the other half hour, the TV was off. The children looked at the TV for only a few seconds at a time and less than once per minute. Nevertheless, background TV significantly reduced toy play episode length as well as focused attention during play. Thus, background television disrupts very young children's play behavior even when they pay little overt attention to it. These findings have implications for subsequent cognitive development.


Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group a streptococcal infections.
The use of clindamycin and intravenous immunoglobulin (IVIG) in treatment of invasive group A streptococcal (iGAS) infection, and the need for prophylactic antibiotics in close contacts, remains contentious. Controlled trials are unlikely to be conducted, so prospective, observational studies provide the best data to inform practice. We conducted population-based, prospective, active surveillance of iGAS infections throughout the state of Victoria, Australia (population 4.9 million), from March 2002 through August 2004. Eighty-four cases of severe iGAS infection (streptococcal toxic shock syndrome, necrotizing fasciitis, septic shock, or GAS cellulitis with shock) were identified. Clindamycin-treated patients had more severe disease than clindamycin-untreated patients but lower mortality (15% vs 39%; odds ratio [OR], 0.28; 95% confidence interval [CI], .10-.80). Among those who received concurrent IVIG, the fatality rate was lower still (7%). The adjusted point estimate of the OR for mortality was lower in clindamycin-treated patients (0.31; 95% CI, .09-1.12) and clindamycin plus IVIG-treated patients (0.12; 95% CI, .01-1.29) compared with clindamycin-untreated patients. Three confirmed cases of iGAS infection occurred in household contacts of index cases. The incidence rate of iGAS disease in contacts was 2011 (95% CI, 413-5929) times higher than the population incidence in Victoria. Our data suggest that clindamycin treatment of patients with severe iGAS infections substantially reduces mortality and that this effect may be enhanced by concurrent treatment with IVIG. The dramatically increased risk of iGAS disease among household contacts within 1 month of the index case highlights a potential role for antibiotic prophylaxis.


Biophysicochemical motifs in T cell receptor sequences as a potential biomarker for high-grade serous ovarian carcinoma.
We previously showed, in a pilot study with publicly available data, that T cell receptor (TCR) repertoires from tumor infiltrating lymphocytes (TILs) could be distinguished from adjacent healthy tissue repertoires by the presence of TCRs bearing specific, biophysicochemical motifs in their antigen binding regions. We hypothesized that such motifs might allow development of a novel approach to cancer detection. The motifs were cancer specific and achieved high classification accuracy: we found distinct motifs for breast versus colorectal cancer-associated repertoires, and the colorectal cancer motif achieved 93% accuracy, while the breast cancer motif achieved 94% accuracy. In the current study, we sought to determine whether such motifs exist for ovarian cancer, a cancer type for which detection methods are urgently needed. We made two significant advances over the prior work. First, the prior study used patient-matched TILs and healthy repertoires, collecting healthy tissue adjacent to the tumors. The current study collected TILs from patients with high-grade serous ovarian carcinoma (HGSOC) and healthy ovary repertoires from cancer-free women undergoing hysterectomy/salpingo-oophorectomy for benign disease. Thus, the classification task is distinguishing women with cancer from women without cancer. Second, in the prior study, classification accuracy was measured by patient-hold-out cross-validation on the training data. In the current study, classification accuracy was additionally assessed on an independent cohort not used during model development to establish the generalizability of the motif to unseen data. Classification accuracy was 95% by patient-hold-out cross-validation on the training set and 80% when the model was applied to the blinded test set. The results on the blinded test set demonstrate a biophysicochemical TCR motif found overwhelmingly in women with HGSOC but rarely in women with healthy ovaries, strengthening the proposal that cancer detection approaches might benefit from incorporation of TCR motif-based biomarkers. Furthermore, these results call for studies on large cohorts to establish higher classification accuracies, as well as for studies in other cancer types.


Prevalence and prognostic association of ventricular arrhythmia in non-ischaemic heart failure patients: results from the DANISH trial.
Improved risk stratification to identify non-ischaemic heart failure patients who will benefit from primary prophylactic implantable cardioverter-defibrillator (ICD) is needed. We examined the potential of ventricular arrhythmia to identify patients who could benefit from an ICD. A total of 850 non-ischaemic systolic heart failure patients with left ventricle ≤35% and elevated N-terminal pro-brain natriuretic peptides had a 24-h Holter monitor recording performed. We examined present non-sustained ventricular tachycardia (NSVT), defined as ≥3 consecutive premature ventricular contractions (PVCs) with a rate of ≥100/min, and number of PVCs per hour stratified into low (<30) and high burden (≥30) groups. Outcome measures were overall mortality, sudden cardiac death (SCD), and cardiovascular death (CVD). In total, 193 patients died, 49 from SCD and 125 from CVD. Non-sustained ventricular tachycardia (365 patients) was significantly associated with increased all-cause mortality [hazard ratio (HR) 1.47; 95% confidence interval (CI) 1.07-2.03; P = 0.02] and to CVD (HR 1.89; CI 1.25-2.87; P = 0.003). High burden PVC (352 patients) was associated with increased all-cause mortality (HR1.38; CI 1.00-1.90; P = 0.046) and with CVD (HR 1.78; CI 1.19-2.66; P = 0.005). There was no statistically significant association with SCD for neither NSVT nor PVC. In interaction analyses, neither NSVT (P = 0.56) nor high burden of PVC (P = 0.97) was associated with survival benefit from ICD implantation. Ventricular arrhythmia in non-ischaemic heart failure patients was associated with a worse prognosis but could not be used to stratify patients to ICD implantation.


Clinical toxicology and military application.
The changing operational tempo and types of deployment have, since the end of the Cold War, required a change in CBRN training. The threat from weapons of mass destruction has been replaced with the threat from improvised explosive devices and insurgent attempts to develop asymmetric weapons to target military and civilian populations. In addition exposure to hazardous materials as well as environmental hazards and natural toxins requires a greater awareness of the necessary supportive and definitive management. Developing a cadre of specialists with an interest in toxicology and environmental medicine, within either emergency or acute medicine, would be advantageous to deployed units as well as specialised units, including those tasked in support of UK homeland security. An established pathway for sub-specialisation in clinical toxicology does not yet exist. With the establishment of the College of Emergency Medicine, as well as the Acute Medicine Society and Intensive Care Society further development of clinical toxicology is likely.


[Are stress fractures "hormone fractures"? On the current discussion of the cause of this sports injury].
Discussion on the causes of stress reactions and/or stress fractures is at present under way. There are some pointers indicating that in women athletes this type of sports injury or damage is promoted by hormonal imbalance. Nevertheless, sports practice should always bear in mind that taking the "pill" cannot prevent stress damage. The primary cause is forced mechanical strain or load combined with improperly balanced training. The author makes specific reference to potentially dangerous types of training, and discusses these.


Visitor restriction policies and practices in children's hospitals in North America: results of an Emerging Infections Network Survey.
To delineate the timing of, indications for, and assessment of visitor restriction policies and practices (VRPP) in pediatric facilities. An electronic survey to characterize VRPP in pediatric healthcare facilities. The Infectious Diseases Society of America Emerging Infections Network surveyed 334 pediatric infectious disease consultants via an electronic link. Descriptive analyses were performed. A total of 170 eligible respondents completed a survey between 12 July and August 15, 2016, for a 51% response rate. Of the 104 respondents (61%) familiar with their VRPP, 92 (88%) had VRPP in all inpatient units. The respondents reported age-based VRPP (74%) symptom-based VRPP (97%), and outbreak-specific VRPP (75%). Symptom-based VRPP were reported to be seasonal by 24% of respondents and to be implemented year-round according to 70% of respondents. According to the respondents, communication of VRPP to families occurred at admission (87%) and through signage in care areas (64%), while communication of VRPP to staff occurred by email (77%), by meetings (55%), and by signage in staff-only areas (49%). Respondents reported that enforcement of VRPP was the responsibility of nursing (80%), registration clerks (58%), unit clerks (53%), the infection prevention team (31%), or clinicians 16 (16%). They also reported that the effectiveness of VRPP was assessed through active surveillance of hospital acquired respiratory infections (62%), through active surveillance of healthcare worker exposures (28%) and through patient/family satisfaction assessments (29%). Visitor restriction policies and practices vary in scope, implementation, enforcement, and physician awareness in pediatric facilities. A prospective multisite evaluation of outcomes would facilitate the adoption of uniform guidance.


