Finite element simulation and experimental investigation of residual stresses in ultrasonic assisted turning.
The residual stresses in the machined workpiece are of great importance due to their influence on the workpiece fatigue life, as well as its dimensional and geometric accuracy. The metal cutting process has always been accompanied by heat generation and severe plastic deformation. This thermo mechanical loading along with the resulted metallurgical changes are the main sources of residual stresses generation at the surface of machined workpiece. The Ultrasonic Assisted Turning (UAT) reduces the temperature in the cutting region and reduces the average machining forces due to the discontinuous contact of the tool and the workpiece. Reducing the intensity of thermo mechanical loading in the UAT process will affect the residual stresses caused by machining. In this paper, the results of thermo mechanical finite element simulation and experimental studies of residual stresses during UAT of AISI 4140 has been studied. The results of this simulation make it possible to determine the effect of vibration and machining parameters (cutting speed and feed rate) on the magnitude and type of surface residual stresses in the workpiece machined by UAT. Finally, the simulation results are compared with experimental measurements of residual stresses using X-ray diffraction technique. Based on the obtained results, the hoop component of the residual stresses in case of UAT became more compressive averagely by about 73.34% compared to the traditional turning; for instance at constant feed of 0.11 mm/rev and cutting speed of 0.261 m/s, for three different vibration amplitudes of 4, 8 and 12 µm, the machining induced residual stresses became more compressive respectively by 53.34%, 73.00% and 100%.


Anti-aggressive activity of methyl jasmonate and the probable mechanism of its action in mice.
This study examines the anti-aggressive activity of methyl jasmonate (MJ) and its probable mechanism of action in mice. Male mice that showed aggression after housing individually with female counterparts for 3 weeks or kept in isolation for 4 weeks were treated with MJ, vehicle or haloperidol (HP) 60 min before the test for aggression. Effects of p-chlorophenylalanine (PCPA) or fluoxetine (FL) given alone or in combination with MJ were also investigated. In the interaction studies, PCPA or FL was given to the animals 30 min after MJ injection and aggression testing was carried out 30 min later. Parameters assessed in the study were latency to attack, frequency of attacks, aggressive postures, lateral threats, tail rattling and pursuit frequency. MJ (1, 5, 10 mg/kg) produced a significant dose-dependent decrease in offensive aggressive behaviors. MJ did not impair the defensive mechanisms of the animals and its anti-aggressive effect was not accompanied by sedation or catalepsy. PCPA (50 mg/kg), an inhibitor of 5-hydroxytryptamine (5-HT) biosynthesis, produced a significant increase in aggressive responses and reversed the anti-aggressive effect of MJ. Additionally, FL (10 mg/kg), a 5-HT reuptake inhibitor, produced a significant suppression of aggressive behaviors and also enhanced the antiaggressive effect of MJ. Taken together, these findings suggest that methyl jasmonate exhibits specific anti-offensive aggressive activity and may be relevant in the treatment of reactive aggression in humans. Although, it appears that MJ may be affecting 5-HT(1B) receptors, additional data are needed to clearly define the mechanism(s) by which MJ exhibit antiaggressive activity.


Impact of COVID-19 outbreak on plastic surgery: Taken precautions, distribution of surgical procedures and changes in admissions to outpatient clinic.
The COVID-19 outbreak is a global problem affecting the world in many respects. In the medical field, its impact on surgical branches as well as clinical branches is inevitable. From the plastic surgery perspective, the COVID-19 outbreak affects the number and distribution of surgeries, patient admissions and educational activities. Although these impacts are predictable, it is beneficial to document these data that would contribute to the proper response to a similar crisis in the future. From this standpoint, the present study aims to analyze the effect of the COVID-19 pandemic on plastic surgery practice in some aspects. Epidemiologic data of the two-time frames, routine period, and pandemic period of plastic surgery were reviewed retrospectively. The ratios of the listed data were compared between the two periods; admissions to the outpatient clinic, surgeries, consultations, anesthesia type, hospitalizations, and demographic data. While the number of outpatient clinic patients was 3511 in the routine period, it was 490 in the pandemic period. Compared to the routine period, the number of surgical interventions was decreased from 793 to 129 during the pandemic period. In particular, a statistically significant increase was observed in the rate of hand trauma and maxillofacial trauma cases during the pandemic period compared with the routine period (p < 0.001, and p = 0.032, respectively). Therefore, high rates of hand trauma and maxillofacial trauma should be taken into consideration when making arrangements such as personnel distribution, use of medical resources, and regulation of hospital infrastructure in extraordinary situations like COVID-19 pandemics.


Experiences of Mothers Participating in a Mother-Child Video Therapy Program.
Responsive and sensitive parenting promotes the development of self-regulation and lowers stress in children, which in turn is associated with greater educational and economic achievement and better physical and emotional health later in life. Dyadic parent-child video-feedback programs can help parents learn effective parenting skills, yet these programs are estimated to retain only about half of eligible participants. Programs vary widely, and little is known about what is valued by parents who do complete these programs. The purpose of this qualitative study was to understand the goals, experiences, and outcomes important to mothers who completed a video-feedback program. Transcripts of exit interviews of participants in a video-feedback program (N = 31) were analyzed using qualitative description methodology. Trustworthiness was achieved through deep engagement with the material, following an iterative process in analyzing transcripts, and member checks to confirm results. Mothers enrolled in the program to better understand their child, help their child learn, and to develop closer connections with their child. Elements of the program that helped mothers achieve these goals were (1) positive feedback and support by the therapist, (2) dedicated one-on-one time spent with their infant, (3) help with concrete needs, and (4) learning from watching videotaped play sessions. As a result, mothers reported greater confidence as caregivers, use of more responsive and sensitive parenting strategies, and improvements in their children's behaviors and their own mental health. Incorporating elements of the program found to be most useful in this study into video-feedback programs may make video-feedback programs more attractive to parents and increase retention. Midwives and women's health care providers may incorporate elements of the program into their clinical practice and advocacy, with special attention to elements most valued by parents themselves.


PEBP1 suppresses HIV transcription and induces latency by inactivating MAPK/NF-κB signaling.
The latent HIV-1 reservoir is a major barrier to viral eradication. However, our understanding of how HIV-1 establishes latency is incomplete. Here, by performing a genome-wide CRISPR-Cas9 knockout library screen, we identify phosphatidylethanolamine-binding protein 1 (PEBP1), also known as Raf kinase inhibitor protein (RKIP), as a novel gene inducing HIV latency. Depletion of PEBP1 leads to the reactivation of HIV-1 in multiple models of latency. Mechanistically, PEBP1 de-phosphorylates Raf1/ERK/IκB and IKK/IκB signaling pathways to sequestrate NF-κB in the cytoplasm, which transcriptionally inactivates HIV-1 to induce latency. Importantly, the induction of PEBP1 expression by the green tea compound epigallocatechin-3-gallate (EGCG) prevents latency reversal by inhibiting nuclear translocation of NF-κB, thereby suppressing HIV-1 transcription in primary CD4+ T cells isolated from patients receiving antiretroviral therapy (ART). These results suggest a critical role for PEBP1 in the regulation of upstream NF-κB signaling pathways governing HIV transcription. Targeting of this pathway could be an option to control HIV reservoirs in patients in the future.


Bacterial persistence: finding the "sweet spot".
Studies described by Eisele et al. (2013) and Xavier et al. (2013) in this issue of Cell Host & Microbe show that the bacterial pathogens Salmonella and Brucella exploit the increased levels of glucose present in alternatively activated macrophages to sustain chronic infections in experimentally infected mice.


Boundary maintenance in the ancestral metazoan Hydra depends on histone acetylation.
Much of boundary formation during development remains to be understood, despite being a defining feature of many animal taxa. Axial patterning of Hydra, a member of the ancient phylum Cnidaria which diverged prior to the bilaterian radiation, involves a steady-state of production and loss of tissue, and is dependent on an organizer located in the upper part of the head. We show that the sharp boundary separating tissue in the body column from head and foot tissue depends on histone acetylation. Histone deacetylation disrupts the boundary by affecting numerous developmental genes including Wnt components and prevents stem cells from entering the position dependent differentiation program. Overall, our results suggest that reversible histone acetylation is an ancient regulatory mechanism for partitioning the body axis into domains with specific identity, which was present in the common ancestor of cnidarians and bilaterians, at least 600 million years ago.


Capturing water vapors from atmospheric air using superporous gels.
Dehumidification performance of most polymer desiccant materials is unsatisfactory because of the complex adsorption mechanism on polymer surface and non-porous structure. A viable alternative of solid desiccants, especially existing polymer desiccants, for capturing water vapors from moist air is the super-porous gels (SPGs). The presence of interconnected channels of pores in its structure facilitates the transfer of water molecules to the internal structure of SPGs. Therefore, in this research work, we are proposing N-isopropylacrylamide (NIPAM) and acrylamide (AM) based thermoresponsive SPGs as a potential alternative to the existing conventional solid desiccants. To ensure the formation of interconnected capillary channels, the SPGs were synthesized via gas blowing and foaming technique. Surface morphology of the SPGs was studied using scanning electron microscopy (SEM) and the other physio-chemical characteristics were studied using different techniques like fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD) and thermo-gravimetric analysis (TGA). Water vapors adsorption properties of the SPGs were explored via adsorption isotherm and kinetics. The adsorption isotherm was found to be of type-III isotherm with a maximum adsorption capacity of 0.75 gw/gads at 25 °C and 90% relative humidity. Experimental isotherm data correlated well with BET, FHH and GAB isotherm models. Adsorption kinetics suggested that the water vapors diffusion followed intraparticle diffusion and liquid field driving mechanisms collectively. SPGs exhibited very good regeneration and reusability for ten continuous adsorption/desorption cycles. Therefore, the dehumidification efficiency of synthesized SPGs shows that they have potential to replace most of the conventional solid desiccant materials in use.


