Chemical modifications of the aliphatic bridge of ansamycins. 3. Synthesis and activity of 21-epi-rifamycin S.
Rifamycins inhibit bacterial DNA-dependent RNA polymerase through the formation of non-covalent bonds by the oxygenated groups at C(1), C(8), C(21), and C(23). These must be unhindered and underivatized, with the antibiotic in a proper overall molecular conformation. The present study shows that contrary to previous conclusions the availability of the hydroxyl group at C(21) is not as important as that of the other three groups. In support of this is the observation that 21-epi-rifamycin S is partially active, both on the isolated DNA-dependent RNA polymerase and on some Gram-positive bacterial strains.


An Introduction to Predictive Processing Models of Perception and Decision-Making.
The predictive processing framework includes a broad set of ideas, which might be articulated and developed in a variety of ways, concerning how the brain may leverage predictive models when implementing perception, cognition, decision-making, and motor control. This article provides an up-to-date introduction to the two most influential theories within this framework: predictive coding and active inference. The first half of the paper (Sections 2-5) reviews the evolution of predictive coding, from early ideas about efficient coding in the visual system to a more general model encompassing perception, cognition, and motor control. The theory is characterized in terms of the claims it makes at Marr's computational, algorithmic, and implementation levels of description, and the conceptual and mathematical connections between predictive coding, Bayesian inference, and variational free energy (a quantity jointly evaluating model accuracy and complexity) are explored. The second half of the paper (Sections 6-8) turns to recent theories of active inference. Like predictive coding, active inference models assume that perceptual and learning processes minimize variational free energy as a means of approximating Bayesian inference in a biologically plausible manner. However, these models focus primarily on planning and decision-making processes that predictive coding models were not developed to address. Under active inference, an agent evaluates potential plans (action sequences) based on their expected free energy (a quantity that combines anticipated reward and information gain). The agent is assumed to represent the world as a partially observable Markov decision process with discrete time and discrete states. Current research applications of active inference models are described, including a range of simulation work, as well as studies fitting models to empirical data. The paper concludes by considering future research directions that will be important for further development of both models.


Heart disease and changes in pulse wave velocity and pulse pressure amplification in the elderly over 80 years: the PARTAGE Study.
Pulse wave velocity (PWV) and pulse pressure amplification (PPA) are independent predictors of cardiovascular risk, mainly in the elderly. The aim of the current research was to determine the influence of PPA and PWV, both manifestations of arterial stiffness, on heart disease in the elderly. The study population consisted of 1042 participants (814 women) aged 80 years and over who participated in the PARTAGE study. Carotid-femoral PWV was determined in order to assess aortic stiffness. Central aortic blood pressure values and central pulse wave analysis were obtained using the calibration method applied on the common carotid artery by a PulsePen tonometer. Amplification phenomenon was expressed as PPA, that is, the percentage of increase of pulse pressure in the brachial artery relative to central pulse pressure. Heart disease was defined as presence of heart failure, ischemic heart disease or atrial fibrillation. PPA was significantly lower in patients with heart disease, independently of the presence of hypertension, diabetes or both. Heart disease was present in 61.8% of participants with PPA less than 10%, in 46.2% of participants with PPA between 10 and 20% (P < 0.01), in 42.6% of participants with PPA between 20 and 30% (P < 0.005) and in 32.5% of participants with PPA more than 30% (P < 0.001). PWV, on the contrary, was not influenced by the presence of heart disease (12.3 ± 4.0 vs. 13.5 ± 4.6 m/s) but significantly increased in presence of hypertension (14.4 ± 5.0 m/s, P < 0.001) or diabetes (16.1 ± 5.1 m/s, P < 0.001). In the very elderly, low brachial/aortic PPA is associated with higher prevalence of heart disease.


Knowledge of family health program practitioners in Brazil about sickle cell disease: a descriptive, cross-sectional study.
Although sickle cell disease is an important public health problem in Brazil, there is a gap in the literature on the level of knowledge of primary health care professionals about the treatment and management of sickle cell disease. Therefore, this study aimed to evaluate the level of knowledge about sickle cell disease of physicians and nurses who work in the Family Health Program in a region of Brazil with a high prevalence of this disease. This is a descriptive, cross-sectional study conducted at the municipality of Montes Claros, in the north of Minas Gerais, Brazil. Study participants included 96 physicians and nurses who work at the Family Health Program in an urban area of the city. Data was collected using an original, partially tested questionnaire based on health care check points for children with sickle cell disease established in educational protocols from the State Health Secretary of Minas Gerais and the Ministry of Health. The structured questionnaire contained 47 questions addressing three axes: epidemiology (8 questions); clinical manifestations (13 questions); and management of children with sickle cell disease (26 questions). Knowledge was measured through mean correct responses to proposed questions. Ethical principles were respected and this project was approved by the Committee of Ethics in Research. 59.4% (57) of the study participants were nurses and 40.6% (39) were physicians. The median length of training and median length of service in primary health care were 4.3 (2.8-8.0) years and 4.0 (2.0-7.1) years, respectively. The mean performance in knowledge tests was < 75%, with 5.7/8 (SD = 1.4) for the "epidemiology" questions; 8.6/13 (SD = 2.2) for "clinical manifestations"; and 17.0/26 (SD = 2.9) for "management of children with sickle cell disease" questions; resulting in a mean total of 31.4/47 (SD = 5.10) correct responses. A statistically significant association was found between the number of correct responses and family health care qualifications (p = 0.015). There is an urgent need to improve primary health care professional training in the care of children with sickle cell disease.


Surface-enhanced hyper-Raman scattering of Rhodamine 6G isotopologues: Assignment of lower vibrational frequencies.
We report a comprehensive experimental and theoretical study of the lower-wavenumber vibrational modes in the surface-enhanced hyper-Raman scattering (SEHRS) of Rhodamine 6G (R6G) and its isotopologue R6G-d4. Measurements acquired on-resonance with two different electronic states, S1 and S2, are compared to the time-dependent density functional theory computations of the resonance hyper-Raman spectra and electrodynamics-quantum mechanical computations of the SEHRS spectra on-resonance with S1 and S2. After accounting for surface orientation, we find excellent agreement between experiment and theory for both R6G and its isotopologue. We then present a detailed analysis of the complex vibronic coupling effects in R6G and the importance of surface orientation for characterizing the system. This combination of theory and experiment allows, for the first time, an unambiguous assignment of lower-wavenumber vibrational modes of R6G and its isotopologue R6G-d4.


Sensitive light scattering probe of enzymatic processes in retinal rod photoreceptor membranes.
Light excitation of as little as 0.05% of the rhodopsin in a retinal rod membrane suspension reduces the near-IR optical transmission by 25%. This transmission decrease requires the presence of guanosine triphosphate, is opposite in sign and 25 times larger in amplitude than a GTP-dependent light-scattering signal previously reported in rod outer segment suspensions [Kuhn, H., Bennett, N., Michel-Vallez, M. & Chabre, M. (1981) Proc. Natl. Acad. Sci. USA, 78, 6873-6877], and is kinetically complex. The initial phase of the optical transmission decrease begins after about a 50-ms lag (at 0.05% bleach) and has a first-order time constant of 300-500 ms. The scattering signal returns to the preactinic baseline in a time dependent on the amount of GTP added. A nonhydrolyzable GTP analogue, guanylyl imidodiphosphate, produces a scattering signal that does not return to the preactinic baseline. Adenosine triphosphate strongly inhibits the return of the GTP-dependent transmission decrease to the preactinic baseline. This effect of ATP on the GTP signal apparently requires ATP hydrolysis because it is inhibited by the simultaneous presence of adenylyl imidodiphosphate, a nonhydrolyzable analogue of ATP. The light-scattering signal and the velocity of the activation of a rod outer segment phosphodiesterase saturate when >0.05% of the rhodopsin is bleached and both show nearly identical dependence on light stimulus. It is suggested that these nucleotide-dependent light-scattering signals arise from changes in the state of membrane aggregation that are controlled by enzymatic processes. This hypothesis is supported by the large amplitude of the signals, sedimentation experiments, and a strong membrane concentration dependence. The ATP effects can be rationalized within the above hypothesis as being due to ATP-dependent rhodopsin phosphorylation that adds negative charges to the membrane surface and tends to keep the membranes disaggregated. An additional signal, which increases light transmission, is produced by a second, much more intense flash. The latter signal is interpreted as the result of proton binding by bleached rhodopsin molecules that decreases the negative charge repulsion between the membranes and allows increased aggregation.


Steady-state pharmacokinetics and pharmacodynamics of cysteamine bitartrate in paediatric nephropathic cystinosis patients.
Cysteamine is used to reduce tissue cystine content in patients suffering from nephropathic cystinosis. The objectives of the current study were to investigate pharmacokinetics and pharmacodynamics of cysteamine bitartrate in children and young adults with nephropathic cystinosis. Cysteamine bitartrate was administered to 11 cystinosis patients at their regular dose level in a single-dose, open-label, steady-state study. Blood samples were collected and analysed for plasma cysteamine and white blood cell cystine content and pharmacokinetic and pharmacodynamic parameters estimated by NONMEM analysis using a linked pharmacokinetic-pharmacodynamic model. Cysteamine was rapidly cleared from the plasma (mean CL/F = 32.3 ml min(-1) kg(-1), range = 17.3-52.2), appeared to be extensively distributed (mean Vss/F = 15.1 l, range 2.7-32.3) and exhibited a mean Tmax of 1.4 h. White blood cell cystine content post-dosing was significantly decreased compared with pre- and post-dose values (average decrement approximately 47%). A counter-clockwise hysteresis was noted in all patients, suggestive of a lag time (mean Tlag = 0.44 h, range 0.22-0.92) between drug concentration and effect. The results of this study establish that cysteamine is rapidly cleared from the plasma but that an every 6 h dosing interval adequately maintains white blood cell cystine content below the target of 1 nmol cystine per mg protein.