RF-MEMS Load Sensors with Enhanced Q-factor and Sensitivity in a Suspended Architecture.
In this paper, we present and demonstrate RF-MEMS load sensors designed and fabricated in a suspended architecture that increases their quality-factor (Q-factor), accompanied with an increased resonance frequency shift under load. The suspended architecture is obtained by removing silicon under the sensor. We compare two sensors that consist of 195 μm × 195 μm resonators, where all of the resonator features are of equal dimensions, but one's substrate is partially removed (suspended architecture) and the other's is not (planar architecture). The single suspended device has a resonance of 15.18 GHz with 102.06 Q-factor whereas the single planar device has the resonance at 15.01 GHz and an associated Q-factor of 93.81. For the single planar device, we measured a resonance frequency shift of 430 MHz with 3920 N of applied load, while we achieved a 780 MHz frequency shift in the single suspended device. In the planar triplet configuration (with three devices placed side by side on the same chip, with the two outmost ones serving as the receiver and the transmitter), we observed a 220 MHz frequency shift with 3920 N of applied load while we obtained a 340 MHz frequency shift in the suspended triplet device with 3920 N load applied. Thus, the single planar device exhibited a sensitivity level of 0.1097 MHz/N while the single suspended device led to an improved sensitivity of 0.1990 MHz/N. Similarly, with the planar triplet device having a sensitivity of 0.0561 MHz/N, the suspended triplet device yielded an enhanced sensitivity of 0.0867 MHz/N.


Gender differences in survival in old age.
Although increased survival among females is observed throughout much of adult life, supporting evidence among the oldest old is lacking. We examined the hypothesis that gender differences in survival diminish with advancing age. The Jerusalem Longitudinal Study follows a representative cohort born 1920-1921, comprehensively assessed at ages 70, 78, 85, and 90 (n=463, 927, 1224, and 673, respectively). Mortality data were collected during 1990-2013. Kaplan-Meier survival curves and mortality hazards ratios (HRs) were determined, adjusting for gender, marital status, education, loneliness, self-rated health, physical activity, functional status, neoplasm, diabetes mellitus, hypertension, and ischemic heart disease. Survival between ages 70-78 was 77.3% (n=358/463), 78-85 was 68.9% (n=635/927), 85-90 years was 71.1% (n=870/1224), and 90-93 years was 80.5% (n=542/673). With advancing age, the survival advantage among females versus men declined-at ages 70-78 (85.6% vs. 71%, p<0.0001), 78-85 (74% vs. 63%, p=0.001), 85-90 (74% vs. 67.5%, p=0.06), and 90-93 (80% vs. 81%, p=0.92). Compared to females (HR=1.0), the adjusted HR for male mortality at ages 70-78 was 2.93 (95% confidence interval [CI] 1.75-4.91), ages 78-85 was 2.1 (95% CI 1.5-2.92), ages 85-90 was 1.6 (95% CI 1.2-2.2), and ages 90-93 was 1.1 (95% CI 0.7-1.8). Our findings confirm the hypothesis that the increased longevity observed among females at age 70 gradually diminishes with advancing age, and disappears beyond age 90.


Communicating, coordinating, and collaborating through diversity.
Culturally diverse people are predicted to comprise the majority of the population in the next century. Advanced practice nurses will be responsible for delivering culturally sensitive care as well as managing a work force of diverse caregivers. This article presents an approach to understanding how best to maximize the richness that diversity brings to the client's care.


Neural correlates of face processing associated with development of social communication in 12-month infants with familial risk of autism spectrum disorder.
Differences in face processing in individuals with ASD is hypothesized to impact the development of social communication skills. This study aimed to characterize the neural correlates of face processing in 12-month-old infants at familial risk of developing ASD by (1) comparing face-sensitive event-related potentials (ERP) (Nc, N290, P400) between high-familial-risk infants who develop ASD (HR-ASD), high-familial-risk infants without ASD (HR-NoASD), and low-familial-risk infants (LR), and (2) evaluating how face-sensitive ERP components are associated with development of social communication skills. 12-month-old infants participated in a study in which they were presented with alternating images of their mother's face and the face of a stranger (LR = 45, HR-NoASD = 41, HR-ASD = 24) as EEG data were collected. Parent-reported and laboratory-observed social communication measures were obtained at 12 and 18 months. Group differences in ERP responses were evaluated using ANOVA, and multiple linear regressions were conducted with maternal education and outcome groups as covariates to assess relationships between ERP and behavioral measures. For each of the ERP components (Nc [negative-central], N290, and P400), the amplitude difference between mother and stranger (Mother-Stranger) trials was not statistically different between the three outcome groups (Nc p = 0.72, N290 p = 0.88, P400 p = 0.91). Marginal effects analyses found that within the LR group, a greater Nc Mother-Stranger response was associated with better expressive language skills on the Mullen Scales of Early Learning, controlling for maternal education and outcome group effects (marginal effects dy/dx = 1.15; p < 0.01). No significant associations were observed between the Nc and language or social measures in HR-NoASD or HR-ASD groups. In contrast, specific to the HR-ASD group, amplitude difference between the Mother versus Stranger P400 response was positively associated with expressive (dy/dx = 2.1, p < 0.001) and receptive language skills at 12 months (dy/dx = 1.68, p < 0.005), and negatively associated with social affect scores on the Autism Diagnostic Observation Schedule (dy/dx = - 1.22, p < 0.001) at 18 months. In 12-month-old infant siblings with subsequent ASD, increased P400 response to Mother over Stranger faces is positively associated with concurrent language and future social skills.


Sexual reproduction between partners of the same mating type in Cryptococcus neoformans.
Cryptococcus neoformans is a globally distributed human fungal pathogen that causes life-threatening meningoencephalitis in immunocompromised patients. It has a defined sexual cycle involving haploid cells of alpha and a mating types, yet the vast majority of environmental and clinical isolates are alpha (ref. 3). Sexual recombination is normally expected to occur between isolates of opposite mating type in organisms with two mating types (or sexes). How sexual reproductive potential can be maintained in an organism with a largely unisexual, nearly clonal population genetic structure is unknown. One clue, however, is that alpha strains undergo fruiting, a process that resembles sexual mating but is thought to be strictly mitotic and asexual. We report here that hallmarks of mating occur during fruiting, including diploidization and meiosis. Pheromone response pathway elements and the key meiotic regulator Dmc1 are required for efficient fruiting. Furthermore, fusion and meiosis can occur between non-isogenic alpha strains, enabling genetic exchange. These studies reveal how sexual reproduction can occur between partners of the same mating type. These findings have implications for the evolution of microbial pathogens, as well as for parthenogenesis, cell fusion events and transitions between self-fertilizing and outcrossing modes of reproduction observed in both fungi and other kingdoms.


Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137).
Integrase (IN), an essential enzyme of human immunodeficiency virus (HIV), is an attractive antiretroviral drug target. The antiviral activity and resistance profile in vitro of a novel IN inhibitor, elvitegravir (EVG) (also known as JTK-303/GS-9137), currently being developed for the treatment of HIV-1 infection are described. EVG blocked the integration of HIV-1 cDNA through the inhibition of DNA strand transfer. EVG inhibited the replication of HIV-1, including various subtypes and multiple-drug-resistant clinical isolates, and HIV-2 strains with a 50% effective concentration in the subnanomolar to nanomolar range. EVG-resistant variants were selected in two independent inductions, and a total of 8 amino acid substitutions in the catalytic core domain of IN were observed. Among the observed IN mutations, T66I and E92Q substitutions mainly contributed to EVG resistance. These two primary resistance mutations are located in the active site, and other secondary mutations identified are proximal to these primary mutations. The EVG-selected IN mutations, some of which represent novel IN inhibitor resistance mutations, conferred reduced susceptibility to other IN inhibitors, suggesting that a common mechanism is involved in resistance and potential cross-resistance. The replication capacity of EVG-resistant variants was significantly reduced relative to both wild-type virus and other IN inhibitor-resistant variants selected by L-870,810. EVG and L-870,810 both inhibited the replication of murine leukemia virus and simian immunodeficiency virus, suggesting that IN inhibitors bind to a conformationally conserved region of various retroviral IN enzymes and are an ideal drug for a range of retroviral infections.


Transient Neonatal Diabetes Mellitus: A Challenge and Opportunity for Specialized Nursing Care.
Transient neonatal diabetes mellitus (TNDM) is a rare disorder, with a reported incidence of approximately 1 in 450,000 live births. It is characterized by insulin-requiring hyperglycemia in the neonatal period. The disease improves by early childhood, but the patient may relapse in later life. Diagnosis is made after genetic testing following presentation with hyperglycemia not conforming to Type 1 or Type 2 diabetes. Management is based on insulin and possible sulfonylurea administration. Three genetically distinct subtypes of TNDM are recognized. Type 1 TNDM is due to overexpression of genes at the 6q24 locus, whereas the 11p15 locus is involved in Type 2 and 3 TNDM. In this article the clinical presentation, management, and genetics of TNDM are discussed, particularly emphasizing the role of the neonatal nurse.