A novel function of Goalpha: mediation of extracellular signal-regulated kinase activation by opioid receptors in neural cells.
Go is the most abundant G protein expressed in brain but its function is less known. Here we show a novel function of Goalpha as a mediator of opioid receptor-induced extracellular signal-regulated kinase activation in neural cells. The current study found that, in neuroblastoma x glioma NG108-15 hybrid cells, activation of extracellular signal-regulated kinase through delta opioid receptors was mediated by pertussis toxin-sensitive G protein and independent of Gbetagamma subunits, PI3 kinase and receptor internalization. Overexpression of a dominant negative form of Goalpha1, but not Gialpha2, completely blocked delta opioid receptor-induced extracellular signal-regulated kinase activity. Decreasing Goalpha expression by RNA interference greatly reduced delta opioid receptor-induced extracellular signal-regulated kinase activity and extracellular signal-regulated kinase-dependent gene expression, while knocking down Gialpha2 did not. By taking advantage of differences between human and mouse Goalpha gene sequences, we simultaneously knocked down endogenous Goalpha expression and expressed exogenous human Goalpha subunits. We found that both human Goalpha1 and Goalpha2 could mediate delta opioid receptor-induced extracellular signal-regulated kinase activation. This study suggests that one of the functions of Goalpha in the brain is to mediate extracellular signal-regulated kinase activation by G protein-coupled receptors.


NK cell activity in pulmonary tuberculosis.
Natural killer (NK) cell activity, which may provide defence mechanism in the immune surveillance system, was studied in 38 patients with active pulmonary tuberculosis and 54 sex-, and age-matched healthy controls. The mean NK cell activity in patients with active pulmonary tuberculosis (58.7 +/- 26.4%) was significantly higher (P less than 0.001) than that in healthy controls (17.4 +/- 12.2%). Classifying the patients into three groups according to the state of excretion of tubercle bacilli, the mean NK cell activity in newly diagnosed patients was 43.2 +/- 20.7%, in advanced disease 59.4 +/- 30.3%, and in successfully treated patients 71.9 +/- 25.9%.


Adaptation of multiformat film holder to real-time ultrasound.
A method is described for adaptation of a multiformat film holder to a free-standing real-time imaging unit. No additional electronics are necessary for modification.


Surface protein expression between human adipose tissue-derived stromal cells and mature adipocytes.
Adipose tissue contains a stroma that can be easily isolated. Thus, human adipose tissue presents an source of multipotent stromal cells. In order to determine the implication of hematopoietic markers in adipocyte biology, we have defined part of the phenotype of the human adipose tissue-derived stromal cells, and compared this to fully differentiated adipocytes. Flow cytometry demonstrates that the protein expression phenotype of both cell types are similar and includes the expression of CD10, CD13, CD34, CD36, CD55, CD59 and CD65. No significant difference between subcutaneous and omental adipose tissue could be demonstrated concerning the expression of these markers. However, the expression of CD34, CD36 and CD65 is cell-dependent. While the expression of CD36 and CD65 doubled between stromal cells and mature adipocytes, the expression of CD34 decreased, despite this protein being present on the mature adipocyte. As CD34 is described as a stem cell marker and it being unlikely to be expressed on differentiated cells, this result was confirmed by immunostaining and western blot. The clear function of this protein on the adipocyte membrane remains to be determined. The characterization of new proteins on mature adipocytes could have broad implications for the comprehension of the biology of this tissue.


[Our experience with tube manometry in chronic otitis media. Part II: clinical use (author's transl)].
The appliance of tube manometry in clinical routine is reported as a simple and valuable method to judge tube function. By tube manometry treatment, conservative and operation, of both tube and middle ear, may be judged. Examples are given for the application of tube manometry in clinical routine.


Association between CCDC132, FDX1 and TNFSF13 gene polymorphisms and the risk of IgA nephropathy.
Previous genome-wide association studies have identified multiple susceptibility loci for IgA nephropathy (IgAN); however, validation of these findings is still needed. We performed a case-control study among 347 Chinese Han IgAN patients and 310 ethnicity-matched controls. Twenty-two single nucleotide polymorphisms (SNPs) were genotyped and association analysis was performed. We found three alleles for IgAN in patients: the allele "C" of rs2188404 in the CCDC132 gene by recessive model (odds ratio (OR), 1.65; 95% confidence interval (CI), 1.10-2.48; P = 0.014) and additive model (OR, 1.29; 95% CI, 1.03-1.61; P = 0.024) analysis, respectively, the allele "A" of rs10488764 in FDX1 gene by additive model (OR, 1.27; 95% CI, 1.00-1.61; P = 0.048) analysis, the allele "A" of rs3803800 in TNFSF13 gene by recessive model (OR, 2.05; 95% CI, 1.16-3.62; P = 0.010) and additive model (OR, 1.35; 95% CI, 1.06-1.72; P = 0.013) analysis, respectively. However, the associations between these SNPs and the risk of IgAN were not significant when adjusted for age and sex. Additionally, we found polymorphisms of rs2188404, rs10488764 and rs3803800 were correlated with urine protein (UPRO), human serum albumin (HSA), total cholesterol (TC) and Lee's pathological grades. We did not find any positive association between these SNPs and the risk of IgAN after adjustment by age and sex, but did find a significant and strong correlation with relevant clinical pathological parameters. Our study may provide a new perspective to understanding the aetiology of IgAN.


Reliability of classifying multiple sclerosis disease activity using magnetic resonance imaging in a multiple sclerosis clinic.
To assess the reliability of new magnetic resonance imaging (MRI) lesion counts by clinicians in a multiple sclerosis specialty clinic. An observational study. A multiple sclerosis specialty clinic. Eighty-five patients with multiple sclerosis participating in a National Institutes of Health–supported longitudinal study were included. Each patient had a brain MRI scan at entry and 6 months later using a standardized protocol. The number of new T2 lesions, newly enlarging T2 lesions, and gadolinium-enhancing lesions were measured on the 6-month MRI using a computer-based image analysis program for the original study. For this study, images were reanalyzed by an expert neuroradiologist and 3 clinician raters. The neuroradiologist evaluated the original image pairs; the clinicians evaluated image pairs that were modified to simulate clinical practice. New lesion counts were compared across raters, as was classification of patients as MRI active or inactive. Agreement on lesion counts was highest for gadolinium-enhancing lesions, intermediate for new T2 lesions, and poor for enlarging T2 lesions. In 18% to 25% of the cases, MRI activity was classified differently by the clinician raters compared with the neuroradiologist or computer program. Variability among the clinical raters for estimates of new T2 lesions was affected most strongly by the image modifications that simulated low image quality and different head position. Between-rater variability in new T2 lesion counts may be reduced by improved standardization of image acquisitions, but this approach may not be practical in most clinical environments. Ultimately, more reliable, robust, and accessible image analysis methods are needed for accurate multiple sclerosis disease-modifying drug monitoring and decision making in the routine clinic setting.


Role of autophagy and apoptosis in wound tissue of deep second-degree burn in rats.
The pathogenesis of burn wound progression is poorly understood. Contributing factors include continuous loss of blood perfusion, excessive inflammation, and elevated apoptosis levels in wound tissue. Macroautophagy (here referred to simply as "autophagy") is associated with many chronic diseases. The authors hypothesized that autophagy is involved in burn wound progression in a rat model of deep second-degree burn. Deep second-degree burns were modeled using a brass rod heated to 100°C applied for 6 seconds to the back skin of Wistar rats. Full-thickness biopsies were obtained from burned and nonburned controls at several times postburn. Western blotting and immunohistochemical (IHC) staining determined expression of the autophagy markers Light Chain 3 (LC3) and beclin-1. Apoptosis was determined by terminal-deoxynucleoitidyl transferase mediated nick end labeling (TUNEL) assay and laser Doppler flowmetry (LDF)-measured tissue perfusion. Myeloperoxidase (MPO) activity assay measured inflammation. Hematoxylin and eosin (H&E) and Masson's trichrome staining-determined pathology and wound depth. The LC3 and beclin-1 protein level in burn wounds decreased to one-fourth of normal levels (p<0.01) over 24 hours and then began to increase but still did not reach their normal level. TUNEL-positive cells in burn wounds were 3.7-fold (p<0.01) elevated over 48 hours and then decreased slightly, yet still remained higher than in normal skin. The burn wound progressed in depth over 72 hours. In addition, significant decrease in LDF values and upregulation of MPO activity were observed. Enhanced LC3-positive cells were observed in the deep dermal layer of burn wounds as shown by IHC staining. A reduction in autophagy and blood flow and an increase in apoptosis and inflammation were observed in burn wounds early during the course of burn injury progression. This suggests that autophagy, complemented by apoptosis, play important roles in burn progression. Enhanced autophagy in the deep dermis may be a prosurvival mechanism against ischemia and inflammation after burn injury.


HIV suppression by host restriction factors and viral immune evasion.
Antiviral restriction factors are an integral part of the host innate immune system that protects cells from viral pathogens, such as human immunodeficiency virus (HIV). Studies of the interactions between restriction factors and HIV have greatly advanced our understanding of both the viral life cycle and basic cell biology, as well as provided new opportunities for therapeutic intervention of viral infection. Here we review the recent developments towards establishing the structural and biochemical bases of HIV inhibition by, and viral countermeasures of, the restriction factors TRIM5, MxB, APOBEC3, SAMHD1, and BST2/tetherin.