Oncologists' attitudes toward KRAS testing: a multisite study.
Recent discoveries promise increasingly to help oncologists individually tailor anticancer therapy to their patients' molecular tumor characteristics. One such promising molecular diagnostic is Kirsten ras (KRAS) tumor mutation testing for metastatic colorectal cancer (mCRC) patients. In the current study, we examined how and why physicians adopt KRAS testing and how they subsequently utilize the information when discussing treatment strategies with patients. We conducted 34 semi-structured in-person or telephone interviews with oncologists from seven different health plans. Each interview was audiotaped, transcribed, and coded using qualitative research methods. Information and salient themes relating to the research questions were summarized for each interview. All of the oncologists in this study reported using the KRAS test at the time of the interview. Most appeared to have adopted the test rapidly, within 6 months of the publication of National Clinical Guidelines. Oncologists chose to administer the test at various time points, although the majority ordered the test at the time their patient was diagnosed with mCRC. While oncologists expressed a range of opinions about the KRAS test, there was a general consensus that the test was useful and provided benefits to mCRC patients. The rapid adoption and enthusiasm for KRAS suggests that these types of tests may be filling an important informational need for oncologists when making treatment decisions. Future research should focus on the informational needs of patients around this test and whether patients feel informed or confident with their physicians' use of these tests to determine treatment access.


mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL.
Resistance to glucocorticoids (GC) is an important adverse risk factor in the treatment of acute lymphoblastic leukemia (ALL). To induce apoptosis, GC bind to the GC receptor (GR), which is regulated by various (co)chaperone proteins such as heat-shock protein 70 (HSP-70), HSP-40, HIP (HSP-70-interacting protein), BAG-1 (BCL-2-associated gene product-1), HOP (HSP-70/HSP-90-Organizing protein), HSP-90, P-23, FKBP-51, FKBP-52 and CYP-40. In this study, we tested the hypothesis that mRNA expression levels of these molecules are determinants of GC resistance in childhood ALL. In all, 20 children with ALL cells in vitro sensitive to prednisolone (LC(50) < 0.1 microg/ml) were compared each with a resistant patient (LC(50) >150 mug/ml), matched for immunophenotype, age and white blood cell count. mRNA expression levels of the (co)chaperone molecules were measured by quantitative real-time RT-PCR and normalized to GAPDH and RNaseP levels. In vitro resistance to prednisolone was measured by MTT assay. HSP-90 mRNA expression levels were 2000-fold higher as compared to HSP-70. Using matched pair analysis, mRNA expression levels of the various (co)chaperone molecules were not significantly different between in vitro-sensitive and -resistant patients. GC resistance in childhood ALL cannot be attributed to different mRNA expression levels of the investigated (co)chaperone molecules involved in GC binding and transport to the nucleus.


The Fagerström Test for Nicotine Dependence: a revision of the Fagerström Tolerance Questionnaire.
We examine and refine the Fagerström Tolerance Questionnaire (FTQ: Fagerström, 1978). The relation between each FTQ item and biochemical measures of heaviness of smoking was examined in 254 smokers. We found that the nicotine rating item and the inhalation item were unrelated to any of our biochemical measures and these two items were primary contributors to psychometric deficiencies in the FTQ. We also found that a revised scoring of time to the first cigarette of the day (TTF) and number of cigarettes smoked per day (CPD) improved the scale. We present a revision of the FTQ: the Fagerström Test for Nicotine Dependence (FTND).


Poliovirus-encoded 2C polypeptide specifically binds to the 3'-terminal sequences of viral negative-strand RNA.
The poliovirus-encoded, membrane-associated polypeptide 2C is believed to be required for initiation and elongation of RNA synthesis. We have expressed and purified recombinant, histidine-tagged 2C and examined its ability to bind to the first 100 nucleotides of the poliovirus 5' untranslated region of the positive strand and its complementary 3'-terminal negative-strand RNA sequences. Results presented here demonstrate that the 2C polypeptide specifically binds to the 3'-terminal sequences of poliovirus negative-strand RNA. Since this region is believed to form a stable cloverleaf structure, a number of mutations were constructed to examine which nucleotides and/or structures within the cloverleaf are essential for 2C binding. Binding of 2C to the 3'-terminal cloverleaf of the negative-strand RNA is greatly affected when the conserved sequence, UGUUUU, in stem a of the cloverleaf is altered. Mutational studies suggest that interaction of 2C with the 3'-terminal cloverleaf of negative-strand RNA is facilitated when the sequence UGUUUU is present in the context of a double-stranded structure. The implication of 2C binding to negative-strand RNA in viral replication is discussed.


Biomimetic modification of poly(vinyl alcohol): Encouraging endothelialization and preventing thrombosis with antiplatelet monotherapy.
Poly(vinyl alcohol) (PVA) has shown promise as a biomaterial for cardiovascular application. However, its antifouling properties prevent in vivo endothelialization. This work examined the endothelialization and thrombogenicity of modified PVA with different concentrations of proteins and adhesion peptides: collagen, laminin, fibronectin, GFPGER, YIGSR, and cRGD. Material surface properties were quantified, and the endothelialization potential was determined with human endothelial colony forming cells. Additionally, platelet attachment was assessed in vitro with human platelet rich plasma, and promising samples were tested in an ex vivo shunt model. This well-established arteriovenous shunt model was used with and without clinically-relevant antiplatelet therapies, specifically acetylsalicylic acid (ASA) with and without clopidogrel to examine the minimum necessary treatment to prevent thrombosis. Collagen, laminin, and GFPGER biomolecules increased endothelialization, with GFPGER showing the greatest effect at the lowest concentrations. GFPGER-PVA tubes tested under whole blood did exhibit an increase in platelet (but not fibrin) attachment compared to plain PVA and clinical controls. However, application of ASA monotherapy reduced the thrombogenicity of GFPGER-PVA below the clinical control with the ASA. This work is significant in developing cardiovascular biomaterials-increasing endothelialization potential while reducing bleeding side effects by using an antiplatelet monotherapy, typical of clinical patients. STATEMENT OF SIGNIFICANCE: We modified the endothelialization potential of synthetic, hydrogel vascular grafts with proteins and peptides of the vascular tissue matrix. Cell attachment was dramatically increased with the GFPGER peptide, and while some additional platelet attachment was seen under flow with whole blood, this was completely knocked down using clinical antiplatelet monotherapy. This indicates that long-term patency of this biomaterial could be improved without the associated bleeding risk of multiple platelet therapies.


The Effect of Microcirculatory Flow on Oscillating Gradient Diffusion MRI and Diffusion Encoding with Dual-Frequency Orthogonal Gradients (DEFOG).
We investigated the effect of microcirculatory flow on oscillating gradient spin echo (OGSE) diffusion MRI at low b-values and developed a diffusion preparation method called diffusion encoding with dual-frequency orthogonal gradients (DEFOG) to suppress the effect. Compared to conventional OGSE sequences, DEFOG adds a pulsed gradient that is orthogonal to the oscillating gradient and has a moderate diffusion weighting (e.g., 300 s/mm2 ). In vivo MRI data were acquired from adult mouse brains (n = 5) on an 11.7 Tesla scanner, with diffusion times from 23.2 to 0.83 ms and b-values from 50 to 700 s/mm2 . Apparent diffusion coefficients (ADCs) measured using a conventional OGSE sequence at low b-values (< 200 mm2 /s) were significantly higher than those measured at moderate b-values (> 300 mm2 /s), potentially due to contributions from microcirculatory flow. In comparison, OGSE ADCs measured using the DEFOG method at low b-values were comparable to those measured at moderate b-values. The effect of microcirculatory flow on diffusion signals was diffusion time-dependent, and this dependency may reflect the capillary geometry and blood flow velocity in the mouse cortex. Microcirculatory flow affects OGSE diffusion MRI measurements at low b-values, and this effect can be suppressed using the DEFOG method. Magn Reson Med 77:1583-1592, 2017. © 2016 International Society for Magnetic Resonance in Medicine.


Assessment of knowledge, attitudes, and practices regarding menstruation and menstrual hygiene among early-reproductive aged women in Bangladesh: a cross-sectional survey.
Poor menstrual hygiene practices during menstruation increases the risk of reproductive tract infections, absenteeism, and negative impact on school performance. Despite being a global problem, there is a lack of knowledge and misconceptions about menstrual hygiene among women of all ages, especially in developing countries like Bangladesh. The study aims to assess the knowledge, attitudes, and practices toward menstrual hygiene among early reproductive-aged women in Bangladesh to help policymakers and planners take effective initiatives. A cross-sectional survey was conducted between July and December 2022 in Dhaka, Rajshahi, Chittagong, Sylhet, and Barisal regions of Bangladesh. A convenience sampling technique was utilized to recruit a total of 1,214 participants (100% female; mean age: 22.87 ± 2.64 years). A semi-structured questionnaire including informed consent, socio-demographic information, as well as questions regarding knowledge (6-item), attitudes (7-item), and practices (6-item) toward menstruation and menstrual hygiene practices, was used to conduct the survey. All analyses were performed using the STATA (Version 15.0) and Statistical Package for the Social Sciences (SPSS version 25.0). The mean scores of the knowledge, attitudes, and practices were 4.9 ± 1.51 (out of 6), 12.58 ± 1.58 (out of 14), and 8.80 ± 1.87 (out of 12), respectively. The higher scores of knowledge, attitudes, and practices were significantly associated with several socio-demographic and menstruation-related factors (education, family type, type of menstruation, duration of menstruation, etc.). This study identified several key factors associated with improved knowledge, attitudes, and practices related to menstrual hygiene, including higher education levels, student status, younger age, non-alcohol consumption, and regular menstrual cycles. To enhance menstrual hygiene practices among women, it is crucial to implement targeted interventions that address knowledge disparities and tackle social and environmental influences.


Plasma androgens in children and adolescents. Part II. A longitudinal study in patients with hypopituitarism.
In this prospective longitudinal study, plasma androgen levels were determined during 1-7 years in 45 patients aged 5.6-23.8 years with either isolated growth hormone (GH) deficiency or multiple pituitary hormone deficiencies. Dehydroepiandrosterone sulfate, dehydroepiandrosterone, delta 4-androstenedione and testosterone were measured by RIA in 339 blood samples collected during the study period. Mean plasma androgen levels are normal in isolated GH deficiency. Patients with multiple pituitary hormone deficiencies, but normal ACTH reserve, have mean levels lower than normal. Patients with multiple deficiencies including ACTH deficiency have still lower plasma androgen levels. Longitudinal analysis of the data, however, shows that patients with either isolated GH deficiency or multiple pituitary deficiencies without ACTH deficiency constitute a heterogeneous population, with either normal or low to very low plasma androgen levels. Treatment with human GH as such does not have any effect on the adrenal androgen secretion. A dissociation is found in some patients between adrenarche and gonadarche, which indicates that the two events are not controlled by the same mechanisms. Our results support the existence of a specific hypothalamic-pituitary adrenal androgen-stimulating hormone (AASH). ACTH, although not identical to AASH, is essential for normal adrenarche. Induced puberty with estrogens in girls does not influence plasma androgen levels, and pubic and axillary hair growth is not achieved. It is suggested that replacement treatment with dehydroepiandrosterone sulfate should be administered to girls with hypopituitarism and very low plasma androgen levels at the time of the induction of puberty. Finally, it appears from this study that, to interpret the plasma androgens in hypopituitarism, body surface is as good as bone age.