Diffuse Lewy body disease presenting as Parkinson's disease with progressive aphasia.
Primary progressive aphasia (PPA) is a progressive language disorder often due to an underlying neurodegenerative disease. The most common pathologies associated with PPA include frontotemporal lobar degeneration (FTLD)-tau, FTLD-associated with transactivation response DNA-binding protein of 43 kDa (TDP-43) (FTLD-TDP), and Alzheimer's disease (AD). Accumulating evidence has suggested that Lewy body disease (LBD) can also be associated with PPA. We herein report a 78-year-old Caucasian woman who initially presented with levodopa-responsive parkinsonism at age 67 and later developed cognitive impairment, visual hallucinations, rapid eye movement sleep behavior disorder, and progressive aphasia, characterized by reduced spontaneous speech, word-finding difficulty, and difficulties in writing and reading. 18 Fluorodeoxyglucoase (FDG)-positron emission tomography (PET) performed at the age of 73 years identified hypometabolism in the frontal (right > left), temporal (left > right), and parietal (left > right) lobes. Neuropathological assessment revealed diffuse LBD (DLBD), AD, and TDP-43 stage 6 with prehippocampal sclerosis. Senile plaques were numerous, but only a few neurofibrillary tangles were present in the neocortex. The Braak neurofibrillary tangle stage was IV, and the Thal amyloid phase was 3. Lewy-related pathology was severe in the neocortex, as well as limbic cortices, basal forebrain, amygdala, and brainstem. Compared to 166 DLBD cases with a clinical diagnosis of dementia with Lewy bodies (DLB), the Lewy body count of the patient in this report was highest in the inferior parietal cortex, followed by midfrontal and superior temporal cortices. The findings suggest that severe cortical LBD pathology has contributed to her progressive aphasia. Autopsy cases of LBD presenting as PPA have been reported, but patients with PD and autopsy-proven DLBD who later developed progressive aphasia have not been reported. Our findings indicate that PD can be associated with progressive aphasia later in the disease course. Although uncommon, LBD should be considered as a differential diagnosis of progressive aphasia.


Management of women who use drugs during pregnancy.
Substance abuse in pregnancy is associated with significant maternal and fetal morbidity. The complication for care is that the mother is the cause of the problem that potentially harms not only herself but also her unborn child. The abuse is further complicated by the associated legal, social and environmental problems. The aim for the obstetrician is to provide a non-judgemental, supportive environment to minimise the risk, not only during pregnancy and the neonatal period, but also in the long term. To achieve this, caregivers need to be multidisciplinary and tolerant of the mother's problem. The aim of antenatal care is to reduce risk, which does not mean that the mother must abstain from drug use. The aim is to keep her within the care system and encourage her to take responsibility for her situation. No-one should be turned away or denied help as, ultimately, this is harmful to the mother and her baby. To provide this care, the obstetrician needs support from midwives, addiction counsellors, social workers, neonatologists, health visitors and general practitioners. Whereas the healthcare structure in the UK lends itself to this approach, this is not the case in other parts of the world. However, programmes of comprehensive antenatal care do not universally improve the health of the mother and the outcome of her pregnancy. The specifics of the care provided are probably less important than the quality of the care given and the degree of engagement of the individual. This chapter outlines the problems and potential solutions with reference to the service in Leeds in the UK.


Posttraumatic Retrograde and Anterograde Amnesia: Pathophysiology and Implications in Grading and Safe Return to Play.
OBJECTIVE: The presence of posttraumatic amnesia (PTA) and loss of consciousness have been main factors used in a number of concussion guidelines. In this article, the focus is on using PTA (both retrograde and anterograde) as salient indicators of traumatic brain injury severity and the most reliable index of outcome prediction, even in mild cases. DATA SOURCES: A MEDLINE search for the years 1990-2000 using the key words posttraumatic retrograde and anterograde amnesia, concussion and mild traumatic brain injury was done. DATA SYNTHESIS: On-the-field testing of PTA is a salient and integral component of the initial and follow-up neurologic assessments of the head-injured athlete. CONCLUSIONS/RECOMMENDATIONS: Initial and follow-up assessments of PTA, anterograde and retrograde, are an essential part of the neurologic evaluation of the head-injured athlete. Increasingly, neuropsychological testing, including computer models, is being employed in this assessment. The importance of not just PTA but all postconcussion signs and symptoms being absent at rest and exertion before allowing the athlete to return to play is emphasized.


[Determination of the blood flow rate in the arteries and veins and its clinical significance].
A noninvasive ultrasonic method (a two-beam Doppler meter with separation of the direction) is suggested for quantitative assessment of localized disorders of hemodynamics of arterial blood flow and venous blood outflow. The authors measured the maximum and mean blood flow rate in the aorta and larger arteries and veins of 23 healthy persons and 94 patients with hypertensive disease, ischemic heart disease, and mitral valvular diseases. Experiments were conducted with measurement of the blood flow rate in the aorta, vena cava superior and pulmonary artery in dogs and the normal values were determined. A decrease in the rate of the blood flow in vessels in the diseases mentioned above, especially in circulatory insufficiency, was found, as well as local asymmetry.


Excretion of metabolites of biogenic amines in patients with irradiated brain tumours.
The metabolities of biogenic amines were determined in the 24-hour urine samples of patients submitted to surgical removal of a malignant brain tumour and subsequently to telecobalt therapy of the corresponding head region. A significant increase in the excretion of 5-hydroxyindoleacetic acid (5-HIAA), vanillinmandelic acid (VMA) as well as of free 3-methoxy-4-hydroxy-phenylglycol (MHPG) during the period of irradiation was found. This increase is presumably the result of radiation induced release of their parent amines from the brain; in the case of VMA the secondary response of the peripheral sympathetic system might occur.


Stat5 opposes the transcription factor Tox and rewires exhausted CD8+ T cells toward durable effector-like states during chronic antigen exposure.
Rewiring exhausted CD8+ T (Tex) cells toward functional states remains a therapeutic challenge. Tex cells are epigenetically programmed by the transcription factor Tox. However, epigenetic remodeling occurs as Tex cells transition from progenitor (Texprog) to intermediate (Texint) and terminal (Texterm) subsets, suggesting development flexibility. We examined epigenetic transitions between Tex cell subsets and revealed a reciprocally antagonistic circuit between Stat5a and Tox. Stat5 directed Texint cell formation and re-instigated partial effector biology during this Texprog-to-Texint cell transition. Constitutive Stat5a activity antagonized Tox and rewired CD8+ T cells from exhaustion to a durable effector and/or natural killer (NK)-like state with superior anti-tumor potential. Temporal induction of Stat5 activity in Tex cells using an orthogonal IL-2:IL2Rβ-pair fostered Texint cell accumulation, particularly upon PD-L1 blockade. Re-engaging Stat5 also partially reprogrammed the epigenetic landscape of exhaustion and restored polyfunctionality. These data highlight therapeutic opportunities of manipulating the IL-2-Stat5 axis to rewire Tex cells toward more durably protective states.


Synthesis of [PtCl2(4,4'-dialkoxy-2,2'-bipyridine)] complexes and their in vitro anticancer properties.
A series of [Pt(II)Cl2(4,4'-dialkoxy-2,2'-bipyridine)] complexes of the general formula of [Pt(II)Cl2(4,4'-bis(RO)-2,2'-bipyridine)] (where R = -(CH2)n-1CH3, n = 2-6, 8) were synthesized and characterized using (1)H NMR, (13)C NMR spectroscopy, elemental analysis, mass spectroscopy, and differential scanning calorimetry measurements. The in vitro anti-proliferative activities of these compounds were evaluated against human cancer cell lines A549 (lung adenocarcinoma), DU145 (prostate carcinoma), MCF-7 (breast adenocarcinoma), and MDA-MB-435 (melanoma) using the MTS cell proliferation assay. Several Pt(II) coordination compounds were found to have greatly enhanced activity compared to cisplatin after a one hour treatment in all cell lines tested. A structure-activity relationship was observed, that is, the activity increases as the carbon chain length of the alkyl group increases. The activity was maximum when the carbon chain length reached four or five carbons and decreased with the longer carbon chain length. Fluorescence microscopy and flow cytometry data indicate that the main mode of cell death is through apoptosis with some necrotic responses.