Routine screening for hepatitis C in pregnancy is cost-effective in a large urban population in Ireland: a retrospective study.
To investigate whether risk factor-based screening in pregnancy is failing to identify women with hepatitis C virus (HCV) infection and to assess the cost-effectiveness of universal screening. Retrospective study and model-based economic evaluation. Two urban tertiary referral maternity units, currently using risk factor-based screening for HCV infection. Pregnant women who had been tested for hepatitis B, HIV but not HCV. Anonymised sera were tested for HCV antibody. Positive sera were tested for HCV antigen. A cost-effectiveness analysis of a change to universal screening was performed using a Markov model to simulate disease progression and Monte Carlo simulations for probabilistic sensitivity analysis. Presence of HCV antigen and cost per quality-adjusted life year (QALY). In all, 4655 samples were analysed. Twenty had HCV antibodies and five HCV antigen. This gives an active infection rate of 5/4655, or 0.11%, compared with a rate of 0.15% in the risk-factor group. This prevalence is 65% lower than a previous study in the same hospitals from 2001 to 2005. The calculated incremental cost-effectiveness ratio (ICER) for universal screening was €3,315 per QALY gained. This study showed that the prevalence of HCV infection in pregnant women in the Dublin region has declined by 65% over the past two decades. Risk factor-based screening misses a significant proportion of infections. A change to universal maternal screening for hepatitis C would be cost-effective in our population. Universal maternal screening for hepatitis C is cost-effective in this urban Irish population.


In vivo 1H2O T2+ measurement in the human occipital lobe at 4T and 7T by Carr-Purcell MRI: detection of microscopic susceptibility contrast.
A high-resolution spin-echo imaging method is presented (called CP-LASER) which exploits the spin refocusing capability of an adiabatic Carr-Purcell (CP) pulse sequence to measure apparent 1H2O transverse relaxation (T2+) and generate contrast based on microscopic tissue susceptibility. High-resolution CP-LASER images of the human occipital lobe were acquired at four different echo times from six subjects at 4T and eight subjects at 7T to investigate the effect of magnetic field strength (B(0)) and the CP interpulse time (tau(cp)) on T2+. Susceptibility contrast was identified and T2+ was quantified for long tau(cp) (>10 ms) and short tau(cp) (7 ms at 4T and 6 ms at 7T) in gray matter, white matter, and cerebral spinal fluid. The 1H2O relaxation rate constants (1/T2+) of gray and white matter each increased approximately linearly with field strength and T2+ was inversely related to tau(cp). The average T2+ value of gray matter was 19% and 9% smaller than that of white matter at 4T and 7T, respectively. These results are consistent with higher levels of compartmentalized ferritin and increased blood volume in gray matter compared to white matter in this region of the brain.


HIV and AIDS in the adolescent and adult: an update for the oral and maxillofacial surgeon.
HIV and AIDS are among the most complex disease states affecting the worldwide population. OMS and other care providers should have a good understanding of the myriad of systemic effects of this disease and its treatment. This disease affects every system in the body, and in order to provide the best care to these patients, a basic knowledge of this disease process is mandatory. The OMS has the potential to assist in the initial diagnosis of HIV and in recognition of worsening disease. Research continues to examine new treatment modalities, and the search for a vaccine continues. Until a cure is found, the stark statistic seen on bumper stickers remains: 40,000,000 infected. 0 cured.


Sexual dysfunction with aging and systemic hypertension.
The incidence of sexual dysfunction increases with age and in the presence of systemic hypertension. An interplay between endocrine, neurologic and vascular systems mediates normal male sexual function. Androgens primarily regulate libido and maintenance of genital tissue, while the autonomic nervous system and arterial blood flow play key roles in the physiology of the male sexual response, particularly penile erection. Vascular disease related to hypertension, diabetes mellitus and atherosclerosis may be the main factor contributing to the sexual dysfunction that occurs with aging. Hormonal alterations probably play less of a role. The importance of neurologic abnormalities remains to be determined. Although specific diagnostic testing can be useful in defining abnormalities in each of these systems, treatment of sexual dysfunction in the setting of hypertension in the elderly patient remains a challenge.


The CNS in inbred transgenic models of 4-repeat Tauopathy develops consistent tau seeding capacity yet focal and diverse patterns of protein deposition.
MAPT mutations cause neurodegenerative diseases such as frontotemporal dementia but, strikingly, patients with the same mutation may have different clinical phenotypes. Given heterogeneities observed in a transgenic (Tg) mouse line expressing low levels of human (2 N, 4R) P301L Tau, we backcrossed founder stocks of mice to C57BL/6Tac, 129/SvEvTac and FVB/NJ inbred backgrounds to discern the role of genetic versus environmental effects on disease-related phenotypes. Three inbred derivatives of a TgTauP301L founder line had similar quality and steady-state quantity of Tau production, accumulation of abnormally phosphorylated 64-68 kDa Tau species from 90 days of age onwards and neuronal loss in aged Tg mice. Variegation was not seen in the pattern of transgene expression and seeding properties in a fluorescence-based cellular assay indicated a single "strain" of misfolded Tau. However, in other regards, the aged Tg mice were heterogeneous; there was incomplete penetrance for Tau deposition despite maintained transgene expression in aged animals and, for animals with Tau deposits, distinctions were noted even within each subline. Three classes of rostral deposition in the cortex, hippocampus and striatum accounted for 75% of pathology-positive mice yet the mean ages of mice scored as class I, II or III were not significantly different and, hence, did not fit with a predictable progression from one class to another defined by chronological age. Two other patterns of Tau deposition designated as classes IV and V, occurred in caudal structures. Other pathology-positive Tg mice of similar age not falling within classes I-V presented with focal accumulations in additional caudal neuroanatomical areas including the locus coeruleus. Electron microscopy revealed that brains of Classes I, II and IV animals all exhibit straight filaments, but with coiled filaments and occasional twisted filaments apparent in Class I. Most strikingly, Class I, II and IV animals presented with distinct western blot signatures after trypsin digestion of sarkosyl-insoluble Tau. Qualitative variations in the neuroanatomy of Tau deposition in genetically constrained slow models of primary Tauopathy establish that non-synchronous, focal events contribute to the pathogenic process. Phenotypic diversity in these models suggests a potential parallel to the phenotypic variation seen in P301L patients.


Nontherapeutic research with children: the Ramsey versus McCormick debate.
The ethical debates about use of children as research subjects are stimulated by reports of actual events. These reports often distort the essential ethical arguments about how and when use of children can be justified. The essential arguments were clearly formulated in an historic debate between two ethicists, Paul Ramsey and Richard McCormick. Their debate laid the foundations for the recommendations of the National Commission for Protection of Human Subjects that have become the current federal regulations governing research with children.


Evidence that 8-methoxypsoralen (8-MOP) is a T-lymphocyte immunomodulatory agent.
This study was designed to characterize the effects of the anti-psoriatic compound 8-methoxypsoralen (8-MOP) on human lymphocyte function in vitro. Normal human peripheral blood mononuclear cells were stimulated with an optimal (1%) or a suboptimal (0.05%) concentration of phytohemagglutinin (PHA). At the optimal concentration of PHA, 8-MOP (140 microM) caused a delay in lymphocyte proliferation, interleukin-2 (IL-2) production/accumulation and IL-2 receptor expression. Addition of exogenous IL-2 to cultures stimulated with an optimal concentration of PHA did not overcome the delay of lymphocyte proliferation and IL-2 receptor expression. At the suboptimal concentration of PHA, 8-MOP (140 microM) caused a sustained inhibition of lymphocyte proliferation, IL-2 production/accumulation and IL-2 receptor expression. Addition of exogenous IL-2 under these conditions restored the magnitude of lymphocyte proliferation and IL-2 receptor expression. However, the responses displayed the delayed lymphocyte proliferation and IL-2 receptor expression typical of cells incubated with 8-MOP and an optimal concentration of PHA.


Anatomic Double-Bundle Posterior Cruciate Ligament Reconstruction.
The posterior cruciate ligament (PCL) is known to be the main posterior stabilizer of the knee. Anatomic single-bundle PCL reconstruction, focusing on reconstruction of the larger anterolateral bundle, is the most commonly performed procedure. Because of the residual posterior and rotational tibial instability after the single-bundle procedure and the inability to restore the normal knee kinematics, an anatomic double-bundle PCL reconstruction has been proposed in an effort to re-create the native PCL footprint more closely and to restore normal knee kinematics. We detail our technique for an anatomic double-bundle PCL reconstruction using Achilles and anterior tibialis tendon allografts.


Timing of serving dessert but not portion size affects young children's intake at lunchtime.
The purpose of this repeated exposure, randomized, cross-over quasi-experimental study was to determine the individual and combined impact of (a) the timing of serving dessert and (b) portion size of main course in 2-5 year old children (n=23) on energy intake at lunch in a childcare setting. Children were served two study lunches (fish or pasta, each with dessert) twice a week for 12 weeks that differed in the timing of dessert (served with or after the main course) and portion size of the main course (reference portion or 50% larger portion). Analyses of variance revealed that serving dessert after the meal resulted in higher energy intakes from both the main course and from dessert, and therefore greater total intake at the meal. Portion size of the main course did not influence total energy intake at the meal. Results indicate that the timing of serving dessert affects children's energy intake regardless of the portion size of the main course. Specifically, serving dessert with the meal reduces total energy intake regardless of the main course portion size. This suggests that offering dessert with the main course may be an effective strategy for decreasing total energy intake at meals in preschool-aged children.