The relationship between variations in cesarean delivery and regional health care use in the United States.
Cesarean delivery rates vary widely across the United States. Health care usage in many other areas of medicine also varies widely across the United States; it is unknown whether the variation in cesarean delivery rates across US communities is correlated with this broader underlying variation in health care usage patterns. The purpose of this study was to determine whether the variation in cesarean delivery rates across US communities is correlated with other measures of health care usage in that community. We performed a population-based observational study that combined multiple national data sources, which included 2010 birth certificate data and Medicare claims data. Cesarean delivery rates in each US community, as defined by the Hospital Service Area, Medicare total spending per beneficiary, and hospital days in the last 6 months were calculated. Cesarean delivery and Medicare spending were on different patient populations; the Medicare variables were used to characterize the broader health care usage and spending pattern of that community. We examined the relationship between a community's cesarean delivery rates and these measures of health care usage using Pearson correlation coefficients. We also stratified by quartile of Medicare spending and hospital use in the last 6 months of life and calculated the cesarean delivery rates per quartile, adjusting for underlying differences in patient characteristics, demographics, hospital structure, and the malpractice environment using a least-squared means method. We compared the amount of variation in cesarean delivery rates across communities that could be explained by differences in health care usage patterns to the amount of variation that was explained by other factors using the R-squared from multivariable models. Cesarean delivery rates varied from 4-65% across communities in the United States. Cesarean delivery rates were correlated positively with total Medicare spending (r = 0.48; P < .001) and hospital use in the last 6 months of life (r = 0.45; P < .001). Similar variation was seen in nulliparous women with a term fetus in vertex presentation (nulliparous, term, singleton, vertex cesarean deliveries), which is a common subset used for analysis of cesarean delivery rates. Communities in the lowest quartile of Medicare spending had the lowest rates of cesarean delivery (29.1% vs 35.7% in the highest quartile; P < .001 for differences across quartiles), which is a difference that persisted after adjustment (29.5% vs 31.8%; P < .001). Similar results were seen for nulliparous, term, singleton, vertex cesarean deliveries and when data were stratified by hospital days in the last 6 months of life. Overall, 28.6% of the total variation in cesarean delivery rates was explained by differences in health care usage patterns, as compared with 16.6% by differences in obstetric procedures, 7.9% by hospital structure, and 2.3% by variations in the malpractice environment. Of the 56.3% of variation that was unexplained by differences in patient characteristics and area demographics, 8.2% could be accounted for by differences in health care usage patterns, as compared with 4.6% by differences in obstetric procedures, 2.1% by hospital structure, and 1.2% by variation in the malpractice environment. Cesarean delivery rates vary widely across US communities; this variation is correlated broadly with the variation that is seen in other measures of health care usage across US communities.


Morus alba L. suppresses the development of atopic dermatitis induced by the house dust mite in NC/Nga mice.
Morus alba, a medicinal plant in Asia, has been used traditionally to treat diabetes mellitus and hypoglycemia. However, the effects of M. alba extract (MAE) on atopic dermatitis have not been verified scientifically. We investigated the effects of MAE on atopic dermatitis through in vitro and in vivo experiments. We evaluated the effects of MAE on the production of nitric oxide (NO) and prostaglandin E2 (PGE2) in RAW 264.7, as well as thymus and activation-regulated chemokine (TARC/CCL17) in HaCaT cells. In an in vivo experiment, atopic dermatitis was induced by topical application of house dust mites for four weeks, and the protective effects of MAE were investigated by measuring the severity of the skin reaction on the back and ears, the plasma levels of immunoglobulin E (IgE) and histamine, and histopathological changes in the skin on the back and ears. MAE suppressed the production of NO and PGE2 in RAW 264.7 cells, as well as TARC in HaCaT cells, in a dose-dependent manner. MAE treatment of NC/Nga mice reduced the severity of dermatitis and the plasma levels of IgE and histamine. MAE also reduced the histological manifestations of atopic dermatitis-like skin lesions such as erosion, hyperplasia of the epidermis and dermis, and inflammatory cell infiltration in the skin on the back and ears. Our results suggest that MAE has potent inhibitory effects on atopic dermatitis-like lesion and may be a beneficial natural resource for the treatment of atopic dermatitis.


High sensitivity fiber optic angular displacement sensor and its application for detection of ultrasound.
In this paper, we report on the development of an intensity-modulated fiber-optic sensor for angular displacement measurement. This sensor was designed to present high sensitivity, linear response, and wide bandwidth and, furthermore, to be simple and low cost. The sensor comprises two optical fibers, a positive lens, a reflective surface, an optical source, and a photodetector. A mathematical model was developed to determine and simulate the static characteristic curve of the sensor and to compare different sensor configurations regarding the core radii of the optical fibers. The simulation results showed that the sensor configurations tested are highly sensitive to small angle variation (in the range of microradians) with nonlinearity less than or equal to 1%. The normalized sensitivity ranges from (0.25×V(max)) to (2.40×V(max)) mV/μrad (where V(max) is the peak voltage of the static characteristic curve), and the linear range is from 194 to 1840 μrad. The unnormalized sensitivity for a reflective surface with reflectivity of 100% was measured as 7.7 mV/μrad. The simulations were compared with experimental results to validate the mathematical model and to define the most suitable configuration for ultrasonic detection. The sensor was tested on the characterization of a piezoelectric transducer and as part of a laser ultrasonics setup. The velocities of the longitudinal, shear, and surface waves were measured on aluminum samples as 6.43, 3.17, and 2.96 mm/μs, respectively, with an error smaller than 1.3%. The sensor, an alternative to piezoelectric or interferometric detectors, proved to be suitable for detection of ultrasonic waves and to perform time-of-flight measurements and nondestructive inspection.


The deaminase APOBEC3B triggers the death of cells lacking uracil DNA glycosylase.
Human cells express up to 9 active DNA cytosine deaminases with functions in adaptive and innate immunity. Many cancers manifest an APOBEC mutation signature and APOBEC3B (A3B) is likely the main enzyme responsible. Although significant numbers of APOBEC signature mutations accumulate in tumor genomes, the majority of APOBEC-catalyzed uracil lesions are probably counteracted in an error-free manner by the uracil base excision repair pathway. Here, we show that A3B-expressing cells can be selectively killed by inhibiting uracil DNA glycosylase 2 (UNG) and that this synthetic lethal phenotype requires functional mismatch repair (MMR) proteins and p53. UNG knockout human 293 and MCF10A cells elicit an A3B-dependent death. This synthetic lethal phenotype is dependent on A3B catalytic activity and reversible by UNG complementation. A3B expression in UNG-null cells causes a buildup of genomic uracil, and the ensuing lethality requires processing of uracil lesions (likely U/G mispairs) by MSH2 and MLH1 (likely noncanonical MMR). Cancer cells expressing high levels of endogenous A3B and functional p53 can also be killed by expressing an UNG inhibitor. Taken together, UNG-initiated base excision repair is a major mechanism counteracting genomic mutagenesis by A3B, and blocking UNG is a potential strategy for inducing the selective death of tumors.


A SORT Plus a GHOST Equals: Experience of Two Forward Medical Teams Supporting Special Operations in Afghanistan 2019.
Theater Special Operations Force (SOF) medical planners have been using Army forward surgical teams (FSTs) to maintain a golden hour for US SOF during Operation Freedom's Sentinel in the form of Golden Hour Offset Surgical Treatment Teams (GHOST-Ts) in Afghanistan. Recently, the Special Operations Resuscitation Team (SORT) was designed to decompress and augment a GHOST-T to help extend a golden hour ring in key strategic locations. This article describes both teams working together in Operation Freedom's Sentinel while deployed in support of SOF in central Afghanistan during the summer fighting season.


Interactions between timing and transmissibility explain diverse flavivirus dynamics in Fiji.
Zika virus (ZIKV) has caused large, brief outbreaks in isolated populations, however ZIKV can also persist at low levels over multiple years. The reasons for these diverse transmission dynamics remain poorly understood. In Fiji, which has experienced multiple large single-season dengue epidemics, there was evidence of multi-year transmission of ZIKV between 2013 and 2017. To identify factors that could explain these differences in dynamics between closely related mosquito-borne flaviviruses, we jointly fit a transmission dynamic model to surveillance, serological and molecular data. We estimate that the observed dynamics of ZIKV were the result of two key factors: strong seasonal effects, which created an ecologically optimal time of year for outbreaks; and introduction of ZIKV after this optimal time, which allowed ZIKV transmission to persist over multiple seasons. The ability to jointly fit to multiple data sources could help identify a similar range of possible outbreak dynamics in other settings.


Transient-rare Bacterial Taxa Are Assembled Neutrally across Temporal Scales.
Despite the importance of microbial communities in ecosystem functions, the mechanisms underlying the assembly of rare taxa over time are poorly understood. It remains largely unknown whether rare taxa exhibit similar assembly processes to common taxa in local communities. We herein retrieved the 16S rRNA sequences of bacteria collected bimonthly for 2 years from the Pohang wastewater treatment plant. The transient-rare taxa showed different abundance distributions from the common taxa. Transient-rare taxon assemblages also exhibited higher temporal variations than common taxon assemblages, suggesting the distinct ecological patterns of the two assemblages. A multivariate analysis revealed that environmental parameters accounted for 25.3 and 61.6% of temporal variations in the transient-rare and common taxon assemblages, respectively. The fitting of all observed taxa to a neutral community model revealed that 96.4% of the transient-rare taxa (relative abundance, 71.4%) and 73.3% of the common taxa (relative abundance, 45.6%) followed the model, suggesting that stochastic mechanisms were more important than deterministic ones in the assembly of the transient-rare taxa. Collectively, the present results indicate that the transient-rare bacterial taxa at the Pohang wastewater treatment plant differed from the common taxa in ecological patterns, suggesting that dispersal is a key process in their assembly.