The effects of focus of attention on attributional bias in patients experiencing auditory hallucinations.
Cognitive models suggest that auditory hallucinations occur as the result of internal events attributed to an external source. The present study represents an attempt to evaluate the source monitoring performance of people who experience auditory hallucinations, specifically in terms of the suggested links between source monitoring, emotionality of stimuli and self-focused attention. The source monitoring performance of a group of 30 patients with a diagnosis of a schizophrenia spectrum disorder who experience auditory hallucinations was compared following successful experimental manipulation of their attention, designed to increase and decrease their levels of self-focused attention. The inclusion of words previously rated as emotionally salient by schizophrenic patients assessed the effect of emotionality on source monitoring performance. This study demonstrated that participants' ratings of both internality and control of their responses to the word association task were lower in the external focus condition than the internal focus condition. Furthermore, it was found that ratings of internality and control were lower for responses to both positive and negative stimuli compared to responses to neutral stimuli, and the magnitude of these differences was amplified in the internal focus condition relative to the external focus condition. Focus of attention has a significant effect on source monitoring performance in people experiencing auditory hallucinations. The theoretical and clinical implications of these findings are discussed.


Angiotensin converting enzyme inhibition reduces the expression of transforming growth factor-beta1 and type IV collagen in diabetic vasculopathy.
The purpose of this study was to assess the role of transforming growth factor (TGF)-beta1 in the development of diabetes-associated mesenteric vascular hypertrophy and in the antitrophic effect of angiotensin converting enzyme inhibitors. Streptozotocin-induced diabetic and control Sprague-Dawley rats were randomly allocated to treatment with the angiotensin converting enzyme inhibitor ramipril or to no treatment and were killed 1 or 3 weeks after the streptozotocin injection. Blood was collected and mesenteric vessels removed. Mesenteric vascular weight was measured and TGF-beta1 and alpha1 (type IV) collagen messenger (m)RNA levels were analysed by Northern analysis. Immunohistochemical analyses for TGF-beta1 and type IV collagen were also performed. The diabetic rats had increased mesenteric vessel weight at 3 weeks but not at 1 week and a concomitant rise in mesenteric TGF-beta1 and in alpha1 (type IV) collagen mRNA levels. Ramipril treatment attenuated mesenteric vessel hypertrophy and prevented the increase in TGF-beta1 and alpha1 (type IV) collagen mRNA levels after 3 weeks of diabetes. The immunohistochemical analysis revealed that diabetes was associated with increased TGF-beta1 and type IV collagen protein and extracellular matrix accumulation in mesenteric vessels, and this increase was reduced by ramipril treatment. These results support the concept that TGF-beta is involved in the changes associated with diabetic vascular disease, and suggest a mechanism by which angiotensin converting enzyme inhibitors exert their antitrophic effects.


A CMOS binary pattern classifier based on Parzen's method.
Biological circuitry in the brain that has been associated with the Parzen method of classification inspired an analog CMOS binary pattern classifier. The circuitry resides on three separate chips. The first chip computes the closeness of a test vector to each training vector stored on the chip where "vector closeness" is defined as the number of bits two vectors have in common above some thresholds. The second chip computes the closeness of the test vector to each possible category where "category closeness" is defined as the sum of the closenesses of the test vector to each training vector in a particular category. Category closenesses are coded by currents which feed into an "early bird" winner-take-all circuit on the third chip that selects the category closest to the test vector. Parzen classifiers offer superior classification accuracy than the common nearest neighbor Hamming networks. A high degree of parallelism allows for O(1) time complexity and the chips are tillable for increased training vector storage capacity. Proof-of-concept chips were fabricated through the MOSIS chip prototyping service and successfully tested.


ADT-OH improves intestinal barrier function and remodels the gut microbiota in DSS-induced colitis.
Owing to the increasing incidence and prevalence of inflammatory bowel disease (IBD) worldwide, effective and safe treatments for IBD are urgently needed. Hydrogen sulfide (H2S) is an endogenous gasotransmitter and plays an important role in inflammation. To date, H2S-releasing agents are viewed as potential anti-inflammatory drugs. The slow-releasing H2S donor 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADT-OH), known as a potent therapeutic with chemopreventive and cytoprotective properties, has received attention recently. Here, we reported its anti-inflammatory effects on dextran sodium sulfate (DSS)-induced acute (7 days) and chronic (30 days) colitis. We found that ADT-OH effectively reduced the DSS-colitis clinical score and reversed the inflammation-induced shortening of colon length. Moreover, ADT-OH reduced intestinal inflammation by suppressing the nuclear factor kappa-B pathway. In vivo and in vitro results showed that ADT-OH decreased intestinal permeability by increasing the expression of zonula occludens-1 and occludin and blocking increases in myosin II regulatory light chain phosphorylation and epithelial myosin light chain kinase protein expression levels. In addition, ADT-OH restored intestinal microbiota dysbiosis characterized by the significantly increased abundance of Muribaculaceae and Alistipes and markedly decreased abundance of Helicobacter, Mucispirillum, Parasutterella, and Desulfovibrio. Transplanting ADT-OH-modulated microbiota can alleviate DSS-induced colitis and negatively regulate the expression of local and systemic proinflammatory cytokines. Collectively, ADT-OH is safe without any short-term (5 days) or long-term (30 days) toxicological adverse effects and can be used as an alternative therapeutic agent for IBD treatment.


Thermodependence of growth and enzymatic activities implicated in pathogenicity of two Erwinia carotovora subspecies (Pectobacterium spp.).
Erwinia carotovora subsp. atroseptica and Erwinia carotovora subsp. carotovora can cause substantial damage to economically important plant crops and stored products. The occurrence of the disease and the scale of the damage are temperature dependent. Disease development consists first of active multiplication of the bacteria in the infection area and then production of numerous extracellular enzymes. We investigated the effects of various temperatures on these two steps. We assayed the specific growth rate and the pectate lyase and protease activities for eight strains belonging to E. carotovora subsp. atroseptica and E. carotovora subsp. carotovora in vitro. The temperature effect on growth rate and on pectate lyase activity is different for the two subspecies, but protease activity appears to be similarly thermoregulated. Our results are in agreement with ecological data implicating E. carotovora subsp. atroseptica in disease when the temperature is below 20 degrees C. The optimal temperature for pathogenicity appears to be different from the optimal growth temperature but seems to be a compromise between this temperature and temperatures at which lytic activities are maximal.


Fusion-activated Ca(2+) entry: an "active zone" of elevated Ca(2+) during the postfusion stage of lamellar body exocytosis in rat type II pneumocytes.
Ca(2+) is essential for vesicle fusion with the plasma membrane in virtually all types of regulated exocytoses. However, in contrast to the well-known effects of a high cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) in the prefusion phase, the occurrence and significance of Ca(2+) signals in the postfusion phase have not been described before. We studied isolated rat alveolar type II cells using previously developed imaging techniques. These cells release pulmonary surfactant, a complex of lipids and proteins, from secretory vesicles (lamellar bodies) in an exceptionally slow, Ca(2+)- and actin-dependent process. Measurements of fusion pore formation by darkfield scattered light intensity decrease or FM 1-43 fluorescence intensity increase were combined with analysis of [Ca(2+)](c) by ratiometric Fura-2 or Fluo-4 fluorescence measurements. We found that the majority of single lamellar body fusion events were followed by a transient (t(1/2) of decay = 3.2 s) rise of localized [Ca(2+)](c) originating at the site of lamellar body fusion. [Ca(2+)](c) increase followed with a delay of approximately 0.2-0.5 s (method-dependent) and in the majority of cases this signal propagated throughout the cell (at approximately 10 microm/s). Removal of Ca(2+) from, or addition of Ni(2+) to the extracellular solution, strongly inhibited these [Ca(2+)](c) transients, whereas Ca(2+) store depletion with thapsigargin had no effect. Actin-GFP fluorescence around fused LBs increased several seconds after the rise of [Ca(2+)](c). Both effects were reduced by the non-specific Ca(2+) channel blocker SKF96365. Fusion-activated Ca(2+)entry (FACE) is a new mechanism that leads to [Ca(2+)](c) transients at the site of vesicle fusion. Substantial evidence from this and previous studies indicates that fusion-activated Ca(2+) entry enhances localized surfactant release from type II cells, but it may also play a role for compensatory endocytosis and other cellular functions.


Osteoarthritis of the knee in Nigerians.
Eighty-one patients with 116 osteoarthritic knees were seen by the author at the University College Hospital (UCH), Ibadan in six years. Below the age of 50 the disease was significantly commoner among Nigerians than Caucasians; 39.5% of our patients were less than 50 years old, compared with 1.1% of Caucasians. In contrast with the latter group, trauma was apparently an insignificant predisposing factor of knee degeneration in our patients. In some cases osteoarthritis was associated with severe valgus deformity in rather young patients, suggesting a probable causal relationship. Multiple joint osteoarthritis was significantly less common in Nigerians than in Caucasians.