Quick and Simple FRAIL Scale Predicts Incident Activities of Daily Living (ADL) and Instrumental ADL (IADL) Disabilities: A Systematic Review and Meta-analysis.
To quantitatively examine frailty defined by FRAIL scale as a predictor of incident disability risks by conducting a systematic review and meta-analysis. Systematic review and meta-analysis. A systematic review was conducted using 4 electronic databases (Embase, MEDLINE, CINAHL, and PsycINFO) in April 2018 for prospective cohort studies of middle-aged or older people examining associations between frailty and incident disability. Reference lists of the included studies were hand-searched for additional studies. Authors of potentially eligible studies were contacted for additional data if necessary. Methodological quality was assessed by the Newcastle-Ottawa scale. Community-dwelling middle-aged and older people. Incident risks of activities of daily living (ADL) or instrumental activities of daily living (IADL) disability according the FRAIL scale-defined frailty. Seven studies provided odds ratios of incident disability risks according to frailty and were included in the meta-analysis. A random effects meta-analysis showed that frailty and prefrailty were significant predictors of ADL [pooled odds ratio (OR) = 9.82, 95% confidence interval (CI) = 4.71-20.46, P < .001 for frailty (FRAIL scale = 3-5) and pooled OR = 2.08, 95% CI = 1.77-2.45, P < .001 for prefrailty (FRAIL scale = 1-2) compared with robustness (FRAIL scale = 0); pooled OR = 4.44, 95% CI = 3.26-6.04, P < .001 for frailty compared with nonfrailty (FRAIL scale = 0-2)] and IADL (pooled OR = 2.50, 95% CI = 1.67-3.73, P < .001, for frailty and pooled OR = 1.74, 95% CI = 1.10-2.77, P = .02, for prefrailty compared with robustness). There was no evidence of publication bias. The current study demonstrated that frailty status defined by the FRAIL scale was a significant predictor of disability among community-dwelling middle-aged and older individuals. In light of feasibility of the FRAIL scale, especially in a clinical setting, it may be a promising tool to facilitate the translation of frailty research into clinical practice.


Pattern and associated factors of the neurolathyrism epidemic in Ethiopia.
To describe the neurolathyrism epidemic in Ethiopia and to identify associated household factors. We interviewed 589 randomly selected heads of household in Debre Sina district of Ethiopia, the area afflicted by the recent neurolathyrism epidemic. Disease information was obtained for 2987 family members. Neurolathyrism patients were detected in 56 (9.5%) households (prevalence rate 2.38%). The mean number of affected family members per household was 1.27 (SD 0.65, range 1-3). Most (77.5%) patients developed the disability during the epidemic (1995-1999). The median age at onset of paralysis was 11 years with a range of 41 (range 3-44). Younger people were more affected during the epidemic than during the non-epidemic period (P=0.01). The presence of a neurolathyrism patient in the family was associated with illiteracy [adjusted OR (95% CI)=2.23 (1.07-5.10)] of the head of household, with owning a grass pea farm [adjusted OR (95% CI)=2.01 (1.04-3.88)] and with the exclusive cooking of grass pea foods using handmade traditional clay pots [adjusted OR (95% CI=2.06 (1.08-3.90)]. Males aged 10-14 years were most affected by neurolathyrism. Increased household risk was associated with illiteracy of the head of the household and exclusive cooking of grass pea foods with handmade traditional clay pots.


Modification by lidocaine of the discharges of primary endings of muscle spindles in cat tenuissimus muscle.
The effects of lidocaine (1--20 microgram/ml) on afferent discharge patterns of primary endings of muscle spindles in cat tenuissimus muscle were investigated. Discharge from the endings, recorded in Ia afferent axons, was evoked by ramp stretch of the muscle, stimulation of single static or dynamic fusimotor axons or by a combination of stretch and fusimotor stimulation. Spontaneous discharge of the endings at the initial length of the muscles was reduced by 2--5 microgram/ml and abolished by 10--15 microgram/ml lidocaine. The static but not the dynamic discharge elicited by muscle stretch was blocked by concentrations of 10--15 microgram/ml. The same concentrations abolished static and dynamic fusimotor influences on primary ending discharge. However, in one experiment where the spindle was microscopically observed, fusimotor stimulation still resulted in contraction of the intrafusal muscle even when fusimotor stimulation failed to elicit changes in discharge response patterns of the primary endings. These findings indicate that lidocaine interferes with the encoding mechanism prior to block of impulse conduction in either the fusimotor or afferent axons.


Differential sensitivity of immature and mature ventral mesencephalic neurons to rotenone induced neurotoxicity in vitro.
Rotenone induced neuronal toxicity in ventral mesencephalic (VM) dopaminergic (DA) neurons in culture is widely accepted as an important model for the investigation of Parkinson's disease (PD). However, little is known about developmental stage dependent toxic effects of rotenone on VM neurons in vitro. The objective of present study is to investigate the effect of rotenone on developing VM neurons at immature versus mature stages. Primary VM neurons were cultured in the absence of glial cells. Exposure of VM neurons to rotenone for 2 days induced cell death in both immature and mature neurons in a concentration-dependent manner, but to a greater extent in mature neurons. While rotenone-treated mature VM neurons showed α-synuclein aggregation and sensitivity to DA neurons, immature VM neurons exhibited only DA neuronal sensitivity but not α-synuclein aggregation. In addition, on rotenone treatment, enhancement of caspase-3 activity and reactive oxygen species (ROS) production were higher in mature VM neurons than in immature neurons. These results suggest that even though both mature and immature VM neurons are sensitive to rotenone, their manifestations differ from each other, with only mature VM neurons exhibiting Parkinsonian conditions.


Need for hepatitis A prevention in patients with chronic liver disease in the changing epidemiological setting of India.
The burden of chronic liver disease (CLD) in India is high, particularly among middle-aged men, with nearly 220,000 deaths due to cirrhosis in 2017. CLD increases the risk of infection, severe disease (e.g. hepatitis A virus or HAV superinfection, acute-on-chronic liver failure, fulminant hepatic failure), and mortality. Hence, various countries recommend HAV vaccination for CLD patients. While historic Indian studies showed high seroprevalences of protective HAV antibodies among Indian adults with CLD, the most recent ones found that nearly 7% of CLD patients were susceptible to HAV infection. Studies in healthy individuals have shown that HAV infection in childhood is decreasing in India, resulting in an increasing population of adults susceptible to HAV infection. As patients with CLD are at increased risk of severe HAV infection, now may be the time to recommend HAV vaccination among people with CLD in India.


Toward a human papillomavirus vaccine.
Much progress has been made over the past 10 years with regard to development of a vaccine active against HPV. Successful protection has been achieved in animal models using species-specific papillomaviruses; however, HPV diversity may delay the development of successful HPV vaccines, especially those designed as therapeutic vaccines for the treatment of HPV-induced carcinoma and high-grade dysplasia of the cervix. Difficulties arise with regard to assessment of efficacy of potential vaccines. The impetus for long-term studies on vaccine efficacy will initially stem from in vitro evidence of responsiveness to the vaccine. The time when a vaccine will have an impact on the prevalence of high-grade dysplasia and invasive cancer is still some way off.


Calcium channel antagonists and adenosine analogues decrease tolerance to opiate pentazocine and U 50488H.
1. A single dose of pentazocine induces cross-tolerance the analgesic effects of the kappa agonist U 50488H. Tolerance is observed by means of the hot plate test or by the i.p. administration of acetic acid 6 or 24 hr after the priming dose, respectively. 2. The administration of the calcium channel antagonists, diltiazem, nifedipine or verapamil, reduces the degree of tolerance as assessed by the hot plate test or acetic acid administration. 3. The adenosine agonist N6-cyclopentyl adenosine significantly reduced the intensity of the process; in contrast, N6-cyclohexyladenosine antagonized the analgesic response to the opiate obscuring its influence on the process. 4. The results are discussed in relation to the interaction of calcium channel function in the analgesic response to the kappa opiates.


Relationship between facet joint tropism and degeneration of facet joints and intervertebral discs based on a histological study.
Evaluate the correlation between lumbar facet joint tropism, lumbar facet joint degeneration, and intervertebral disc degeneration. Forty-two of facet joints were evaluated histologically and radiologically. The correlation between facet joint tropism and histologic, CT, and MRI grading was -0.159 (P = 0.339), 0.025 (P = 0.226) and -0.270 (P = 0.102), respectively. The correlation between facet joint tropism and intervertebral disc MRI grading was 0.346 (P = 0.033), and that between facet joint and intervertebral disc MRI grading was 0.208 (P = 0.210). Facet joint tropism was correlated with intervertebral disc degeneration but not with facet joint degeneration.


Dosimetric assessment of antitumor treatment by enhanced bleomycin delivery via electroporation and sonoporation.
Targeted and controlled techniques of intratumoral delivery of chemotherapeutic agents are under extensive development, since they diminish detrimental side-effects of conventional anticancer drugs. We investigated the effectiveness of chemotherapy using bleomycin (1 mg/ml) and Sonovue microbubbles combined with: electroporation (EP), mainly designed for subcutaneous tumor therapy, and sonoporation (SP) - for deeper localized tumors. Research was performed on hepatoma MH-22A tumors in murine models, exposed to EP or SP and combined (EP + SP) treatment. Animal survival time and the rate/ speed of tumor growth reduction were examined. Study demonstrated that both EP or SP and their combination (EP + SP) were able to induce the reduction of tumor volume from the 3rd day after treatment. The employment of EP before SP allowed to significantly reduce the values of inertial cavitation dose (ICD), necessary to induce complete tumor reduction and prolong animal survival. The analysis of ultrasound (US) side-scattered signals and B-scan imaging indicated the occurrence of inertial cavitation at our experimental conditions. Strong (R2 = 0.88; p < 0.0001) correlation of ICD with the survival time of corresponding unrecovered mice indicates the option for the dosimetric control and standardization of cavitation activities for in vivo practice.