Shedding Light on Proton and Electron Dynamics in [FeFe] Hydrogenases.
[FeFe] hydrogenases are highly efficient catalysts for reversible dihydrogen evolution. H2 turnover involves different catalytic intermediates including a recently characterized hydride state of the active site (H-cluster). Applying cryogenic infrared and electron paramagnetic resonance spectroscopy to an [FeFe] model hydrogenase from Chlamydomonas reinhardtii (CrHydA1), we have discovered two new hydride intermediates and spectroscopic evidence for a bridging CO ligand in two reduced H-cluster states. Our study provides novel insights into these key intermediates, their relevance for the catalytic cycle of [FeFe] hydrogenase, and novel strategies for exploring these aspects in detail.


Molecular characterization, tissue distribution, and mRNA expression profiles of two Kiss genes in the adult male and female chub mackerel (Scomber japonicus) during different gonadal stages.
Kisspeptins, encoded by the Kiss1 gene, have emerged as key modulators of reproduction in mammals. In contrast to the placental mammals, some teleosts express two Kiss genes, Kiss1 and Kiss2. In the present study, full-length cDNAs of Kiss1 and Kiss2 in the chub mackerel were cloned and sequenced. Chub mackerel Kiss1 and Kiss2 cDNAs encode 105 and 123 amino acids, respectively. A comparison of the deduced amino acid sequences of chub mackerel Kiss1 and Kiss2 with those of other vertebrate species showed a high degree of conservation only in the kisspeptin-10 region (Kp-10). The Kp-10 of chub mackerel Kiss1 (YNFNSFGLRY) and Kiss2 (FNFNPFGLRF) showed variations at three amino acids. Tissue distribution analysis using quantitative real-time PCR (qRT-PCR) revealed that the Kiss1 and Kiss2 transcripts were expressed in different tissues of adult chub mackerel. In addition, their levels in the adipose tissue exhibited sexually dimorphic expression. Further, to have a basic understanding on the involvement of Kiss1 and Kiss2 in the seasonal gonadal development, their relative mRNA expression profiles in the brain, pituitary, and gonads at different gonadal stages were analyzed using qRT-PCR. Kiss1 and Kiss2 levels in the brain showed a differential expression profile between male and female fish. In males, Kiss1 and Kiss2 levels gradually decreased from the immature stage to spermiation and reached a minimal level during the post-spawning period. In contrast, Kiss1 levels in the brain of females did not vary significantly among the different gonadal stages. However, Kiss2 levels fluctuated as that of males, gradually declining from the immature stage to the post-spawning period. The pituitary Kiss1 levels did not show significant fluctuations. However, Kiss1 levels in the gonads were highly elevated during spermiation and late vitellogenesis compared to the immature and post-spawning period. These results suggest the possible involvement of two Kiss genes in the brain and Kiss1 in the gonads of chub mackerel during seasonal gonadal development.


[Evaluation of left ventricular function in acute and old myocardial infaraction by non-invasive method with special reference to systolic time intervals].
Systolic time intervals were studied in acute and old myocardial infarction, and the following conclusions were drawn: 1. Acute myocardial infarction. a) LVET was the shortest on the 3rd and 4th day of the illness, normalizing on the 14th day in cases without heart failure; but generally lower values were encountered in cases with heart failure, with a delay in recovery. b) PEP tended to be prolonged in the initial stage in cases with heart faii showed scarcely any change. d) PEP/LVET was the greatest prolongation near the 4th day of the illness, normalizing on the 14th day in cases without heart failure; but no recovery was seen after 10th week in cases with heart failure. e) Correlation was found between LVET or PEP/LVET and SI, but no concentration was seen between Q-II or PEP and SI. f) A tendency of correlation was noted between Peel's prognostic index and LVET or PEP/LVET. g) A marked deviation of either one of STI, especially that of PEP/LVET, suggests a poor prognosis. Persistence of the LVET value less than 240 msec up to the 7th day of the illness suggests the complication of heart failure. 2. Old myocardial infarction. While LVET was almost normal, PEP was considerably high regardless of the presence or absence of heart failure, with a tendency of aggravation in the course of years. The tendency of PEP/LVET was similar to that of PEP.


Implementing Interprofessional Alcohol Screening, Brief Intervention, and Referral to Treatment in the Emergency Department: An Evidence-Based Quality Improvement Initiative.
Alcohol misuse is one of the leading causes of illness, disease, injury, and death in the Unites States. For many patients, the emergency department (ED) visit may provide the only therapeutic opportunity to influence problematic drinking behavior. Screening, brief intervention, and referral to treatment (SBIRT) is an evidence-based approach that may reduce alcohol-related morbidity and mortality and improve health outcomes and quality of life. Developing and implementing an alcohol SBIRT educational module for ED nurses and social workers is an efficient and effective mechanism to provide education about alcohol SBIRT, and revising the electronic health record to include an alcohol SBIRT protocol provides a standard mechanism for documentation by the interprofessional team of ED nurses and social workers. By integrating SBIRT knowledge as standard of practice in the ED setting, providers can positively impact the health and well-being of patients.


Spontaneous formation and base pairing of plausible prebiotic nucleotides in water.
The RNA World hypothesis presupposes that abiotic reactions originally produced nucleotides, the monomers of RNA and universal constituents of metabolism. However, compatible prebiotic reactions for the synthesis of complementary (that is, base pairing) nucleotides and mechanisms for their mutual selection within a complex chemical environment have not been reported. Here we show that two plausible prebiotic heterocycles, melamine and barbituric acid, form glycosidic linkages with ribose and ribose-5-phosphate in water to produce nucleosides and nucleotides in good yields. Even without purification, these nucleotides base pair in aqueous solution to create linear supramolecular assemblies containing thousands of ordered nucleotides. Nucleotide anomerization and supramolecular assemblies favour the biologically relevant β-anomer form of these ribonucleotides, revealing abiotic mechanisms by which nucleotide structure and configuration could have been originally favoured. These findings indicate that nucleotide formation and selection may have been robust processes on the prebiotic Earth, if other nucleobases preceded those of extant life.


Simultaneous imaging of a lacZ-marked tumor and microvasculature morphology in vivo by dual-wavelength photoacoustic microscopy.
Photoacoustic molecular imaging, combined with the reporter-gene technique, can provide a valuable tool for cancer research. The expression of the lacZ reporter gene can be imaged using photoacoustic imaging following the injection of X-gal, a colorimetric assay for the lacZ-encoded enzyme β-galactosidase. Dual-wavelength photoacoustic microscopy was used to non-invasively image the detailed morphology of a lacZ-marked 9L gliosarcoma and its surrounding microvasculature simultaneously in vivo, with a superior resolution on the order of 10 μm. Tumor-feeding vessels were found, and the expression level of lacZ in tumor was estimated. With future development of new absorption-enhancing reporter-gene systems, we anticipate this strategy can lead to a better understanding of the role of tumor metabolism in cancer initiation, progression, and metastasis, and in its response to therapy.


Sustainable long-term conservation of rare cattle breeds using rotational AI sires.
The development of inbreeding in rotation breeding schemes, sequentially using artificial insemination (AI) sires over generations, was investigated for a full AI scheme. Asymptotic prediction formulae of inbreeding coefficients were established when the first rotation list of AI sires (possibly related) was in use. Simulated annealing provided the optimal rotation order of sires within this list, when the sires were related. These methods were also used for subsequent rotation lists, needed by the exhaustion of semen stores for the first bulls. Simulation was carried out starting with groups of independent sires, with different sizes. To generate a yearly inbreeding rate substantially lower than 0.05% (considered to be within reach by conventional conservation schemes using frequent replacements), the results obtained showed that the number of sires should be at least 10-15 and that the same sires should be used during at least 50 years. The ultimate objective was to examine the relevance of implementing rotation in breeding schemes on the actual rare French cattle breeds under conservation. The best candidate for such a test was the Villard-de-Lans breed (27 bulls and 73,000 doses for only 340 females) and it turned out to be the best performer with an inbreeding coefficient of only 7.4% after 500 years and five different sire lists. Due to the strong requirements on semen stores and on the stability of population size, actual implementation of this kind of conservation scheme was recommended only in special (;niche') cattle populations.


[Hypolipidemic action of soy fiber and its effects on platelet aggregation and coagulation time in rats].
In order to lay a scientific basis for the development and use of soy bean, six per cent of soy fiber (SF) and pure cellulose were added to normal feed containing 1% of cholesterol and 0.2% bile salt, to feed SD rats, as compared with a control group of rats fed only with the normal feed, to study the effects of fibers on blood lipid concentration, platelet aggregation and clotting time. Results showed SF could not only significantly lower serum total cholesterol (TC), LDL-C and atherosclerotic index, and increase the ratio of HDL-L/TC, but also significantly lower serum fibrinogen (FB) and platelet aggregation, prolong clotting time (P < 0.01). NO such effects were observed in rats fed with pure cellulose. The authors believed that hypolipidemic effect of SF was achieved by lowering LDL-C in animals with hyperlipemia, and lowering of blood lipid and FB were major reasons to make animals fed with SF-added feed lower their platelet aggregation and prolong their clotting time.


Attitudes of dental students towards using computers in education--a mixed design study.
This mixed design study explored attitudes of dental students towards use of computers. It employed quantitative analyses of a questionnaire answered by 979 students and qualitative analysis of suggestions by a subgroup of 339. Positive attitudes towards computers were predicted by "computer use for > 1 year" and "year of study". Qualitative analysis of students' suggestions confirmed these findings and brought up new issues such as the need for establishing a website for the faculty. The results indicate that careful planning is needed to improve students' skills and incorporate computer applications in educational curricula.


Increased phosphorylation of myosin light chain kinase after an increase in cyclic AMP in intact smooth muscle.
The role of cyclic adenosine monophosphate-mediated phosphorylation of myosin light chain kinase in relaxing smooth muscle was examined. The kinase was immunoprecipitated from tissue extracts and the phosphate content was determined. The addition of forskolin to resting or methacholine-contracted muscles resulted in an increase in myosin light chain kinase phosphorylation of myosin light chain kinase is one of the reactions in the process by which cyclic adenosine monophosphate causes relaxation of smooth muscle.