Decreased Visual Search Behavior in Elderly Drivers during the Early Phase of Reverse Parking, But an Increase during the Late Phase.
The aim of this study was to assess the characteristics of visual search behavior in elderly drivers in reverse parking. Fourteen healthy elderly and fourteen expert drivers performed a perpendicular parking task. The parking process was divided into three consecutive phases (Forward, Reverse, and Straighten the wheel) and the visual search behavior was monitored using an eye tracker (Tobii Pro Glasses 2). In addition, driving-related tests and quality of life were evaluated in elderly drivers. As a result, elderly drivers had a shorter time of gaze at the vertex of the parking space both in direct vision and reflected in the driver-side mirror during the Forward and the Reverse phases. In contrast, they had increased gaze time in the passenger-side mirror in the Straighten the wheel phase. Multiple regression analysis revealed that quality of life could be predicted by the total gaze time in the Straighten the wheel phase (β = -0.45), driving attitude (β = 0.62), and driving performance (β = 0.58); the adjusted R2 value was 0.87. These observations could improve our understanding of the characteristics of visual search behavior in parking performance and how this behavior is related to quality of life in elderly drivers.


Insulin does not mediate glucose stimulation of proinsulin biosynthesis.
It has recently been suggested that insulin augments its own production by a physiologically important feed-forward autocrine loop. We studied the kinetics of glucose-regulated proinsulin gene expression and proinsulin biosynthesis in normal rat islets with emphasis on the potential role of insulin as a mediator of the glucose effect. There was a time-dependent increase in steady-state proinsulin mRNA in islets cultured at 16.7 mmol/l compared with 3.3 mmol/l glucose; no early (1-3 h) increase in proinsulin gene expression was observed. In contrast, there was a threefold increase in proinsulin biosynthesis within 1 h of glucose stimulation that was not affected by inhibition of glucose-stimulated proinsulin gene transcription with actinomycin D. In addition, inhibition of glucose-stimulated insulin secretion with diazoxide had no effect on glucose-stimulated proinsulin mRNA or biosynthesis. Furthermore, addition of different concentrations of insulin to islets cultured in low glucose failed to affect proinsulin biosynthesis. Taken together, our data suggest that the early glucose-dependent increase in proinsulin biosynthesis is mainly regulated at the translational level, rather than by changes in proinsulin gene expression. Moreover, we could not demonstrate any effect of insulin on islet proinsulin mRNA level or rate of proinsulin biosynthesis. Thus, if insulin has any effect on the proinsulin biosynthetic apparatus, it is a minor one. We conclude that the secreted insulin is not an important mediator of insulin production in response to glucose.


Implementation Challenges Using a Novel Method for Collecting Patient-Reported Outcomes After Injury.
Monitoring longitudinal patient-reported outcomes after injury is important for comprehensive trauma care. Current methodologies are resource-intensive and struggle to engage patients. Patients ≥18 y old admitted to the trauma service were prospectively enrolled. The following inclusion criteria were used: emergency operation, ICU length of stay ≥2 midnights, or hospital length of stay ≥4 d. Validated and customized questionnaires were administered using a novel internet-based survey platform. Three-month follow-up surveys were administered. Contextual field notes regarding barriers to enrollment/completion of surveys and challenges faced by participants were recorded. Forty-seven patients were eligible; 26 of 47 (55%) enrolled and 19 of 26 (73%) completed initial surveys. The final sample included 14 (74%) men and 5 (26%) women. Primary barriers to enrollment included technological constraints and declined participation. Contextual field notes revealed three major issues: competing hospital tasks, problems with technology, and poor engagement. The average survey completion time was 43 ± 27 min-21% found this too long. Seventy-four percent reported the system "easy to use" and 95% reported they would "very likely" or "definitely" respond to future surveys. However, 10 of 26 (38%) patients completed 3-mo follow-up. Despite a well-rated internet-based survey platform, study participation remained challenging. Lack of email access and technological issues decreased enrollment and the busy hospitalization posed barriers to completion. Despite a thoughtful operational design and implementation plan, the trauma population presented a challenging group to engage. Next steps will focus on optimizing engagement, broadening access to survey reminders, and enhancing integration into clinical workflows.


Anesthesia Management of a Premature Neonate with Congenital Heart Disease during Emergency Diaphragmatic Hernia Surgery: A Case Report.
In this medical report, we successfully implemented anesthesia management for an infant with congenital heart disease undergoing congenital diaphragmatic hernia (CDH) repair. Left-sided CDH was diagnosed on a postnatal chest X-ray on day 1 of her life. The child was complicated with congenital heart diseases and pulmonary hypertension and showed severe dyspnea immediately after birth. Thoracoscopic CDH repair puts forward high requirements for anesthesia. Neonatal CDH combined with congenital heart disease brings more challenges to anesthesia. For high-risk premature neonates, anesthesia selections are essential, as those factors directly affect the prognosis. We report the application of S-ketamine as an anesthetic in this kind of operation for the first time. The postoperative recovery was uneventful. This case report reviews anesthesia management of critical CDH neonates, hoping to provide information to healthcare professionals unfamiliar with the treatment of this kind of patient.


Mast cell degranulation mediates compound 48/80-induced hyperalgesia in mice.
Mast cells mediate allergies, hypersensitivities, host defense, and venom neutralization. An area of recent interest is the contribution of mast cells to inflammatory pain. Here we found that specific, local activation of mast cells produced plantar hyperalgesia in mice. Basic secretagogue compound 48/80 induced plantar mast cell degranulation accompanied by thermal hyperalgesia, tissue edema, and neutrophil influx in the hindpaws of ND4 Swiss mice. Blocking mast cell degranulation, neutrophil extravasation, and histamine signaling abrogated these responses. Compound 48/80 also produced edema, pain, and neutrophil influx in WT C57BL/6 but not in genetically mast cell-deficient C57BL/6-Kit(W-sh)(/)(W-sh) mice. These responses were restored following plantar reconstitution with bone marrow-derived cultured mast cells.


Influence of intracoronary nifedipine on left ventricular function, coronary vasomotility, and myocardial oxygen consumption.
The effect of intracoronary nifedipine on regional and global left ventricular performance, coronary vasomotility, and myocardial oxygen consumption is reported. Left ventricular pressures and volume indices of contractility and relaxation were simultaneously recorded in five patients without coronary artery disease. In these patients, nifedipine in the left main coronary artery not only delayed (+115 ms) anterior wall contraction but also slowed (3.5 vs 1.9 cm/s) and depressed it (-26%), resulting in a depression of global left ventricular ejection. This asynchrony and depression of regional contraction is considered to be responsible for the slowed isovolumic contraction and relaxation of the whole ventricle. In 10 other patients with coronary artery disease, coronary sinus blood flow and myocardial oxygen consumption were measured before and after intracoronary nifedipine. The observed decrease in myocardial oxygen consumption (-28%) depended primarily on a decrease in contractility and left ventricular performance. In a third study group of 12 patients with coronary artery disease, the effects of intracoronary nifedipine on the coronary vasomotility of 40 coronary segments (normal, prestenotic, stenotic, poststenotic) were quantitatively determined. Left ventricular haemodynamics and coronary sinus saturation were monitored while the cineangiograms were recorded before and after nifedipine. Nifedipine provoked vasodilatation of the normal (+10.3%), prestenotic, stenotic (+4 to 30%), and poststenotic (+16.4%) coronary segments, which persisted after the disappearance of its direct effects on the myocardium. This transient regional "cardioplegic" effect of nifedipine, associated with an increase in coronary blood flow, a reduction in myocardial oxygen consumption, and a vasodilatation of the epicardial vessels is likely to be beneficial during temporary coronary occlusion such as occurs in spasm or transluminal angioplasty.


Radix entomolaris in permanent mandibular first molars: case reports and literature review.
This article presents three cases involving permanent mandibular first molars with unusual root morphology. While the permanent mandibular first molar normally has two roots (one mesial and one distal), an additional root sometimes is found distolingually; this condition is known as radix entomolaris (RE). This article also reviews the literature concerning the morphology, prevalence, etiology, classification, diagnosis, and significance of RE.


Interaction of subtype-selective antagonists with alpha 1-adrenergic receptor binding sites in rat tissues.
(+)-Niguldipine inhibited specific 125I-BE 2254 binding more potently in membrane preparations from rat tissues enriched in the alpha 1A subtype (hippocampus and vas deferens) than those with the alpha 1B subtype (liver and spleen). Inhibition curves for (+)-niguldipine were better fit by a two-site model in most tissues, although Kl values for each site varied markedly between tissues. The potency of this lipophilic drug was highly dependent on tissue concentration, probably accounting for most of this variability. Pretreatment of membranes with chloroethylclonidine (CEC) to inactivate the alpha 1B subtype did not completely eliminate the low affinity sites for (+)-niguldipine, particularly in heart. Saturation analysis showed that (+)-niguldipine competitively inhibited both alpha 1A and alpha 1B subtypes. However, substantial non-competitive inhibition was also observed in several tissues. Analysis of inhibition curves for 5-methylurapidil gave similar proportions of alpha 1A and alpha 1B receptor sites as were calculated for (+)-niguldipine in various tissues. Although (+)-niguldipine and 5-methylurapidil revealed variable proportions of low affinity sites in CEC-pretreated hippocampus and heart, this was not observed with inhibition curves for WB 4101 and phentolamine. These results are generally consistent with the previously defined alpha 1A and alpha 1B subtypes. 5-Methylurapidil currently appears to be the best antagonist for discriminating these subtypes; (+)-niguldipine shows similar selectivity but is complicated by a high lipophilicity. However, the persistence of low affinity sites for 5-methylurapidil and (+)-niguldipine after CEC pretreatment and the noncompetitive effects of (+)-niguldipine in some tissues raise the possibility of an additional subtype(s) of alpha 1-adrenergic receptors in rat tissues.