Diagnostic accuracy of tests for type 2 diabetes and prediabetes: A systematic review and meta-analysis.
This systematic review aimed to ascertain the diagnostic accuracy (sensitivity and specificity) of screening tests for early detection of type 2 diabetes and prediabetes in previously undiagnosed adults. This systematic review included published studies that included one or more index tests (random and fasting tests, HbA1c) for glucose detection, with 75-gram Oral Glucose Tolerance Test (or 2-hour post load glucose) as a reference standard (PROSPERO ID CRD42018102477). Seven databases were searched electronically (from their inception up to March 9, 2020) accompanied with bibliographic and website searches. Records were manually screened and full text were selected based on inclusion and exclusion criteria. Subsequently, data extraction was done using standardized form and quality assessment of studies using QUADAS-2 tool. Meta-analysis was done using bivariate model using Stata 14.0. Optimal cut offs in terms of sensitivity and specificity for the tests were analysed using R software. Of 7,151 records assessed by title and abstract, a total of 37 peer reviewed articles were included in this systematic review. The pooled sensitivity, specificity, positive (LR+) and negative likelihood ratio (LR-) for diagnosing diabetes with HbA1c (6.5%; venous sample; n = 17 studies) were 50% (95% CI: 42-59%), 97.3% (95% CI: 95.3-98.4), 18.32 (95% CI: 11.06-30.53) and 0.51 (95% CI: 0.43-0.60), respectively. However, the optimal cut-off for diagnosing diabetes in previously undiagnosed adults with HbA1c was estimated as 6.03% with pooled sensitivity of 73.9% (95% CI: 68-79.1%) and specificity of 87.2% (95% CI: 82-91%). The optimal cut-off for Fasting Plasma Glucose (FPG) was estimated as 104 milligram/dL (mg/dL) with a sensitivity of 82.3% (95% CI: 74.6-88.1%) and specificity of 89.4% (95% CI: 85.2-92.5%). Our findings suggest that at present recommended threshold of 6.5%, HbA1c is more specific and less sensitive in diagnosing the newly detected diabetes in undiagnosed population from community settings. Lowering of thresholds for HbA1c and FPG to 6.03% and 104 mg/dL for early detection in previously undiagnosed persons for screening purposes may be considered.


Locking of the thumb in a patient with de Quervain's disease: a case report.
We report a patient with a locked left thumb in association with de Quervain's disease. While bathing her baby 1 month after giving birth a 32-year-old woman suddenly noticed that she could not radially abduct her left thumb. Magnetic resonance imaging showed thickening of the abductor pollicis longus tendon with a heterogeneous signal intensity on T2-weighted images. Bandage fixation for 4 weeks did not improve her thumb movement, and she was subsequently treated by surgery. Operative findings revealed inhibition of the tendon gliding proximally as a result of nodule formation in the abductor pollicis longus tendon distal to the first dorsal compartment. This condition, locking of the thumb, was improved by excising the extensor retinaculum of the first dorsal compartment and tenosynovium around the abductor pollicis longus and extensor pollicis brevis tendon. At the 1-year follow-up examination the patient had no limitations or pain during active radial abduction of the left thumb.


Physical Health Symptoms and Hurricane Katrina: Individual Trajectories of Development and Recovery More Than a Decade After the Storm.
Objectives. To examine how physical health symptoms developed and resolved in response to Hurricane Katrina.Methods. We used data from a 2003 to 2018 study of young, low-income mothers who were living in New Orleans, Louisiana, when Hurricane Katrina struck in 2005 (n = 276). We fit logistic regressions to model the odds of first reporting or "developing" headaches or migraines, back problems, and digestive problems, and of experiencing remission or "recovery" from previously reported symptoms, across surveys.Results. The prevalence of each symptom increased after Hurricane Katrina, but the odds of developing symptoms shortly before versus after the storm were comparable. The number of traumatic experiences endured during Hurricane Katrina increased the odds of developing back and digestive problems just after the hurricane. Headaches or migraines and back problems that developed shortly after Hurricane Katrina were more likely to resolve than those that developed just before the storm.Conclusions. While traumatic experiences endured in disasters such as Hurricane Katrina appear to prompt the development of new physical symptoms, disaster-induced symptoms may be less likely to persist or become chronic than those emerging for other reasons.


Measurement of phenotypic resilience to gastro-intestinal nematodes in Merino sheep and association with resistance and production variables.
A cross-over experiment was conducted to compare six different phenotypic measures of resilience to gastro-intestinal nematodes (predominantly Haemonchus contortus) in Merino sheep and their association with resistance and production levels. On each of six farms, 120 ewes born in 2006 and 120 older mixed age ewes were selected at shearing in 2007. Of these, 60 in each mob were serially treated with long-acting anthelmintics to suppress worm populations. The other 60 ewes were managed according to management practices employed on the farm (infected, INF). At shearing in 2008, the experimental sheep had their anthelmintic treatments switched. The experiment concluded at shearing in 2009. Measures of resilience were greasy fleece weight (GFW), live weight gain (LWG) and haematocrit (HCT) when infected and the difference in these variables between infected and suppressed. Resistance was determined from multiple faecal worm egg counts (WEC) when infected. Measures of resilience based on GFW, LWG and HCT were moderately correlated with each other (r=0.25-0.50) suggesting that they represent different traits. Correlations between a measure in infected animals, and the difference in the same measurement between infected and uninfected animals were higher (r=-0.37 to -0.82), indicating that measurement during infection is an adequate measure of resilience. WEC was negatively correlated with LWG and HCT during infection but not GFW. Correlations with resilience measures based on difference between infected and uninfected were positive. Surviving infected sheep were found to have higher haematocrit (HCT), and lower WEC in summer and autumn than sheep that died following the measurement. These results show that measurement of performance traits while infected is a reasonable approximation of measurement of resilience based on the difference in performance between infected and non-infected. They also show that resilience to worm infection is not a single trait, but rather a suite of moderately correlated traits.


Electrolyte Abnormalities in Patients Presenting With Ventricular Arrhythmia (from the LYTE-VT Study).
Electrolyte abnormalities are a known trigger for ventricular arrhythmia, and patients with heart disease on diuretic therapy may be at higher risk for electrolyte depletion. Our aim was to determine the prevalence of electrolyte depletion in patients presenting to the hospital with sustained ventricular tachycardia or ventricular fibrillation (VT/VF) versus heart failure, and identify risk factors for electrolyte depletion. Consecutive admissions to a tertiary care hospital for VT/VF were identified between July 2016 and October 2018 using the electronic medical record and compared with an equal number of consecutive admissions for heart failure (CHF). The study included 280 patients (140 patients in each group; mean age 63, 60% male, 59% African American). Average EF in the VT/VF and CHF groups was 30% and 33%, respectively. Hypokalemia (K < 3.5 mmol/L) and severe hypokalemia (K < 3.0 mmol/L) were present in 35.7% and 13.6%, respectively, of patients with VT/VF, compared to 12.9% and 2.7% of patients with CHF (p < 0.001 and p = 0.001, respectively, between groups). Hypomagnesemia was found in 7.8% and 5.8% of VT/VF and CHF patients, respectively (p = 0.46). Gastrointestinal illness and recent increases in diuretic dose were strongly associated with severe hypokalemia in VT/VF patients (odds ratio: 11.1 and 21.9, respectively; p < 0.001). In conclusion, hypokalemia is extremely common in patients presenting with VT/VF, much more so than in patients with CHF alone. Preceding gastrointestinal illness and increase in diuretic dose were strongly associated with severe hypokalemia in the VT/VF population, revealing a potential opportunity for early intervention and arrhythmia risk reduction.


Synaptic mechanisms underlying auditory processing.
In vivo voltage clamp recordings have provided new insights into the synaptic mechanisms that underlie processing in the primary auditory cortex. Of particular importance are the discoveries that excitatory and inhibitory inputs have similar frequency and intensity tuning, that excitation is followed by inhibition with a short delay, and that the duration of inhibition is briefer than expected. These findings challenge existing models of auditory processing in which broadly tuned lateral inhibition is used to limit excitatory receptive fields and suggest new mechanisms by which inhibition and short term plasticity shape neural responses.


Stabilization and rovibronic spectra of the T-shaped and linear ground-state conformers of a weakly bound rare-gas-homonuclear dihalogen complex: He...Br2.
Laser-induced fluorescence spectra of Br(2) entrained in a He supersonic expansion have been recorded in the Br(2) B-X, 8-0, 12-0, and 21-0 spectral regions at varying downstream distances, and thus different temperature regimes. Features associated with transitions of the T-shaped and linear He...Br(2)(X,nu(") = 0) complexes are identified. The changes in the relative intensities of the T-shaped and linear features with cooling in the expansion indicate that the linear conformer is energetically more stable than the T-shaped conformer. A He + Br(2)(X,nu(") = 0) ab initio potential-energy surface, computed at the coupled cluster level of theory with a large, flexible basis set, is used to calculate the binding energies of the two conformers, 15.8 and 16.5 cm(-1) for the T-shaped and linear complexes, respectively. This potential and an excited-state potential [M. P. de Lara-Castells, A. A. Buchachenko, G. Delgado-Barrio, and P. Villareal, J. Chem. Phys. 120, 2182 (2004)] are used to calculate the excitation spectra of He...(79)Br(2)(X,nu(") = 0) in the Br(2) B-X, 12-0 region. The calculated spectra are used to make spectral assignments and to determine the energies of the excited-state intermolecular vibrational levels accessed in the observed transitions. Temperature-dependent laser-induced fluorescence spectra and a simple thermodynamic model [D. S. Boucher, J. P. Darr, M. D. Bradke, R. A. Loomis, and A. B. McCoy, Phys. Chem. Chem. Phys. 6, 5275 (2004)] are used to estimate that the linear conformer is 0.4(2) cm(-1) more strongly bound than the T-shaped conformer. Two-laser action spectroscopy experiments reveal that the binding energy of the linear He...(79)Br(2)(X,nu(") = 0) conformer is 17.0(8) cm(-1), and that of the T-shaped He...(79)Br(2)(X,nu(") = 0) conformer is then 16.6(8) cm(-1), in good agreement with the calculated values.