Mystery Story about Erythropoietin (Epo) and Erythropoietin Receptor (EpoR) are Disguised?
In this review we would like to focus our attention upon very controversial reports on Erythropoietin (Epo) and Erythropoietin Receptor (EpoR) expression in cancer patients. The effects of Epo on cancerous tissues are poorly understood. Hypoxia results in an increase in the level of the production of both Epo and EpoR via activation of the hypoxia-inducible factor 1 (HIF-1) pathway. HIF-1α, promotes the expression of vascular endothelial growth factor (VEGF). The signaling through VEGF in both a paracrine and an autocrine manner is required for the homeostasis of adult vessels. Macrophages stimulate vessel sprouting via a soluble factor other than VEGF, rather than through direct contact with endothelial cells. The intriguing questions are set about many researches to link Epo/EpoR expression and function in order to establish one of the mechanisms of tumor growth, disease progression of cancer patient. However, it is uncertain role in tumour angiogenesis as promoter and stimulator of tumour growth which should need to be furtherly validated.


Ruptured PICA aneurysms: presentation and treatment outcomes compared to other posterior circulation aneurysms. A Swiss SOS study.
Aneurysms of the posterior inferior cerebellar artery (PICA) are relatively uncommon and evidence is sparse about patients presenting with ruptured PICA aneurysms. We performed an analysis of the Swiss SOS national registry to describe clinical presentation, treatment pattern, and neurological outcome of patients with ruptured PICA aneurysms compared with other ruptured posterior circulation (PC) aneurysms. This was a retrospective analysis of anonymized data from the Swiss SOS registry (Swiss Study on Aneurysmal Subarachnoid Hemorrhage; 2009-2014). Patients with ruptured PC aneurysms were subdivided into a PICA and non-PICA group. Clinical, radiological, and treatment-related variables were identified, and their impact on the neurological outcome was determined in terms of modified Rankin score at discharge and at 1 year of follow-up for the two groups. Data from 1864 aneurysmal subarachnoid hemorrhage patients were reviewed. There were 264 patients with a ruptured PC aneurysm. Seventy-four PICA aneurysms represented 28% of the series; clinical and radiological characteristics at admission were comparable between the PICA and non-PICA group. Surgical treatment was accomplished in 28% of patients in the PICA group and in the 4.8% of patients in the non-PICA group. No statistically significant difference was found between the two groups in terms of complications after treatment. Hydrocephalus requiring definitive shunt was needed in 21.6% of PICA patients (p = 0.6); cranial nerve deficit was present in average a quarter of the patients in both PICA and non-PICA group with no statistical difference (p = 0.3). A more favorable outcome (66.2%) was reported in the PICA group at discharge (p < 0.05) but this difference faded over time with a similar neurological outcome at 1-year follow-up (p = 0.09) between both PICA and non-PICA group. The Kaplan-Meyer estimation showed no significant difference in the mortality rate between both groups (p = 0.08). In the present study, patients with ruptured PICA aneurysms had a favorable neurological outcome in more than two thirds of cases, similar to patients with other ruptured PC aneurysms. Surgical treatment remains a valid option in a third of cases with ruptured PICA aneurysms.


Adaptive phenotypic variation among clonal ant workers.
Phenotypic variations are observed in most organisms, but their significance is not always known. The phenotypic variations observed in social insects are exceptions. Genetically based response threshold variances have been identified among workers and are thought to play several important adaptive roles in social life, e.g. allocating tasks among workers according to demand, promoting the sustainability of the colony and forming the basis of rationality in collective decision-making. Several parthenogenetic ants produce clonal workers and new queens by asexual reproduction. It is not clearly known whether such genetically equivalent workers show phenotypic variations. Here, we demonstrate that clonal workers of the parthenogenetic ant Strumigenys membranifera show large threshold variances among clonal workers. A multi-locus genetic marker confirmed that colony members are genetic clones, but they showed variations in their sucrose response thresholds. We examined the changing pattern of the thresholds over time generating hypotheses regarding the mechanism underlying the observed phenotypic variations. The results support the hypothesis that epigenetic modifications that occur after eclosion into the adult form are the cause of the phenotypic variations in this asexual species.


Significant Reduction of Late Toxicities in Patients With Extremity Sarcoma Treated With Image-Guided Radiation Therapy to a Reduced Target Volume: Results of Radiation Therapy Oncology Group RTOG-0630 Trial.
We performed a multi-institutional prospective phase II trial to assess late toxicities in patients with extremity soft tissue sarcoma (STS) treated with preoperative image-guided radiation therapy (IGRT) to a reduced target volume. Patients with extremity STS received IGRT with (cohort A) or without (cohort B) chemotherapy followed by limb-sparing resection. Daily pretreatment images were coregistered with digitally reconstructed radiographs so that the patient position could be adjusted before each treatment. All patients received IGRT to reduced tumor volumes according to strict protocol guidelines. Late toxicities were assessed at 2 years. In all, 98 patients were accrued (cohort A, 12; cohort B, 86). Cohort A was closed prematurely because of poor accrual and is not reported. Seventy-nine eligible patients from cohort B form the basis of this report. At a median follow-up of 3.6 years, five patients did not have surgery because of disease progression. There were five local treatment failures, all of which were in field. Of the 57 patients assessed for late toxicities at 2 years, 10.5% experienced at least one grade ≥ 2 toxicity as compared with 37% of patients in the National Cancer Institute of Canada SR2 (CAN-NCIC-SR2: Phase III Randomized Study of Pre- vs Postoperative Radiotherapy in Curable Extremity Soft Tissue Sarcoma) trial receiving preoperative radiation therapy without IGRT (P < .001). The significant reduction of late toxicities in patients with extremity STS who were treated with preoperative IGRT and absence of marginal-field recurrences suggest that the target volumes used in the Radiation Therapy Oncology Group RTOG-0630 (A Phase II Trial of Image-Guided Preoperative Radiotherapy for Primary Soft Tissue Sarcomas of the Extremity) study are appropriate for preoperative IGRT for extremity STS.


Use of non-occupational post-exposure prophylaxis does not lead to an increase in high risk sex behaviors in men who have sex with men participating in the EXPLORE trial.
Non-occupational post-exposure prophylaxis (nPEP) use is an HIV prevention strategy that has been recommended by the CDC to prevent HIV infection after a high risk sexual exposure since 1997. In a behavioral intervention trial of 4,295 MSM we assessed perceptions and use of nPEP over 4 years in six cities across the United States. Overall, 1.9% of MSM reported use of nPEP prior to enrollment, and 6.3% at least once during the trial. Awareness of nPEP was reported by 47.5%, with higher awareness in two sites with funded nPEP programs. Three seroconversions occurred in the 384 visits where nPEP courses were reported, with no effect of nPEP on risk of HIV acquisition in this cohort (hazard ratio = 0.91, 95% confidence interval [0.29, 2.86]). NPEP users were a riskier group: increased odds of nPEP use were observed in association with multiple partners and unprotected receptive and insertive anal sex with HIV infected partners and partners with unknown HIV status. NPEP use was also associated with use of illicit drugs (injection drugs, crack cocaine, hallucinogens, and amphetamines). Importantly, willingness to use nPEP after high risk sex was associated with lower odds of high risk sex. After an episode of nPEP use, nPEP users remained more likely to report high risk sex than those in this cohort who had not previously used nPEP. However, within the subset of people who had previously reported high risk sex, previous nPEP use was not associated with higher odds of high risk sex, thus allaying fears that availability of nPEP would lead to an increase in high risk sex.


Human fibroblasts, a convenient nuclear substrate for detection of anti-nuclear antibodies including anti-centromere antibodies.
Human fibroblast monolayers were applied as a nuclear substrate in indirect immunofluorescence for the detection of anti-nuclear antibodies (ANA). Comparison of the results obtained with this substrate and with conventional rat liver sections led to the conclusion that the application of human fibroblast monolayers as a substrate has the following advantages: 1) better recognition of the distinct nuclear staining patterns; 2) more convenient serum titrations, since a cryostat is not needed and twelve tests can be performed on one slide; 3) detection of significantly higher ANA titres in sera from patients with SLE and MCTD; 4) recognition of a type of ANA that was not detected on rat liver sections. These latter antibodies produced a discrete speckled pattern of fluorescence, which was completely lost after acid elution of the fibroblasts. Using HEp-2 cells in metaphase, it was shown that the antibodies were directed against the centromere regions of the chromosomes. These anti-centromere antibodies were detected in sera from patients with severe Raynaud's phenomenon. Underlying disorders were scleroderma (8 patients, 5 of them with CREST syndrome), Sjögren's syndrome (2 patients), and Raynaud's phenomenon in combination with a few symptoms of connective tissue diseases without fulfilling the criteria for a specific disease (5 patients).


Conservative surgical procedures for tubal pregnancy.
The early diagnosis of tubal pregnancy has become easier with recent diagnostic techniques. Early diagnosis provides a greater opportunity for conservative surgery in women who wish to maintain fertility. The procedure chosen will depend on the location of the pregnancy. One must differentiate between a pregnancy in the ampullary portion of the fallopian tube and one in the isthmic portion, and one must also determine whether a rupture has occurred.


Sciatica management: chemonucleolysis vs. surgical discectomy.
True sciatica, and the back pain associated with it, are symptoms stemming from a common anatomical lumbar distortion--compression of a spinal nerve root. Two therapeutic approaches have evolved: surgical laminectomy and discectomy for relief of compression of a lumbar nerve root; and chemonucleolysis, a tissue modification technique using the intradiscal injection of the proteolytic enzyme chymopapain. Chemonucleolysis has been demonstrated to have a successful outcome at the 75% level in 6 weeks and at the 80% level in 6 months. Lumbar microdiscectomy appears to be 85% effective at 3 months.


Neuropsychiatric systemic lupus erythematosus: lessons learned from magnetic resonance imaging.
The clinical manifestations of nervous system involvement in systemic lupus erythematosus (neuropsychiatric SLE [NPSLE]) are highly diverse, and their etiology is incompletely understood. The aim of this study was to provide an inventory of abnormalities on conventional brain magnetic resonance imaging (MRI) in NPSLE and to interpret the findings in relation to possible underlying pathogenetic mechanisms. MR images of the first episode of active NPSLE in 74 patients were retrospectively reviewed. All patients fulfilled the American College of Rheumatology (ACR) 1982 revised criteria for the classification of SLE and were classified according to the 1999 ACR case definitions for NPSLE syndromes. We excluded patients with a history of brain disease and patients in whom other mechanisms unrelated to SLE caused the neuropsychiatric symptoms. The principal findings were: 1) focal hyperintensities in white matter (WM) (49% of all patients) or both WM and gray matter (GM) (5% of all patients), suggestive of vasculopathy or vasculitis; 2) more widespread, confluent hyperintensities in the WM, suggestive of chronic hypoperfusion due to the same mechanisms; 3) diffuse cortical GM lesions (12% of all patients), compatible with an immune response to neuronal components or postseizure changes; and 4) absence of MRI abnormalities, despite signs and symptoms of active disease (42% of all patients). Several distinct brain MRI patterns were observed in patients with active NPSLE, suggestive of different pathogenetic mechanisms. To advance our understanding of the various processes leading to NPSLE, the radiographic manifestations may be a good starting point and useful for categorization of patients in further research.