Helicobacter pylori infection enhances N-methyl-N-nitrosourea-induced stomach carcinogenesis in the Mongolian gerbil.
No previous report has demonstrated the relationship between Helicobacter pylori (HP) infection and gastric carcinogenesis in an experimental animal model. A total of 170 male Mongolian gerbils (MGs) were divided into nine groups (18 < or = n < or = 20 for each group). MGs of four groups were inoculated with HP before or after continuous N-methyl-N-nitrosourea (MNU) administration via the drinking water. Both intestinal-type and diffuse-type adenocarcinomas, including signet ring-cell carcinomas, were found at 40 weeks after the study commenced, but only in the HP inoculation groups with MNU exposure and not in the MNU alone or HP inoculation alone control groups. The present findings demonstrate that HP infection increases the incidence of MNU-induced adenocarcinoma of the glandular stomach in MGs.


Effect of depot oral cholecalciferol treatment on secondary hyperparathyroidism in stage 3 and stage 4 chronic kidney diseases patients.
By the time patients require dialysis replacement therapy, nearly all chronic kidney diseases (CKD) patients are affected with uremic bone diseases. High-turnover osteodystrophy can be prevented; patients with CKD should be monitored for imbalances in calcidiol (25 OH vitamin D), calcium, and phosphate homeostasis. We aimed to determine the effect of a monthly oral 300,000 IU vitamin D(3) (cholecalciferol) supplementation on the uremic bone diseases (UBD) markers such as iPTH and alkaline phosphatase in CKD patients. Among a total of 70 patients under treatment in the nephrology unit, 40 predialysis CKD patients (mean age of 49 +/- 14, male/female 20/20) were included the study. The patients were randomly divided into two groups. Treatment group included 20 patients (mean age of 51 +/- 14, male/female 9/11), and the control group comprised 20 patients (mean age of 47 +/- 14, male/female 9/11). Treatment group patients were given a single dose of Devit3 ampoule (300,000 U cholecalciferol) per month orally way. Patients in the control group did not take any vitamin D for a month. The level of calcidiol was lower than normal range in two groups. After a month, treatment group patient's calcidiol increased statistically significant (6.8 +/- 3.5 to 17.8 +/- 21.4 ng/mL, p < 0.001). After a month, iPTH level decreased in the treatment group statistically significantly (368 +/- 274 to 279 +/- 179 pg/ml, p < 0.001). At the 30(th) day of the treatment, in 9/20 of the treatment group patients (45%), the iPTH value decreased at least 30% (p < 0.001). We suggest that oral depot cholecalciferol treatment causes a statistically significant decrease of serum iPTH level but does not cause a statistically significant change in Ca, P, ratio of Ca x P, or urinary calcium creatinine rate in UBD predialysis CKD. This treatment can be used safely for the predialysis CKD patients, along with the cautious control of serum calcium and phosphor.


Cytochrome C on silica nanoparticles: influence of nanoparticle size on protein structure, stability, and activity.
The structure, thermodynamic and kinetic stability, and activity of cytochrome c (cyt c) on silica nanoparticles (SNPs) of different sizes have been studied. Adsorption of cyt c onto larger SNPs results in both greater disruption of the cyt c global structure and more significant changes of the local heme microenvironment than upon adsorption onto smaller SNPs. The disruption of the heme microenvironment leads to a more solvent-accessible protein active site, as suggested by Soret circular dichroism spectroscopy and through an increase in peroxidase activity as a function of increased SNP size. Similarly, the stability of cyt c decreases more dramatically upon adsorption onto larger SNPs. These results are consistent with changes in protein-nanoparticle interactions that depend on the size or surface curvature of the supporting nanostructure. This study provides further fundamental insights into the effects of nanoscale surfaces on adsorbed protein structure and function.


Cardiac arrhythmias and risk stratification after myocardial infarction: results of the CARISMA pilot study.
CARISMA is a multicenter study enrolling patients with a left ventricular ejection fraction < or = 40% after acute myocardial infarction (AMI), in whom an electrocardiogram (ECG) loop recorder (ILR) is implanted to measure the incidence of tachyarrhythmia and bradyarrhythmia episodes. The value of 24 hour ambulatory ECG, signal-averaged ECG late potentials, QT dispersion, T wave alternans, and electrophysiologic testing as predictors of life-threatening arrhythmias is examined. The study tested the automatic documentation of arrhythmias by the ILR in 30 post-AMI patients. At a mean follow-up of 47 days, the ILR had detected atrial tachyarrhythmias in 8 of 28 patients, nonsustained ventricular tachycardias in 2, and transient third degree atrioventricular block in 3. An indication for implantation of an implantable cardioverter defibrillator (ICD) or permanent pacemaker (PM) was observed in 9 out of 29 patients (31%). An average of 2.3 events stored by the ILR were due to inappropriate triggering. Because its memory size is limited to a maximum of 14 episodes, the ILR was unable to store arrhythmias 28% of the follow-up time. False events rate and monitoring time were improved by suturing the device within its pocket. The ILR allowed the automatic detection of brady- and tachyarrhythmias in post-AMI patients, though a high incidence of false activations were observed. Clinically significant arrhythmias were recorded in a large number of patients with depressed left ventricular function early after AMI. This prompted the implantation of ICD or PM in nearly one third of patients.


Evoked potentials during isoflurane anaesthesia.
Somatosensory, visual and brainstem auditory evoked potentials were recorded in 10 unpremedicated patients anaesthetized with isoflurane in oxygen. Recordings were made at 0.5%, 1.1% and 1.65% (six patients) end-tidal isoflurane concentration. There were statistically significant increases in the latencies of the somatosensory (N20), visual and brainstem auditory potentials (waves III and V) with increasing concentrations of isoflurane. The central conduction time was prolonged. Amplitudes of the somatosensory and visual potentials were reduced with increasing concentrations of isoflurane. The effects of isoflurane on evoked potentials are similar to those of halothane and enflurane. It is possible that changes in evoked potential measurements may be useful as a neurophysiological indicator of anaesthetic depth.


Corneal birefringence mapped by scanning laser polarimetry.
Corneal birefringence affects polarization-sensitive optical measurements of the eye. Recent literature supports the idea that corneal birefringence is biaxial, although with some disagreement among reports and without considering corneas with very low values of central retardance. This study measured corneal retardation in eyes with a wide range of central corneal retardance by means of scanning laser polarimetry (GDx-VCC, Carl Zeiss Meditec, Inc.), which computes the retardance and slow axis of the cornea from images of the bow tie pattern formed by the radial birefringence of the macula. Measurements were obtained at many points on the cornea by translating the instrument. Data were compared to calculations of the retardation produced by a curved biaxial material between two spherical surfaces. Most corneas showed one or two small areas of zero retardance where the refracted ray within the cornea aligned with an optical axis of the material. The retardation patterns in these corneas could be mimicked, but not accurately described, by the biaxial model. Two corneas with large areas of low retardance more closely resembled a uniaxial model. We conclude that the cornea, in general, behaves as a biaxial material with its fastest axis perpendicular to its surface. Some locations in a few corneas can be uniaxial with the optical axis perpendicular to the surface. Importantly, corneal birefringence varies greatly among people and, within a single cornea, significantly with position.


[Use of bioflavonoids to prevent the harmful action of tetracycline on the liver].
It was shown in experiments on male albino rats that the plant bioflavonoids flamin, flakumin and tanaflon had hepatoprotective properties in liver function impairment caused by tetracycline intoxication. This was evident from a significant improvement of biliary secretion, synthesis and secretion of bile acids and bile secretion of bilirubin and cholesterol not only in the animals untreated with tetracycline but also in the controls. A decrease in the activity of alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase in the serum was indicative of the pronounced hepatoprotective effect of the bioflavonoids. They inhibited lipid peroxidation in the hepatocyte membranes evident from a decrease in the content of malonic dialdehyde and diene conjugates in liver homogenates. The antioxidant properties were especially pronounced in tanaflon. Correlation between lipid peroxidation, activity of the transferases and alkaline phosphatase and cholopoiesis both in tetracycline intoxication and in the prophylaxis and treatment with flamin, flakumin and tanaflon was shown.