Gorham disease: correlation of MR findings with histopathologic changes.
Gorham disease is a rare disorder of unknown etiology characterized by bone destruction and abnormal proliferation of thin-walled vascular channels including lymphatic capillaries. Starting monocentrically in a single bone, the angiomatous masses in this disease extend to adjacent bones and soft tissues without respecting articular barriers. Herein we report a case of Gorham disease with its MR and histopathologic appearance.


Partial trisomy 6p with karyotype 46,XY,der(22), t(6;22)(p22;q13)mat.
A case of partial trisomy 6p is reported with a review of the various characteristics of this syndrome.


Kinome-wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics.
Metastatic uveal melanoma (UM) is invariably fatal, usually within a year of diagnosis. There are currently no effective therapies, and clinical studies employing kinase inhibitors have so far demonstrated limited success. This is despite common activating mutations in GNAQ/11 genes, which trigger signalling pathways that might predispose tumours to a variety of targeted drugs. In this study, we have profiled kinome expression network dynamics in various human ocular melanomas. We uncovered a shared transcriptional profile in human primary UM samples and across a variety of experimental cell-based models. The poor overall response of UM cells to FDA-approved kinase inhibitors contrasted with much higher sensitivity to the bromodomain inhibitor JQ1, a broad transcriptional repressor. Mechanistically, we identified a repressed FOXM1-dependent kinase subnetwork in JQ1-exposed cells that contained multiple cell cycle-regulated protein kinases. Consistently, we demonstrated vulnerability of UM cells to inhibitors of mitotic protein kinases within this network, including the investigational PLK1 inhibitor BI6727. We conclude that analysis of kinome-wide signalling network dynamics has the potential to reveal actionable drug targets and inhibitors of potential therapeutic benefit for UM patients.


Lipid, protein and carbohydrate intake in relation to body mass index.
To examine whether the same amount of energy intake has different consequences on body mass index (BMI), depending on the source of energy from specific macronutrients. Cross-sectional study, in the context of the European Prospective Investigation into Cancer and nutrition (EPIC). Communities all over Greece. A total of 27 862 apparently healthy volunteers, men and women, ages 25-82 y. None. Dietary information was collected through an interviewer-administered semi-quantitative food frequency questionnaire. In the context of a cross-sectional analysis, we calculated changes of BMI per increments of energy intake from protein, carbohydrates, saturated, polyunsaturated and monounsaturated lipids and ethanol, controlling for mutual confounding and other confounders, among all participants, and after exclusion of under-reporters and/or those on a diet. Protein intake was positively associated with BMI. The association was evident when nutrients were not mutually adjusted for and increased after mutual adjustment among nutrients (beta=0.80 kg/m(2) per 418.4 kJ or 100 kcal increment, 95% confidence interval 0.55-1.06 for men, and beta=1.59, 95% CI 1.30-1.88 for women), as well as after exclusion of under-reporters and/or those on a diet. The effects of other macronutrients were less substantial or consistent. There is evidence indicating that protein intake is conducive to obesity. Moreover, our data suggest that neither saturated or monounsaturated lipids nor carbohydrates are likely to play a major role in increasing BMI over and beyond that indicated by their energy content.


Comparison of the hemodynamics between patients with alcoholic or HCV-related cirrhosis.
Hyperdynamic circulation, which is characterized by increased cardiac output (CO), normal or low arterial blood pressure (BP), and decreased systemic vascular resistance (SVR), occurs in patients with liver cirrhosis (LC). However, differences of hemodynamics between patients with alcoholic LC (ALC) and viral LC are not well understood. The aim of the present study was to compare hemodynamics between patients with alcoholic LC and patients with HCV-related LC (CLC). Eighteen healthy Japanese volunteers (HV), 10 patients with chronic hepatitis (CH), 46 patients with CLC, and 22 ALC patients with ALC were included in the study. The CLC group was divided into two subgroups (34 non-ascites and 12 ascites patients), as was the ALC group (11 non-ascites and 11 ascites patients). The CO, portal blood flow (PBF), and hepatic congestion index (HCI) were measured by ultrasound. The CO of the CLC and the ALC groups was higher than that of the HV group, while the SVR of the CLC and ALC groups was lower than that of the HV group. These changes were more marked in the ALC group. The HCI of the ascitic ALC subgroup was higher than that of the HV group. PBF did not differ among the CLC, ALC and HV groups. Progression of liver diseases such as ALC or CLC leads to a hyperdynamic circulation. The decrease of SVR was more marked in ALC patients than that CLC patients and an increase of the HCI was only found in ALC patients with ascites.


Epididymo-orchitis due to Pseudomonas pseudomallei.
We report the first case of epididymo-orchitis caused by Pseudomonas pseudomallei. The diagnosis was made by isolation of the organism from testicle pus and urine. Treatment was successful with chloramphenicol and co-trimoxazole.


Technical and biologic sources of variability in the mapping of aortic, mitral and tricuspid color flow jets.
The quantification of valvular regurgitation by 2-dimensional Doppler imaging depends on identifying and minimizing variability. Aortic, mitral and tricuspid regurgitant jet areas were measured in 50 patients with sinus rhythm or atrial fibrillation to analyze the variables of reading error, valve site, jet size, rhythm and frame rate. One technician recorded jet velocities at 1 frame/cycle at a triggered interval after the electrocardiographic R wave and at frame rates of 7.5 and 15 frames/s. Jet areas from 5 consecutive beats were measured by planimetry by 1 observer. Coefficients of variation between and among groups were compared by analysis of variance; mean values were 14 to 22%. Jets grouped less than 2.5, 2.5 to 5 and greater than 5 cm2 showed the variance of small jets exceeding that of medium and large jets. Aortic regurgitant jets were largest and had smaller variance than mitral tricuspid jets. Variability due to atrial fibrillation and the slower frame rate was marginal. Intraobserver error was 4.3% and interobserver 15.4%. Thus, reproducing jet areas carries a minimum variability of 15% or higher, depending on jet size. Valve site could not be excluded as a separate variable. Comparative quantification is best limited to 1 observer.


A poliovirus type 1 neutralization epitope is located within amino acid residues 93 to 104 of viral capsid polypeptide VP1.
Using nuclease Bal31, deletions were generated within the poliovirus type 1 cDNA sequences, coding for capsid polypeptide VP1, within plasmid pCW119. The fusion proteins expressed in Escherichia coli by the deleted plasmids reacted with rabbit immune sera directed against poliovirus capsid polypeptide VP1 (alpha VP1 antibodies). They also reacted with a poliovirus type 1 neutralizing monoclonal antibody C3, but reactivity was lost when the deletion extended up to VP1 amino acids 90-104. Computer analysis of the protein revealed a high local density of hydrophilic amino acid residues in the region of VP1 amino acids 93-103. A peptide representing the sequence of this region was chemically synthesized. Once coupled to keyhole limpet hemocyanin, this peptide was specifically immunoprecipitated by C3 antibodies. The peptide also inhibited the neutralization of poliovirus type 1 by C3 antibodies. We thus conclude that the neutralization epitope recognized by C3 is located within the region of amino acids 93-104 of capsid polypeptide VP1.


A monoclonal antibody with specificity for murine mu heavy chain which inhibits the formation of antigen-specific direct IgM plaques.
A panel of monoclonal rat antibodies binding to mouse mu heavy chain were tested for their ability to inhibit the formation of antigen-specific plaques in the hemolytic plaque assay. Nine antibodies inhibited SRC-specific direct IgM plaques at high concentrations (greater than 20 micrograms/ml). In contrast to all others, however, one antibody inhibited these plaques at much lower concentrations (down to 0.4 microgram/ml) when added to the assay. This antibody also inhibited plaques formed by cells secreting antibodies against trinitrophenyl or phosphorylcholine determinants. IgG plaques with any of the above specificities were not inhibited. IgM secretion was unaffected by the monoclonal anti-mu antibody. Its inhibitory effect on plaque formation rather appears to be a consequence of its ability to inhibit complement dependent, IgM mediated lysis of erythrocytes. This monoclonal anti-IgM antibody therefore provides a convenient reagent to distinguish specific direct IgM plaques from indirect IgG plaques.


NIPA2 located in 15q11.2 is mutated in patients with childhood absence epilepsy.
While pathogenic copy number variations (CNVs) in 15q11.2 were recently identified in Caucasian patients with idiopathic generalized epilepsies (IGEs), the epilepsy-associated gene(s) in this region is/are still unknown. Our study investigated whether the CNVs in 15q11.2 are associated with childhood absence epilepsy (CAE) in Chinese patients and whether the selective magnesium transporter NIPA2 gene affected by 15q11.2 microdeletions is a susceptive gene for CAE. We assessed IGE-related CNVs by Affymetrix SNP 5.0 microarrays in 198 patients with CAE and 198 controls from northern China, and verified the identified CNVs by high-density oligonucleotide-based CGH microarrays. The coding region and exon-intron boundaries of NIPA2 were sequenced in all 380 patients with CAE and 400 controls. 15q11.2 microdeletions were detected in 3 of 198 (1.5%) patients and in no controls. Furthermore, we identified point mutations or indel in a heterozygous state of the NIPA2 gene in 3 out of 380 patients, whereas they were absent in 700 controls (P = 0.043). These mutations included two novel missense mutations (c.532A>T, p.I178F; c.731A>G, p.N244S) and one small novel insertion (c.1002_1003insGAT, p.N334_335EinsD). No NIPA2 mutation was found in 400 normal controls. We first identified that NIPA2, encoding a selective magnesium transporter, is a susceptible gene of CAE, and 15q11.2 microdeletions are important pathogenic CNVs for CAE with higher frequency in Chinese populations than that previously reported in Caucasians. The haploinsufficiency of NIPA2 may be a mechanism underlying the neurological phenotypes of 15q11.2 microdeletions.