Variant deep cerebral venous drainage in idiopathic subarachnoid hemorrhage.
Variant deep cerebral venous drainage, primarily involving the basal vein of Rosenthal (BVR), may be a cause of idiopathic subarachnoid hemorrhage (SAH). In this study, deep venous drainage was compared between 13 patients with idiopathic SAH and 35 control patients with aneurysmal SAH diagnosed by digital subtraction angiography (DSA). Venous return was evaluated by DSA on 25 sides in patients with idiopathic SAH and 67 sides in patients with aneurysmal SAH, and the relationship between the BVR and the vein of Galen was classified into 3 categories: types A (normal continuous), B (normal discontinuous), and C (primitive variant). The occurrence rates of the three categories were: idiopathic SAH, type A 24%, type C 40%; and aneurysmal SAH, type A 49.3%, type C 10.4% (p = 0.003). Combined bilateral venous drainage was classified as normal combination (AA), discontinuous combination (AB, BB), and primitive combination (AC, BC, CC), with rates: idiopathic SAH, normal 0%, primitive 58.3%; and aneurysmal SAH, normal 42.4%, primitive 21.2%. Venous drainage on either the left or right side was more commonly type C (primitive) in idiopathic SAH (p = 0.006). Three patients with left-right differences in hematoma distribution on brain computed tomography had types A, B, and C on the SAH dominant side in one patient each. No clear trend was observed between hematoma distribution and primitive variant side. Some patients with idiopathic SAH had thick hematoma in the basal cistern. Further, 3 patients with idiopathic SAH had an aneurysmal pattern, rather than a perimesencephalic pattern. All these patients had type C either on the left or right side. Therefore, although the mechanism of involvement of venous drainage in idiopathic SAH is unknown, hemorrhage is not limited to a perimesencephalic pattern. The present findings support a previous hypothesis that variant venous drainage is involved in the occurrence of idiopathic SAH. The absence of a normal combination of venous drainage is an important factor to diagnose idiopathic SAH.


[Anthropometric indices of gastroenterology patients at a sanatorium].
Patients treated at a gastroenterological sanatorium were studied with respect to their food status according to a specially developed table for measuring their skin-fat fold. Excessive body weight and obesity were recorded in 26.7 and 24.6% of the patients, respectively. The underweight patients comprised only 7.2%. Statistically significant obesity (P less than 0.05) was more often observed in women than in men (28.2 and 13.6%, respectively).


Fracture penis: a case more heard about than seen in general surgical practice.
A 36-year-old man presented to the emergency department with a history of trauma to genitalia during intercourse. The patient reported the forceful collision between his penis and the bed and audible clicking sound with swollen penis thereafter. On examination, the genitalia was swollen with an 'S' shaped deformity. The skin over the swelling was apparently normal, with no local rise of temperature. A provisional diagnosis was made after clinical evaluation. Scrotum and testes examination revealed no abnormality. A subcoronal circumferential incision with de-gloving of penile skin was used to access the tunica. A rent in tunica albuginea and corpora cavernosa identified and the defect repaired with absorbable suture material after removal of clot and properly maintaining haemostasis. The patient's postoperative recovery was uneventful. The following case report demonstrates a typical case of fracture penis.


Ultrafast dynamics in C 1s core-excited CF4 revealed by two-dimensional resonant Auger spectroscopy.
Following core excitation in an isolated molecule, ultrafast dissociation of one particular chemical bond can occur, where "ultrafast" is defined as taking place during the lifetime of the core hole, of the order of few femtoseconds. The signature of such phenomenon can be observed in resonant Auger spectra following core excitation. We present here an investigation of ultrafast dissociation following C 1s-to-σ* core excitation in CF4, with high-resolution resonant Auger spectroscopy. We are able to characterize final states of both the molecular ion and the CF3 (+) fragment. We use two-dimensional (2D) maps to record resonant Auger spectra across the resonance as a function of photon energy and to characterize ultrafast dynamics. This method provides immediate visual evidence of one of the important characteristics of the study of spectral features related to molecular versus fragment ionic final states, and namely their dispersion law. In the 2D maps we are also able to identify the dissociation limit for one of the molecular final states.


Effects of clotrimazol on the acute necrotizing pancreatitis in rats.
This study aims to investigate the influence of clotrimazol (CLTZ) on acute necrotizing pancreatitis (ANP) induced by glycodeoxycholic acid in rats. Rats were divided into five groups as sham + saline, sham + CLTZ, sham + polyethylene glycol, ANP + saline, and ANP + CLTZ. ANP in rats was induced by glycodeoxycholic acid. The extent of acinar cell injury, mortality, systemic cardiorespiratory variables, functional capillary density (FCD), renal/hepatic functions, and changes in some enzyme markers for pancreatic and lung tissue were investigated during ANP in rats. The use of CLTZ after the induction of ANP resulted in a significant decrease in the mortality rate, pancreatic necrosis, and serum activity of amylase, alanine aminotransferase, interleukin-6, lactate dehydrogenase in bronchoalveolar lavage fluid, serum concentration of urea, and tissue activity of myeloperoxidase, and malondialdehyde in the pancreas and lung and a significant increase in concentrations of calcium, blood pressure, urine output, pO2, and FCD. This study showed that CLTZ demonstrated beneficial effect on the course of ANP in rats. Therefore, it may be used in the treatment of acute pancreatitis.


The social utility of community treatment orders: Applying Girard's mimetic theory to community-based mandated mental health care.
Serious mental illness (SMI) has long posed a dilemma to society. The use of community treatment orders (CTOs), a legal means by which to deliver mandated psychiatric treatment to individuals while they live in the community, is a contemporary technique for managing SMI. CTOs (or a similar legal mechanism) are used in every province in Canada and in many jurisdictions around the world in the care and management of clients with severe and persistent mental illness (most frequently schizophrenia) who have a history of treatment non-compliance and subsequent relapse. Although there is ongoing controversy around CTOs, their use continues to be on the rise. René Girard's mimetic theory, in which he posits the social utility of the scapegoat mechanism, may shed some light on how established cultural patterns contribute to contemporary responses to SMI: how culture depends on the reproduction of certain narratives, and how these act to shape the identity of those involved. The CTO specifically can be seen to act as a scapegoating mechanism, wherein, by singling out and controlling individuals who appear to threaten social order, social order is restored. This paper reviews Girard's theory, looks at how it has been applied to SMI, and then considers how it may illuminate the social role of the CTO. This examination may provide mental health nurses with insight into the constructed identities of their patients, as well as the role of mental health care within broader cultural narratives.


Cross-platform immunophenotyping of human peripheral blood mononuclear cells with four high-dimensional flow cytometry panels.
Immunophenotyping using high dimensional flow cytometry is a central component of human immune system multi-omic studies. We present four high parameter flow cytometry panels for deep immunophenotyping of human peripheral blood mononuclear cells (PBMC). This set of four 25+ color panels include 64 cell surface markers to resolve broad immune compartment populations, as well as activation and memory of specific T, B, natural killer (NK), and myeloid lineages. Common lineage bridging markers are integrated into each panel to allow for inter-panel quality control through major lineage frequency verification. These panels were developed using a five laser BD Symphony A5 conventional cytometer and successfully transferred to a five laser Cytek Aurora spectral cytometer capable of acquiring the panels. Nine representative PBMC samples were stained with the four phenotyping panels and acquired on both instruments to evaluate population frequency and visual staining patterns for gating between the systems. Both instruments produced comparable high quality flow cytometry data and supported our decision to acquire samples on the spectral cytometer moving forward. This modular set of panels and instrument performance metrics provide guidelines for designing flow cytometry experiments suitable for longitudinal or cross-sectional immune profiling.


Imaging of melanoma with L-131-labeled monoclonal antibodies.
Mouse monoclonal antibodies and Fab fragments specific for p97, a melanoma-associated antigen, were used to image metastatic human melanoma. Preclinical studies in athymic mice showed antigen-specific uptake in melanoma xenografts, and toxicity tests in rabbits gave no evidence for tissue damage after injection of up to 100 times the amount of antibody used in humans. Six patients received 1 mg labeled antibody, and one patient received 1 mg of labeled Fab. No. toxic side effects were observed. All of the six patients had positive scans, visualizing 22 of 25 (88%) of lesions larger than 1.5 cm. In tumors from two patients, greater uptake of p97-specific, versus control IgG and Fab, respectively, was documented by biopsy. Antibodies to mouse immunoglobulin appeared in three patients receiving 1 mg or more of radiolabeled mouse antibody.


An interpretative phenomenological analysis of an improvisational music therapy program for cancer patients.
Although there are an increasing number of qualitative studies investigating the benefits of music therapy interventions in cancer care settings, few studies have adopted a phenomenological approach to explore how and why such interventions work. The aim of this study was to explore the psychological processes involved in an improvisational music therapy program for cancer patients. Nine individuals took part in an improvisational music therapy program and participated in semi-structured interviews. Interpretative Phenomenological Analysis (IPA) was employed as a theoretical and methodological framework for the analysis of the interviews. Recurrent themes revealed a variety of social and psychological benefits related to the experience of music therapy, such as facilitating peer support and group interaction, increasing self-confidence, relaxation, the generation of positive feelings, stress relief and feelings of enhanced communication through music. There was also an emphasis upon the importance of social interaction and communication. This paper highlights a number of key benefits connected with music therapy for patients with cancer and the effectiveness of IPA in applied health psychology research.