Polyphenol content and antioxidant properties of colored soybean seeds from central Europe.
The antioxidant activity and contents of various polyphenol classes in the seeds of seven soybean varieties of different seed color and one yellow seed cultivar, representing a reference genotype, were evaluated. Total polyphenols and tannins were determined after extraction of plant material with 70% aqueous acetone, and total flavonoids were extracted with methanol and acetic acid, whereas anthocyanins were extracted with 20% aqueous ethanol. In addition, isoflavone content and composition were determined using high-performance liquid chromatography analysis. Antioxidant activity of seed extracts was evaluated by the 2,2-diphenyl-1-picrylhydrazyl free radical scavenging activity assay. A positive linear correlation between antioxidant activity and contents of total polyphenols and anthocyanins was established. The highest antioxidant activity was observed in the extracts of black and brown varieties, which also showed high levels of all polyphenol classes examined. Yellow seed had the highest total isoflavone content (3.62 mg/g of dry material). The highest concentration of total daidzein was determined in black seeds (>2.0 mg/g of dry material), and the highest total glycitein and genistein contents occurred in the yellow cultivar (0.53 and 1.49 mg/g of dry material, respectively). According to our results, varieties of black and brown seeds could be of special interest not only for their large content of total polyphenols, ranging from 4.94 to 6.22 mg of gallic acid equivalents/g of dry material, but also for their high content of natural antioxidants such as anthocyanins.


A Dendritic Cell Vaccine Combined With Radiotherapy Activates the Specific Immune Response in Patients With Esophageal Cancer.
Dendritic cells (DC) are highly efficient antigen-presenting cells. DC may be used to create DC vaccines against cancer, but the optimal strategies remain to be elucidated. This study aimed to examine the benefits and adverse effects of using esophageal cancer cell antigens to stimulate DC to trigger the specific immune response in patients with esophageal cancer undergoing radiotherapy. This was an observational cohort study performed at Lianshui County People's Hospital between September 2010 and June 2012. Forty patients with esophageal cancer planned to receive radiotherapy were selected, and 28 received the DC vaccine. DC were isolated, loaded with antigens, and intradermally injected after being cultured for 1 week. One week after injection, the patients underwent a delayed-type hypersensitivity test. Serum Th1 cytokines [interleukin (IL)-2, IL-12, and interferon (IFN)-γ] and antigen-specific IFN-γCD8 T cells were tested before and after vaccination. Patients were followed up for 2 years. Adverse events were monitored. Patients in the vaccine group tolerated the DC vaccine. Levels of serum IL-2 (+92.4%), IL-12 (+70.9%), and IFN-γ (+214.3%) as well as the proportion of IFN-γCD8 T cells (3.0-16.4-fold) were significantly increased compared with baseline and the control group (all P<0.05). The 1- (82.1% vs. 50.0%, P=0.04) and 2-year survival (67.8% vs. 33.3%, P=0.04) was improved by vaccination. Only 2 patients showed mild fever. In conclusion, the DC vaccine triggered the specific immune response and induced the secretion of Th1 cytokines. The vaccine may lead to better survival, but this have to be confirmed. Adverse events were rare and mild.


Social status-dependent nest choice of territorial males under reproductive parasitism in a Lake Tanganyika cichlid Telmatochromis vittatus.
Field and laboratory studies were conducted to examine how territorial males of a Lake Tanganyika cichlid Telmatochromis vittatus balance the conflicting demands on nest choice between occupying large nests with more females and avoiding reproductive parasitism (nest piracy, which is adopted by the largest males in the population). Pirates less frequently intruded the nests farther from neighbours, perhaps due to the costs associated with travelling between nests. The field experiment showed that territorial male T. vittatus sacrificed the fitness benefits that large nests offer and instead prioritized occupying the nests farther from neighbours on which fewer pirates intruded. The field observations suggested that they adopt different strategies for nest choice according to their relative competitive ability to pirates; the large territorial males, who are size-matched to pirates and can defend their nests against them, compete for larger nests among the more-isolated nests, whereas subordinate territorial males, which are smaller than pirates and thus inferior to them, compete for the more-isolated nests among the less-isolated nests. These findings suggest that the territorial male T. vittatus chooses the more-isolated nests to avoid pirate males at the expense of occupying large nests.


A Case Presentation Emphasizing the Value of Full-field ERG in Retinal Dystrophies.
A case presentation is used to discuss the value of full-field ERG in the diagnosis of cone-rod dystrophy. A 49 year old female patient known with amblyopia and myopic astigmatism since childhood, visited us complaining of decreased visual acuity and photophobia. Her BCVA was 0.6 in the RE and 0.4 in the LE. The fundus examination revealed normal colored and sharply limited papilla, normal macula and narrower vascularization. The Ishihara test was 10/15 in both eyes. The fundus autofluorescence and optical coherence tomography were normal. The DA 3 ERG was decreased and slightly delayed as well as the DA 0.01 ERG. Regarding the cone response, the LA 3.0 and 30 Hz flicker ERG were markedly reduced and delayed. The ERG findings indicated cone-rod dystrophy. At the 8 years follow-up examination, the BCVA decreased to 0.4 and 0.2 in the right and left eye, respectively, the Ishihara test was 1/15 in both eyes and the fundus examination showed a macula with no reflex, otherwise no changes compared to the first examination. The fundus autofluorescence and OCT were still normal. The ERG showed a much decreased and delayed rod response compared to the first examination, while the cone response was undetectable. Our case demonstrates the importance of standard full-field ERG in diagnosing CRD. The Full-field ERG responses were decreased and delayed, or even undetectable, while morphological examinations were still unchanged.


Variation in use of surveillance colonoscopy among colorectal cancer survivors in the United States.
Clinical practice guidelines recommend colonoscopies at regular intervals for colorectal cancer (CRC) survivors. Using data from a large, multi-regional, population-based cohort, we describe the rate of surveillance colonoscopy and its association with geographic, sociodemographic, clinical, and health services characteristics. We studied CRC survivors enrolled in the Cancer Care Outcomes Research and Surveillance (CanCORS) study. Eligible survivors were diagnosed between 2003 and 2005, had curative surgery for CRC, and were alive without recurrences 14 months after surgery with curative intent. Data came from patient interviews and medical record abstraction. We used a multivariate logit model to identify predictors of colonoscopy use. Despite guidelines recommending surveillance, only 49% of the 1423 eligible survivors received a colonoscopy within 14 months after surgery. We observed large regional differences (38% to 57%) across regions. Survivors who received screening colonoscopy were more likely to: have colon cancer than rectal cancer (OR = 1.41, 95% CI: 1.05-1.90); have visited a primary care physician (OR = 1.44, 95% CI: 1.14-1.82); and received adjuvant chemotherapy (OR = 1.75, 95% CI: 1.27-2.41). Compared to survivors with no comorbidities, survivors with moderate or severe comorbidities were less likely to receive surveillance colonoscopy (OR = 0.69, 95% CI: 0.49-0.98 and OR = 0.44, 95% CI: 0.29-0.66, respectively). Despite guidelines, more than half of CRC survivors did not receive surveillance colonoscopy within 14 months of surgery, with substantial variation by site of care. The association of primary care visits and adjuvant chemotherapy use suggests that access to care following surgery affects cancer surveillance.


Observation of Flat Electron Temperature Profiles in the Lithium Tokamak Experiment.
It has been predicted for over a decade that low-recycling plasma-facing components in fusion devices would allow high edge temperatures and flat or nearly flat temperature profiles. In recent experiments with lithium wall coatings in the Lithium Tokamak Experiment (LTX), a hot edge (>200 eV) and flat electron temperature profiles have been measured following the termination of external fueling. Reduced recycling was demonstrated by retention of ∼60% of the injected hydrogen in the walls following the discharge. Electron energy confinement followed typical Ohmic confinement scaling during fueling, but did not decrease with density after fueling terminated, ultimately exceeding the scaling by ∼200%. Achievement of the low-recycling, hot edge regime has been an important goal of LTX and lithium plasma-facing component research in general, as it has potentially significant implications for the operation, design, and cost of fusion devices.