Brain-wide mapping of c-Fos expression with fluorescence micro-optical sectioning tomography in a chronic sleep deprivation mouse model.
Chronic sleep deprivation (SD) is a common problem for humans and can lead to many deleterious effects, including depression, anxiety, stroke, permanent cognitive deficits, stress, and other physiological diseases. It is vital to acquire information about the relevant neural activities at the whole-brain level to systematically explore the mechanisms of brain dysfunction related to SD. Expression of the immediate-early gene (IEG) Fos in the mouse brain has been widely used as a functional marker of brain activity in the field of neuroscience. However, most previous studies only analyzed the change of c-Fos in several specific brain regions using traditional research methods or in short-term SD model. Here, we applied c-Fos mapping through the fluorescence micro-optical sectioning tomography (fMOST) technique and AAV-PHP.eB to comprehensive analysis the state of cumulative activation across the whole brain in a mouse model of chronic SD. The chronic rapid eyes movement (REM) SD model was induced by moving mice to a separate holding area filled with water. The experimental period lasted for 6 h per day. The results showed that after 14 days of SD, the mice displayed anxiety-like behaviors in open field test and elevated plus maze test, and displayed depression-like behaviors in tail suspension test and the sucrose preference test. The c-Fos + cells were detected in a maximum of 230 brain regions. SD-induced stress model evoked c-Fos expression in several brain regions compared to the control group. In particular, the isocortex-cerebral cortex plate area, including the retrosplenial, anterior cingulate, agranular insular, gustatory, and parasubiculum, appear to be the most sensitive regions after chronic REM SD.


Evaluation of a workplace weight management program based on WeChat platform for obese/overweight people in China using the RE-AIM framework.
A Weight Management Program (WMP) is a critical and promising approach to losing excess weight and maintaining a healthy lifestyle for obese/overweight people. This study used the RE-AIM framework to retrospectively evaluate a WeChat-based workplace WMP that include low- and high-intensity interventions - self-management (SM) and intensive support (IS) - designed for employees with varying levels of health risk at a Chinese company. Both interventions incorporated with a variety of m-health technologies and behavioral strategies. While the IS group additionally received personalized feedback on diet record and intensive social support. Approximately 26% of all overweight/obese employees in the company enrolled in the program. Both groups lost a significant amount of weight at the endpoint (P < 0.001). In comparison to the SM group, the IS group had significantly higher level of compliance with self-monitoring. At six-month, 67% of individuals reported no additional weight gain. The WeChat-based WMP has received widespread praise from program participants and intervention providers in spite of difficulties encountered. This comprehensive and meticulous evaluation revealed both the strengths and weaknesses of the program, which will assist in improving implementation and balancing the cost and effectiveness of online WMP.


Lamivudine treatment for acute hepatitis B after liver transplantation.
Acute hepatitis caused by recurrent or de novo hepatitis B virus (HBV) infection after liver transplantation frequently induces aggressive disease leading to liver failure. The aim of this study was to determine the efficacy and safety of lamivudine treatment in post-transplant acute hepatitis B. Twelve patients with acute hepatitis B were started on lamivudine 100 mg p.o. daily within 8 weeks of the appearance of HBsAg. One patient was excluded after 1 month because of hepatocellular carcinoma recurrence. Patients were followed for an average of 68.6 weeks (range 32-108), and were clinically and biochemically evaluated on a monthly basis. They had a histological assessment at baseline, after at least 6 months, and whenever clinically indicated. Basal HBV-DNA ranged between 13 and 1288 pg/ml and serum alanine aminotransferase between 97 and 1036 U/l. HBV-DNA became undetectable within 8 weeks and transaminases normalized within 24 weeks in all cases. At the last visit, eight patients (73%) remained HBV-DNA negative by liquid hybridization and had normal or close to normal alanine aminotransferase. Five patients (45%) were also HBsAg negative and HBV-DNA negative by polymerase chain reaction. HBV-DNA and transaminase breakthrough occurred in three patients (27%). Histology after 6-9 months showed chronic hepatitis in seven patients. Lamivudine was well tolerated without serious adverse reactions. These results indicate that lamivudine treatment induces sustained inhibition of viral replication and normalization of transaminases in the majority of post-transplant patients with acute hepatitis B. HBsAg loss may be achieved in a considerable number of cases. Although viral resistance is relatively frequent, early initiation of lamivudine appears to be effective and safe.


Low let-7d microRNA levels in chick embryos enhance innate immunity against Mycoplasma gallisepticum by suppressing the mitogen-activated protein kinase pathway.
Chick embryos are a valuable model for studying immunity and vaccines. Therefore, it is crucial to investigate the molecular mechanism of the Mycoplasma gallisepticum (MG)-induced immune response in chick embryos for the prevention and control of MG. In this study, we screened for downregulated let-7d microRNA in MG-infected chicken embryonic lungs to explore its involvement in the innate immune mechanism against MG. Here, we demonstrated that low levels of let-7d are a protective mechanism for chicken embryo primary type II pneumocytes (CP-II) in the presence of MG. Specifically, we found that depressed levels of let-7 in CP-II cells reduced the adhesion capacity of MG. This suppressive effect was achieved through the activated mitogen-activated protein kinase phosphatase 1 (MKP1) target gene and the inactivated mitogen-activated protein kinase (MAPK) pathway. Furthermore, MG-induced hyperinflammation and cell death were both alleviated by downregulation of let-7d. In conclusion, chick embryos protect themselves against MG infection through the innate immune molecule let-7d, which may result from its function as an inhibitor of the MAPK pathway to effectively mitigate MG adhesion, the inflammatory response and cell apoptosis. This study may provide new insight into the development of vaccines against MG.


Relative importance of phosphorus, fish biomass, and watershed land use as drivers of phytoplankton abundance in shallow lakes.
Phytoplankton abundance in shallow lakes is potentially influenced by ambient phosphorus concentrations, nutrient loading accentuated by human activities in lake watersheds, and abundance of planktivorous and benthivorous fish. However, few studies have simultaneously assessed the relative importance of these factors influencing phytoplankton abundance over large spatial scales. We assessed relative influences of watershed characteristics, total phosphorus concentrations, and fish biomass on phytoplankton abundance in 70 shallow lakes in western Minnesota (USA) during summer 2005 and 2006. Our independent variables included total phosphorus (TP), benthivore biomass, planktivore biomass, summed planktivore and benthivore biomass (summed fish), areal extent of agriculture in the watershed, region (prairie versus parkland lakes), and year. Predictive models containing from one to three independent variables were compared using an information theoretic approach. The most parsimonious model consisted of TP and summed fish, and had over 10,000-fold greater support compared to models using just TP or summed fish, or models comprised of other variables. We also found no evidence that relative importance of predictor variables differed between regions or years, and parameter estimates of TP and summed fish were temporally and spatially consistent. TP and summed fish were only weakly correlated, and the model using both variables was a large improvement over using either variable alone. This indicates these two variables can independently increase phytoplankton abundance, which emphasizes the importance of managing both nutrients and fish when trying to control phytoplankton abundance in shallow lakes.


Prognostic Impact of High-Sensitivity C-Reactive Protein in Patients Undergoing Percutaneous Coronary Intervention According to BMI.
The aim of this study was to determine the prevalence and prognostic implications of elevated high-sensitivity C-reactive protein (hsCRP) in patients undergoing percutaneous coronary intervention (PCI) according to body mass index (BMI). Whereas elevated hsCRP predicts adverse clinical outcome after PCI in the general population, the impact of BMI on its prognostic utility remains unclear. Data from 14,140 patients who underwent PCI between January 2009 and June 2017 at a large tertiary care center were analyzed. Patients were divided into 4 BMI categories: normal (BMI 18.5 to <25 kg/m2, n = 2,808), overweight (BMI 25 to <30 kg/m2, n = 6,015), obese (BMI 30 to <35 kg/m2, n = 3,490), and severely obese (BMI ≥35 kg/m2, n = 1,827). Elevated hsCRP was defined as >3 mg/l. The primary endpoint of interest was the occurrence of major adverse cardiac events (MACE; defined as death, myocardial infarction, or target vessel revascularization) within 1 year after PCI. Elevated hsCRP was present in 18.9%, 23.6%, 33.3%, and 47.7% of the normal, overweight, obese, and severely obese groups, respectively. MACE rates were consistently higher in patients with elevated hsCRP across all BMI categories (normal, 13.4% vs. 8.3%; overweight, 11.2% vs. 7.2%; obese, 10.6% vs. 7.5%; severely obese, 11.9% vs. 6.5%; p < 0.01 for all). After multivariate adjustment, hsCRP elevation remained significantly associated with MACE independent of BMI (hazard ratios: normal, 1.43 [95% confidence interval: 1.04 to 1.95]; overweight, 1.56 [95% confidence interval: 1.21 to 1.88]; obese, 1.40 [95% confidence interval: 1.06 to 1.84]; severely obese, 1.92 [95% confidence interval: 1.35 to 2.75]; p < 0.05 for all). Among patients undergoing PCI, the prevalence of hsCRP elevation progressively increased with higher BMI. Measurement of hsCRP facilitates prognostic risk assessment for adverse outcome after PCI across a broad range of BMI.