Global occurrence of infant botulism, 1976-2006.
To summarize the worldwide occurrence of reported infant (intestinal toxemia) botulism cases since first recognition of the disease in 1976. We collected information on infant botulism cases by active and passive surveillance, by provision of therapeutic Human Botulism Immune Globulin to suspected cases, and by searching the medical literature. We defined a case as laboratory-confirmed botulism that occurred in an infant <or=12 months of age that was not caused by the ingestion of botulinum toxin in food. Twenty-six countries representing 5 continents reported the occurrence of at least 1 case of infant botulism among their residents. The United States, Argentina, Australia, Canada, Italy, and Japan, in this order, reported the largest number of cases. A history of honey exposure was significantly more common among case subjects hospitalized outside of the United States than among those who were recently hospitalized in California. Most countries have not yet reported cases of infant botulism. This limited reporting of the disease to date contrasts with the known global occurrence of Clostridium botulinum spores in soils and dust and suggests that infant botulism may be under-recognized, underreported, or both. When bulbar palsies, hypotonia, and weakness are present, physicians should consider the possibility of infant botulism even if the patient has not been fed honey. Publication of additional case reports and surveillance summaries will enhance understanding of the occurrence and extent of this under-recognized disease.


[Age-related characteristics of breast invasive ductal carcinoma].
377 patients aged 30 to 79 years who had breast carcinoma were examined to study the age-related features of tumor anaplasia. The degree of tumor anaplasia was studied, in primary nodules, less and more than 2.5 cm in diameter in patients of different ages. This index decreased with age. This may explain more a malignant course of the disease in young patients.


Corticotropin releasing factor increases in brown adipose tissue thermogenesis and heart rate through dorsomedial hypothalamus and medullary raphe pallidus.
Corticotropin releasing factor, acting at hypothalamic corticotropin releasing factor receptors, contributes to the neural signaling pathways mediating stress-related responses, as well as those involved in maintaining energy balance homeostasis. Sympathetically-regulated lipid metabolism and heat production in brown adipose tissue contributes to the non-shivering thermogenic component of stress-evoked hyperthermia and to energy expenditure aspects of body weight regulation. To identify potential central pathways through which hypothalamic corticotropin releasing factor influences brown adipose tissue thermogenesis, corticotropin releasing factor was microinjected into the lateral ventricle (i.c.v.) or into hypothalamic sites while recording sympathetic outflow to brown adipose tissue, brown adipose tissue temperature, expired CO2, heart rate and arterial pressure in urethane/chloralose-anesthetized, artificially-ventilated rats. I.c.v. corticotropin releasing factor or corticotropin releasing factor microinjection into the preoptic area or the dorsomedial hypothalamus, but not the paraventricular nucleus of the hypothalamus, elicited sustained increases in brown adipose tissue sympathetic nerve activity, brown adipose tissue temperature, expired CO2 and heart rate. These sympathetic responses to i.c.v. corticotropin releasing factor were eliminated by inhibition of neuronal activity in the dorsomedial hypothalamus or in the raphe pallidus, a putative site of sympathetic premotor neurons for brown adipose tissue, and were markedly reduced by microinjection of ionotropic glutamate receptor antagonists into the dorsomedial hypothalamus. The increases in brown adipose tissue sympathetic outflow, brown adipose tissue temperature and heart rate elicited from corticotropin releasing factor into the preoptic area were reversed by inhibition of neuronal discharge in dorsomedial hypothalamus. These data indicate that corticotropin releasing factor release within the preoptic area activates a sympathoexcitatory pathway to brown adipose tissue and to the heart, perhaps similar to that activated by increased prostaglandin production in the preoptic area, that includes neurons in the dorsomedial hypothalamus and in the raphe pallidus.


Ozone treatment and biodegradation of industrial wastewater containing thioethers.
Wastewater from an Akzo Nobel production site contains refractory sulfur components (cyclic thioethers). These components end up in the effluent of the existing biological wastewater treatment plant. The possibilities of (partial) oxidation and increasing biodegradability by ozone treatment for these types of compounds have been investigated. Ozonation experiments were carried out at laboratory scale, varying pH, temperature and catalysts. Biodegradability was evaluated from BOD measurements and BOD/COD ratios. Ozonation experiments at pH = 10 without catalyst addition or heating were found to give the best results with the simplest means: COD was removed for 80-90% and biodegradability increased from BOD/COD = 0.2-0.3 to > 0.7. These results could not be improved any further by adding catalysts like iron and manganese (hydr)oxides or activated carbon, by heating or by further increasing pH. Aftertreatment at pH = 10 required about 3 kg ozone per m3 for about 80-90% removal of the total COD. This results in high annual operating costs and is therefore less suitable in practice. Biodegradability already increased to 60% at COD removal of 50% and ozone consumption of 1.4 kg/m3 wastewater. On the basis of these findings, it was calculated that ozonation has potential as pretreatment for a side stream containing the major fraction of the cyclic thioethers mixture.


Development and validation of an Arabic language eye-tracking paradigm for the early screening and diagnosis of autism spectrum disorders in Qatar.
Abnormal eye gaze is a hallmark characteristic of autism spectrum disorder (ASD). The primary aim of the present research was to develop an Arabic version of an objective measure of ASD, the "autism index" (AI), based on eye gaze tracking to social and nonsocial stimuli validated initially in the United States. The initial phase of this study included the translation of English language eye-tracking stimuli into stimuli appropriate for an Arabic-speaking culture. During the second phase, we tested it on a total of 144 children with ASD, and 96 controls. The AI had excellent internal consistency and test-retest reliability. Moreover, the AI showed good differentiation of ASD from control cases (AUC = 0.730, SE = 0.035). The AI was significantly positively correlated with SCQ total raw scores (r = 0.46, p < 0.001). ADOS-2 scores were only available in the ASD group and did not show a significant relationship with AI scores (r = 0.10, p = 0.348), likely due to the restricted range. The AI, when implemented using Arabic-translated stimuli in a Qatari sample, showed good diagnostic differentiation and a strong correlation with parent-reported ASD symptoms. Thus, the AI appears to have cross-cultural validity and may be useful as a diagnostic aide to inform clinical judgment and track ASD symptom levels as part of the evaluation process.


Noncanonical secondary structure stabilizes mitochondrial tRNA(Ser(UCN)) by reducing the entropic cost of tertiary folding.
Mammalian mitochondrial tRNA(Ser(UCN)) (mt-tRNA(Ser)) and pyrrolysine tRNA (tRNA(Pyl)) fold to near-canonical three-dimensional structures despite having noncanonical secondary structures with shortened interhelical loops that disrupt the conserved tRNA tertiary interaction network. How these noncanonical tRNAs compensate for their loss of tertiary interactions remains unclear. Furthermore, in human mt-tRNA(Ser), lengthening the variable loop by the 7472insC mutation reduces mt-tRNA(Ser) concentration in vivo through poorly understood mechanisms and is strongly associated with diseases such as deafness and epilepsy. Using simulations of the TOPRNA coarse-grained model, we show that increased topological constraints encoded by the unique secondary structure of wild-type mt-tRNA(Ser) decrease the entropic cost of folding by ∼2.5 kcal/mol compared to canonical tRNA, offsetting its loss of tertiary interactions. Further simulations show that the pathogenic 7472insC mutation disrupts topological constraints and hence destabilizes the mutant mt-tRNA(Ser) by ∼0.6 kcal/mol relative to wild-type. UV melting experiments confirm that insertion mutations lower mt-tRNA(Ser) melting temperature by 6-9 °C and increase the folding free energy by 0.8-1.7 kcal/mol in a largely sequence- and salt-independent manner, in quantitative agreement with our simulation predictions. Our results show that topological constraints provide a quantitative framework for describing key aspects of RNA folding behavior and also provide the first evidence of a pathogenic mutation that is due to disruption of topological constraints.


Can Dietary Intake of Vitamin C-Oriented Foods Reduce the Risk of Osteoporosis, Fracture, and BMD Loss? Systematic Review With Meta-Analyses of Recent Studies.
Background: Several epidemiological studies have been performed to evaluate the association of dietary intake of vitamin C-oriented foods (DIVCF) with risk of fracture and bone mineral density (BMD) loss, but the results remain controversial. Therefore, we conducted a systematic meta-analysis to assess this correlation. Methods: We searched EmBase, PubMed, Web of Science, and the Chinese database CNKI for relevant articles published up to August 2019. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated using the random- or fixed-effects model. Discrepancies were resolved by consultation with a third expert. Results: A total of 13 eligible articles (including 17 studies) with 19,484 subjects were identified for the present meta-analysis. The pooled RR of hip fracture for the highest vs. lowest category was 0.66 (95% CI, 0.47-0.94) for DIVCF, i.e., people with a greater frequency of Vitamin C uptake had a 34% (95% CI, 6%-53%) lower prevalence of hip fracture. In subgroup analyses stratified by study design, gender, and age, the negative associations were statistically significant. Furthermore, the statistical analysis of the association between DIVCF and risk of osteoporosis (RR, 0.66; 95% CI, 0.48-0.92), BMD at the lumbar spine (pooled r, 0.15; 95% CI, 0.09-0.23), and BMD at the femoral neck (pooled r, 0.20; 95% CI, 0.11-0.34) showed beneficial effects of DIVCF. Conclusion: Our meta-analysis indicates that DIVCF is negatively associated with the risk of hip fracture, osteoporosis, and BMD loss, suggesting that DIVCF decreases the risk of hip fracture, osteoporosis, and BMD loss.


[Legal regulation and management of fee for services in the state expert institutions].
With due regard for the economic situation in regions, differences in the material-technical and personnel provision of each forensic-medical bureau (FMB), paying capacity of local residents and for other factors, a method for estimating the cost of forensic medical services was elaborated and offered for use. The formula of cost estimation for rendered services allow for basic wages (BW) and bonuses, sick-list and vacation payments, overhead charges (including FMB wear-and-tear), and BW assignment to off-budget funds (which constitute, in total, the self-cost of services) as well as the planned profit and road taxes.


MICA: a multi-omics method to predict gene regulatory networks in early human embryos.
Recent advances in single-cell omics have transformed characterisation of cell types in challenging-to-study biological contexts. In contexts with limited single-cell samples, such as the early human embryo inference of transcription factor-gene regulatory network (GRN) interactions is especially difficult. Here, we assessed application of different linear or non-linear GRN predictions to single-cell simulated and human embryo transcriptome datasets. We also compared how expression normalisation impacts on GRN predictions, finding that transcripts per million reads outperformed alternative methods. GRN inferences were more reproducible using a non-linear method based on mutual information (MI) applied to single-cell transcriptome datasets refined with chromatin accessibility (CA) (called MICA), compared with alternative network prediction methods tested. MICA captures complex non-monotonic dependencies and feedback loops. Using MICA, we generated the first GRN inferences in early human development. MICA predicted co-localisation of the AP-1 transcription factor subunit proto-oncogene JUND and the TFAP2C transcription factor AP-2γ in early human embryos. Overall, our comparative analysis of GRN prediction methods defines a pipeline that can be applied to single-cell multi-omics datasets in especially challenging contexts to infer interactions between transcription factor expression and target gene regulation.