The effect of glycosaminoglycans and proteoglycans on lipid peroxidation.
Recent investigations show that glycosaminoglycans (GAGs) and proteoglycans (PGs) have the ability to affect lipid peroxidation, one the best characterized forms of free radical mediated biological damage. A protective effect of these extracellular matrix (ECM) components has been demonstrated in various experimental systems, including fatty acids and liposomes, where oxidation was induced by transition metals, including copper and iron. The effect was specific and dependent on the type and structural features of GAGs and PGs. The mechanism of peroxidation inhibition was likely to be dependent, at least to a large extent, on the sequestration of transition metals by GAG chains. Thus, it is conceivable that GAGs in the ECM and in the pericellular space may contribute to protecting cells against free radical damage. It is of particular interest that in certain tissues (cornea and aorta) aging was associated with a decrease of content of the GAGs which were most effective as anti-oxidant. This suggests that age-induced modifications of ECM composition in certain tissues may increase the susceptibility to oxidative stress. The investigation on the effect of GAGs on lipoprotein oxidation led to apparently conflicting results. An interesting reconciliation is possible, according to which GAGs exerted their protective effect under experimental conditions not compatible with the formation of lipoprotein-GAG complexes; rather, lipoproteins exhibited increased susceptibility to metal-catalyzed oxidation (MCO), possibly due to structural modifications of the particle after binding to GAGs or PGs. This process is likely to occur in the intimal matrix of arteries.


Achilles tendons: clinical relevance of neovascularization diagnosed with power Doppler US.
To evaluate the clinical relevance of neovascularization diagnosed with power Doppler ultrasonography (US) in Achilles tendons in patients with chronic achillodynia. Forty consecutive patients (mean age, 52 years; age range, 30-72 years) were examined. US was performed bilaterally and repeated after 3 months. Shape and echogenicity were assessed with gray-scale US and vascularization with power Doppler US. All patients were treated conservatively. Clinical assessment was performed after 0, 3, and 6 months by using visual analogue scale (VAS) scores (0, no pain; 100, unbearable pain). The VAS scores were compared with the initial US findings, and analysis of variance was used for repeated measurements. Neovascularization was present in 30 of 55 painful tendons and in one of 25 asymptomatic tendons. The mean VAS scores at 0, 3, and 6 months, respectively, for tendons with neovascularization were 52, 26, and 20; those for tendons without neovascularization were 39, 19, and 18 (P =.15). Forty-eight painful and nine asymptomatic tendons were spindle shaped. The mean VAS scores at 0, 3, and 6 months, respectively, for the spindle-shaped tendons were 48, 25, and 20; those for normally shaped tendons were 33, 10, and 16 (P =.17). Thirty-five painful and four asymptomatic tendons were inhomogeneous. The mean VAS scores at 0, 3, and 6 months, respectively, for symptomatic inhomogeneous tendons were 54, 29, and 25; those for symptomatic homogeneous tendons were 32, 12, and 9 (P <.001). Although neovascularization is a specific sign for pain, it does not indicate an unfavorable outcome. Conversely, tendon inhomogeneity seems to be associated with an unfavorable outcome.


Evaluation of levalbuterol metered dose inhaler in pediatric patients with asthma: a double-blind, randomized, placebo- and active-controlled trial.
To evaluate the efficacy and safety of levalbuterol metered dose inhaler (MDI) in children aged 4-11 years (n = 173). Multicenter, randomized, double-blind 28-day study of QID levalbuterol 90 microg, racemic albuterol 180 mug, and placebo (2:1:1 ratio). Serial spirometry was performed on Days 0, 14, and 28. The primary endpoint was the double-blind average peak percent (%) change in FEV(1) from visit pre-dose; the primary comparison was with placebo. Secondary endpoints included the area under the FEV(1) percent change from pre-dose curve and peak % predicted FEV(1). Safety endpoints included adverse events, laboratory tests, rescue medication use, and electrocardiograms. Levalbuterol significantly improved the least square mean peak percent change in FEV(1) compared with placebo (levalbuterol 25.6% +/- 1.3% [p < 0.001]; racemic albuterol 21.8% +/- 1.8% [p = ns]; placebo 16.8% +/- 1.9%). Results for levalbuterol were similar for the other spirometry endpoints (p < 0.05 vs. placebo). No levalbuterol-treated patients had a peak percent change in FEV(1) < 10% (compared with 15.8% of racemic albuterol-treated patients and 30.3% of placebo-treated patients). The incidence of adverse events was 43.4% for levalbuterol, 56.4% for racemic albuterol, and 51.4% for placebo. The rate of discontinuation was 1.3% for levalbuterol, 2.6% for racemic albuterol, and 8.6% for placebo. The rate of asthma attacks (10.5%, 12.8%, 14.3%, respectively) was similar among treatments. Levalbuterol and racemic albuterol both reduced rescue medication use (p < 0.01 vs. placebo) and produced changes in ventricular heart rate and QT(c-F) that were similar to placebo. In this study, levalbuterol administered via MDI significantly improved airway function in comparison with placebo in asthmatic children aged 4-11 years with a safety profile that was similar to placebo.


Regional intestinal absorption and biliary excretion of fluvastatin in the rat: possible involvement of mrp2.
The first purpose of this study was to investigate the in vivo absorption, biliary secretion, and first-pass effect of fluvastatin following regional intestinal dosing in the rat. We also examined the membrane transport mechanisms and made in silico predictions of the relative importance of various intestinal regions to the human absorption of fluvastatin. Fluvastatin was administered intravenously (2, 10, and 20 micromol/kg) and into the duodenum (1.46, 2.92, 7.32, and 14.6 micromol/kg), jejunum (14.6 micromol/kg), ileum (1.46 and 14.6 mciromol/kg), and colon (1.46 and 14.6 micromol/kg) as a solution to conscious rats. In a separate group of rats, bile was collected after an i.v. dose of fluvastatin (2 micromol/kg). In the Caco-2 model the bidirectional transport of fluvastatin (16 microM) was investigated with and without various efflux inhibitors (verapamil, vinblastine, probenecid, and indomethacin, 160 microM). The human in vivo absorption of fluvastatin from an oral immediate release tablet and that from an oral extended release tablet (both 40 mg) were simulated in GastroPlus. Neither the dose nor the intestinal region influenced the bioavailability of fluvastatin significantly. The rate of absorption was, however, affected by both the dose and the site of administration; duodenum = jejunum > colon > ileum, and higher following the high dose. Increasing the i.v. dose from 2 to 20 micromol/kg decreased the clearance (26 +/- 3 to 12 +/- 1 mL/min/kg), the hepatic extraction (66 +/- 8 to 30 +/- 2%), and the volume of distribution (7.3 +/- 0.3 to 2.1 +/- 0.7 L/kg) for fluvastatin (p < 0.05). Neither bile cannulation nor bile sampling affected the pharmacokinetics. Fluvastatin was secreted into the bile, probably by active transport. The in vitro permeability for fluvastatin was high (>10 x 10(-6) cm/s). Indomethacin, but not the other inhibitors, affected the transport in both directions suggesting mrp2 to be involved. In silico, 93% of the dose was absorbed from the small intestine and 6% from the colon when given as an immediate release formulation. The corresponding values for an extended release formulation were 21% and 74%, respectively. In conclusion, fluvastatin exhibits dose-dependent pharmacokinetics in the rat. The rate of absorption (Cmax, Tmax, and Cmax/AUC(lqc)) from the intestinal tract is both region and dose-dependent in the rat. This may be due to the involvement of mrp2 in the intestine and/or in the liver. These absorption properties have to be considered in the development of an extended release formulation of fluvastatin.


beta-Carboline alkaloids: biochemical and pharmacological functions.
beta-Carboline alkaloids are a large group of natural and synthetic indole alkaloids with different degrees of aromaticity, some of which are widely distributed in nature, including various plants, foodstuffs, marine creatures, insects, mammalians as well as human tissues and body fluids. These compounds are of great interest due to their diverse biological activities. Particularly, these compounds have been shown to intercalate into DNA, to inhibit CDK, Topisomerase, and monoamine oxidase, and to interact with benzodiazepine receptors and 5-hydroxy serotonin receptors. Furthermore, these chemicals also demonstrated a broad spectrum of pharmacological properties including sedative, anxiolytic, hypnotic, anticonvulsant, antitumor, antiviral, antiparasitic as well as antimicrobial activities. In this review, we summerized the biochemical and pharmacological functions of beta-carboline alkaloids.


Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor.
The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.


Personal finances for the physician: a primer on maintaining and protecting your earnings.
Personal finance is a key component to your success as a physician. Your clinical practice does not exist in a vacuum unaffected by circumstances and decisions in your personal life. Though some events in your personal life that can negatively affect your practice are random and unavoidable, consistently making sound decisions regarding your personal life and finances will allow you to continue practicing at a high level. Most core principles of personal finance are common sense and do not involve high level math. Although the concepts are straightforward, people, including physicians, routinely fail to make good decisions at the most elementary level. The core common sense principles for financial success are: do not get divorced, manage your own money, live in a state without state income tax, and drive an old car. Follow these tenants and the path to successful and satisfactory retirement will be smooth.