Nucleotide binding and sulfation catalyzed by phenol sulfotransferase.
The sulfation of a nucleotide is an indispensable step for the sulfuryl group transfer in a biological system. The product and cosubstrate of sulfotransferase in physiological condition are adenosine 3',5'-bisphosphate (PAP) and 3'-phospho adenosine 5'-phosphosulfate (PAPS), respectively. We find that ribose and adenine, two major parts of the adenosine nucleotide, bind tightly to phenol sulfotransferase (PST) separately, and various nucleotides also bind tightly to PST. We determine the dissociation constants of a variety of nucleotides and examine their potential as cofactors or cosubstrates of PST. Using 4-nitrophenyl sulfate as the sulfuryl group donor, three nucleotides, adenosine 5'-monophosphate (AMP), adenosine 2',5'-bisphosphate (2',5'-PAP), and adenosine 2':3'-cyclic phosphate 5'-phosphate (2':3'-cyclic PAP), are shown here for the first time to be sulfated at 5'-phopho position by a PST catalyzed reaction. Spectrophotometry, HPLC, and (31)P NMR are used to determine the activity of PST and identify the sulfated nucleotides. The V(max) of PST and K(m) of these nucleotides are determined when they are used as cofactors or cosubstrates for the sulfuryl group transfer. The existence and possible physiological significance of these newly reported binding and sulfation of nucleotides by PST in biology is yet to be discovered.


Adapting an adherence support workers intervention: engaging traditional healers as adherence partners for persons enrolled in HIV care and treatment in rural Mozambique.
Systematic adaptation of evidence-informed interventions that increase retention in care and improve adherence to antiretroviral therapy (ART) are essential to ending the HIV epidemic in rural sub-Saharan Africa. We selected and adapted an adherence support worker intervention employed in Malawi for use by traditional healers in rural Mozambique. Given the levels of trust and dependence previously expressed by persons living with HIV (PLHIV) for traditional medicine, we adapted the program to engage traditional healers within the allopathic health system. Adaption followed a theoretically driven approach to intervention adaption: the Assessment-Decision-Administration-Production-Topical Experts-Integration-Training-Testing (ADAPT-ITT) model. Three rounds of performance feedback, based on theater presentations of the adapted intervention for stakeholders and idea generation, were completed with 12 groups from March to July 2016 to develop the final model. We offered healer support to 180 newly diagnosed HIV-infected patients. Traditional healers were an acceptable group of community health workers to assist with patient adherence and retention. Traditional healers, clinicians, and interested community members suggested novel strategies to tailor the adherence support worker intervention, revealing a local culture of HIV denialism, aversion to the health system, and dislike of healthcare providers, as well as a preference for traditional treatments. Proposed changes to the intervention included modifications to the training language and topics, expanded community-based activities to support acceptability of an HIV diagnosis and to facilitate partner disclosure, and accompaniment to the health facility by healers to encourage delivery of respectful clinical care. PLHIV, healers, and clinicians deemed the intervention socially acceptable during focus groups. We subsequently recruited 180 newly diagnosed HIV-infected patients into the program: 170 (94%) accepted. Systematic translation of interventions, even between regions with similar social and economic environments, is an important first step to successful program implementation. Efforts previously limited to community health workers can be tailored for use by traditional healers-an underutilized and often maligned health workforce. It proved feasible to use theater-based performances to demonstrate delivery of the intervention in low-literacy populations, generating discussions about social norms, community concerns, and the merits of an acceptable strategy to improve retention and adherence to ART.


Neuronal responses in sensorimotor cortex to ramp displacements and maintained positions imposed on hindlimb of the unanesthetized monkey.
1. Neuronal responses to passively imposed displacements of the foot were examined in area 3a, the precentral motor cortex (MI), and the first somatic sensory cortex (SI) of unanesthetized monkeys. The foot displacements, in the form of "ramps" and maintained displacements, were applied at several different velocities and achieved a number of maintained positions. The response in relation to the ramp was termed a "dynamic" response, while that in association with the maintained displacement was termed a "static" response. 2. Units in the rostral part of MI (MI/r) and in area 3a usually responded in relation both the ramps and to maintained displacements. The activity of the majority of area 3a and MI/r units was strongly modulated only during ramps of one direction. Such response properties contrast with those observed in the caudal part of MI (MI/c) and areas 3b and 1 of SI, where most units responded in relation to the ramp phase of the displacement in both of two ramp directions and not to the maintained displacements. 3. Virtually all units, including those in MI, displayed a dynamic response. However, the dynamic response amplitude of area 3a neurons greatly exceeded that of MI units for equal velocities of displacement. 4. For area 3a units, peak neuronal activity was well correlated with ramp velocity over the range examined. Such units were a minority in areas 3b and 1 of SI (excluding area 3a) and MI. 5. Most area 3a units and almost half of MI/r units displayed, in addition to a dynamic response, a static response that reflected foot position. MI units were more sensitive than area 3a units to equal degrees of maintained displacement. 6. These results demonstrate that in the unanesthetized, intact animal, responses of most neurons in area 3a and MI fall into two categories: a) mixed dynamic-static responses resembling those of muscle spindle afferents, and b) purely dynamic responses. These data are consistent with the hypothesis that afferent input concerning the velocity and position of a segment of a limb may have a role in cortically mediated regulation of movement and posture, and that both areas 3a and the MI cortex may be directly involved in this regulation. 7. The cytoarchitectonic characteristics of area 3a, as defined in single-unit studies, are discussed. It is argued that the salient characteristic of area 3a in the primate is a thinned internal granular layer (layer IV) that contrasts with the heavily granular area 3b and the agranular area 4.


[Cardiac manifestations of muscular dystrophies].
Muscular dystrophies (MD) are a clinically and genetically heterogeneous disease group. In the last few years, remarkable progress has been made in understanding the close und various relations between skeletal muscle disease and heart muscle disease. Cardiac involvement has been documented in a number of primary MDs and is even the dominant feature in some of them. The myocardium can be affected in the form of a dilated cardiomyopathy while the conduction system can be affected resulting in arrhythmias and conduction defects. Many patients with MD die because of cardiac complications like sudden cardiac death or congestive heart failure. Detailed clinical data about cardiac involvement are available for Duchenne/Becker MD, Emery-Dreifuss MD, myotonic dystrophy, and the different limb girdle MDs. Cardiac manifestations were also found in congenital MD, central core disease, proximal myotonic myopathy, and nemaline myopathy. No data about cardiac abnormalities are available in oculopharyngeal MD and rippling muscle disease. The heart of patients with primary MD should be carefully investigated because of the life-threatening events caused by cardiac complications. There is a strong need for a close collaboration between neurologists and cardiologists in order to provide optimal disease management for the affected patients.


Each N-glycan on human IgA and J-chain uniquely affects oligomericity and stability.
Immunoglobulin A (IgA) plays a pivotal role in various immune responses, especially that of mucosal immunity. IgA is usually assembled into dimers with the contribution of J-chains. There are two N-glycosylation sites in human IgA1-Fc and one in the J-chain. There is no consensus as yet on the functional role of the N-glycosylation. To gain a better understanding of their role, we designed a series of IgA1-Fc mutants, which were expressed in the absence or presence of the J-chain. IgA1-Fc without the J-chain, was predominantly expressed as a monomer, and in its presence dimers and some polymers appeared. N263 (Fc Cα2), N459 (Fc tailpiece) and N49 (J-chain) were shown to be site-specifically modified with N-glycans by mass spectrometry analysis. Mutant IgA1-Fc N459Q failed to form a proper dimer in the presence of the J-chain, instead higher-order aggregates appeared. Fluorescence experiments suggest that the N459-glycans cover a hydrophobic surface at the Fc tailpiece that prevents other Fc molecules from approaching the dimeric IgA. A thermofluor assay revealed that the N-glycans at N263 (Fc) and N49 (J-chain) both contribute in different ways to the thermal stability of the Fc-J-chain complex. NMR analysis of 13C-labeled Fc suggests that the N459-glycan is relatively flexible while the N263-glycan is more rigid. We conclude that the N459-glycan of IgA1-Fc is essential for dimer formation and prevention of higher-order aggregates while those at N263 (Fc) and N49 (J-chain) stabilize the Fc-J-chain complex. Site-specific role for N-glycan in molecular assembly is addressed.


Non-Gaussian diffusion imaging: a brief practical review.
The departure from purely mono-exponential decay of the signal, as observed from brain tissue following a diffusion-sensitized sequence, has prompted the search for alternative models to characterize these unconventional water diffusion dynamics. Several approaches have been proposed in the last few years. While multi-exponential models have been applied to characterize brain tissue, several unresolved controversies about the interpretations of the results have motivated the search for alternative models that do not rely on the Gaussian diffusion hypothesis. In this brief review, diffusional kurtosis imaging (DKI) and anomalous diffusion imaging (ADI) techniques are addressed and compared with diffusion tensor imaging. Theoretical and experimental issues are briefly described to allow readers to understand similarities, differences and limitations of these two non-Gaussian models. However, since the ultimate goal is to improve specificity, sensitivity and spatial localization of diffusion MRI for the detection of brain diseases, special attention will be paid on the clinical feasibility of the proposed techniques as well as on the context of brain pathology investigations.


Outcomes comparison of solo-practitioner and group practice models.
A solo-practitioner care delivery model is utilized in the predoctoral teaching clinics at the University of Washington School of Dentistry. This model requires students to independently manage their practices using central resources. The model is perceived as cumbersome for patients and students and as failing to achieve optimum educational and productivity outcomes. During the 1995-96 academic year, a group practice model of patient care delivery was pilot tested to assess whether productivity, educational, and care delivery outcomes could be enhanced in comparison to the solo-practitioner model. This group practice model combined third- and fourth-year students for purposes of sharing resources and collaborating in patient care delivery. Resources dedicated to each group practice included a practice advisor, shared patient care coordinator, dental assistant, and shared clinic receptionist. Two group practices and twenty-five student solo practitioners participated in the study. Based upon an analysis of productivity, participant, and patient data, the group practice participants had greater billing volume, better attendance, enhanced satisfaction with the staff/faculty support and their ability to fill appointments, and generally comparable patient satisfaction ratings. These results suggest that the group practice model, through the dedication of resources and collaboration of providers, could enhance the outcomes of the clinical education program.