[Artificial intelligence : What do urologists need to know?]
In the past 10 years, the methods of artificial intelligence (AI) have experienced breakthroughs that have opened up a multitude of new fields of application for information technology. AI is particularly strong in those areas where patterns have to be recognized and conclusions and forecasts based on large, multiparametric data sets have to be drawn. Computers are superior to us in terms of precision and speed in these problems. These advances in information technology reach us at a time when innovations in diagnostics and sensor technology enable more precise patient stratification and confront medical personnel with an increasing quantity and quality of patient data. Urology is symbolic of this new complexity of medicine, in which multi-layered diagnostic cascades require a high degree of interdisciplinarity and, especially in uro-oncology, therapeutic strategies are becoming more differentiated and require the interpretation of multiple clinical and diagnostic data. Here, methods of Artificial Intelligence will in future support medical personnel in diagnostics and therapy decisions and thus come closer to the goal of precision medicine. A prerequisite for the success of AI-based support tools will be the transparent development and validation of the software, as well as the population-based visualization of decision parameters.


Blinding Approaches for Large Clinical Trials Involving Sub-Cutaneous Administration of Biologicals - A CMC Perspective.
A well-controlled clinical trial is one of the critical steps to evaluate the efficacy and safety of novel medicaments. The use of a placebo is employed in several types of clinical trials in order to set a baseline against which the efficacy of the investigational drug is evaluated. An ideal placebo should match the final formulation as close as possible such that the patient/health care providers are unable to identify any difference. This is difficult for high concentration biologic intended for subcutaneous administration, mainly because of their color and viscosity. Currently, the challenge is overcome by using opaque labels or by unblinded pharmacists, both solutions are expensive. The present study provides an efficient alternative where a protein excipient (recombinant albumin) is used to prepare a placebo for biologicals. We have demonstrated that the use of recombinant albumin can match the color of the active when used in the right quantity. The evaluated solution is highly flexible and has the potential to match the color of different biopharmaceuticals at different concentrations/formulations.


Screening Clinical Cell Products for Replication Competent Retrovirus: The National Gene Vector Biorepository Experience.
Replication-competent retrovirus (RCR) is a safety concern for individuals treated with retroviral gene therapy. RCR detection assays are used to detect RCR in manufactured vector, transduced cell products infused into research subjects, and in the research subjects after treatment. In this study, we reviewed 286 control (n = 4) and transduced cell products (n = 282) screened for RCR in the National Gene Vector Biorepository. The transduced cell samples were submitted from 14 clinical trials. All vector products were previously shown to be negative for RCR prior to use in cell transduction. After transduction, all 282 transduced cell products were negative for RCR. In addition, 241 of the clinical trial participants were also screened for RCR by analyzing peripheral blood at least 1 month after infusion, all of which were also negative for evidence of RCR infection. The majority of vector products used in the clinical trials were generated in the PG13 packaging cell line. The findings suggest that screening of the retroviral vector product generated in PG13 cell line may be sufficient and that further screening of transduced cells does not provide added value.


Trend of immunity against measles and varicella zoster virus in healthcare workers in Korea.
To examine the seroprevalence of measles and varicella zoster virus (VZV) among healthcare workers (HCW) and evaluate the concordance between self-reported history of previous disease or vaccination and seropositivity. A seroprevalence study and survey. A university-affiliated tertiary care hospital. All HCWs working in high-risk services in 2017 underwent serologic tests and survey; all new HCWs employed in the subsequent years, serologic tests only. A serologic study was conducted using chemiluminescence immunoassay (2017) or enzyme immunoassays (2018 and later). HCWs who underwent serological testing in 2017 completed a self-administered questionnaire on their history of infection and vaccination. A total of 10,278 and 9607 HCWs underwent serologic tests for measles and VZV IgG, respectively, from 2017 to 2022. The overall seropositivity rates for measles and VZV were 78.1 % and 92.8 %, respectively. Measles seropositivity declined gradually from >90 % in the HCWs born in the 1960s to <80 % in those born in the 1990s. There was a significant difference in measles seropositivity between the birth cohorts (BCs) 1967-1984 and 1985-1999 (P < 0.001; odds ratio, 1.16; 95 % confidence interval, 1.14-1.18). The seropositivity for VZV was stable, at >90 % in all BCs. The self-reported vaccination history was not independently associated with seropositivity, and the negative predictive value of the survey was very low (9.6 % and 13.1 %, respectively). Measles seropositivity showed a substantial decline among HCWs born in 1985 or later, while varicella seropositivity remained high. The self-reported vaccination history was not sufficiently reliable for screening HCWs.


Family cohesion and conflict in an American Indian community.
To assess the feasibility of using a portion of the Family Environment Scale (FES) with American Indian families and to describe the mean family profile exhibited by one Native community. The cohesion, expressiveness, conflict and active-recreational orientation subscales of the FES were administered to 130 adults, representing 65 families. Mean responses reveal a pattern of average levels of cohesion and expressiveness, concurrent with high levels of family conflict. Outcomes illustrate the feasibility and utility of this scale in assessing and guiding health promotion services within Native communities. Results suggest Native families have a distinctive family profile.


Thermodynamics of the interaction of insulin with its receptor.
Insulin binding to its cellular receptors is markedly dependent on the temperature. The thermodynamic parameters for the reaction of insulin with the high affinity state of its receptor have been evaluated with equilibrium studies at multiple temperatures between 5 degrees and 37 degrees C. The thermodynamics of the insulin-receptor interaction is not classical. The van't Hoff plot is not linear. Both the enthalpy and entropy changes, due to the formation of the hormone . receptor complex, decrease markedly with temperature, corresponding to a large heat capacity change of -766 cal/(mol deg) at 25 degrees C. The reaction is endothermic and entropically driven at low temperature and exothermic and enthalpically driven at higher temperature. This thermodynamic behavior is suggestive of a hydrophobic reaction and supports Blundell's concept that the loss of non-polar surface residues in the formation of the hormone . receptor complex is an important driving force of the reaction. Alternatively, this nonclassical behavior may indicate that the reaction of insulin with its receptor involves more than one step.


Laparoscopic resection for sigmoid and rectosigmoid colon cancer performed by trainees: impact on short-term outcomes and selection of suitable patients.
This study aimed (1) to evaluate the impact of clinical factors, particularly operation by trainees, on the short-term outcomes of laparoscopic resection for sigmoid and rectosigmoid cancer, and (2) to determine patients suitable for operation by trainees. From a prospectively maintained single-institution database, we identified 133 patients who underwent laparoscopic resection for sigmoid or rectosigmoid cancer between 2007 and 2010. Gender, age, body mass index (BMI), previous abdominal surgery, tumor location, tumor size, tumor stage, extent of lymph node dissection, and primary surgeon were evaluated using univariate and multivariate analyses to determine the predictive significance of these variables on surgical outcomes including operative time, blood loss, complication, postoperative stay, and retrieved lymph nodes. Multivariate analysis showed that location of the tumor in the rectosigmoid (p < 0.001), higher BMI (p < 0.001), operation by trainees (p < 0.001), male gender (p = 0.002), and greater tumor depth (p = 0.011) were independently predictive of longer operative time. Larger tumor size (p = 0.025) and higher BMI (p = 0.040) were independently predictive of greater blood loss. Larger tumor size was also related to longer postoperative stay (p = 0.001) and a greater number of retrieved lymph nodes (p = 0.001). This study identified operation by trainees as an independent risk factor for longer operative time but with no negative impact on any of the other outcomes. Female patients with a low BMI, sigmoid cancer, shallow tumor depth, and/or small tumor are suitable for operation by trainees.


Natural Products Drug Discovery: On Silica or In-Silico?
Natural products have been the most important source for drug development throughout the human history. Over time, the formulation of drugs has evolved from crude drugs to refined chemicals. In modern drug discovery, conventional natural products lead-finding usually uses a top-down approach, namely bio-guided fractionation. In this approach, the crude extracts are separated by chromatography and resulting fractions are tested for activity. Subsequently, active fractions are further refined until a single active compound is obtained. However, this is a painstakingly slow and expensive process. Among the alternatives that have been developed to improve this situation, metabolomics has proved to yield interesting results having been applied successfully to drug discovery in the last two decades. The metabolomics-based approach in lead-finding comprises two steps: (1) in-depth chemical profiling of target samples, e.g. plant extracts, and bioactivity assessment, (2) correlation of the chemical and biological data by chemometrics. In the first step of this approach, the target samples are chemically profiled in an untargeted manner to detect as many compounds as possible. So far, NMR spectroscopy, LC-MS, GC-MS, and MS/MS spectrometry are the most common profiling tools. The profile data are correlated with the biological activity with the help of various chemometric methods such as multivariate data analysis. This in-silico analysis has a high potential to replace or complement conventional on-silica bioassay-guided fractionation as it will greatly reduce the number of bioassays, and thus time and costs. Moreover, it may reveal synergistic mechanisms, when present, something for which the classical top-down approach is clearly not suited. This chapter aims to give an overview of successful approaches based on the application of chemical profiling with chemometrics in natural products drug discovery.


Epigenetic control of plant development by Polycomb-group proteins.
Recent genetic studies indicate that the plant Polycomb-group genes play much broader roles in development than was initially apparent from their single mutant phenotypes. At the mechanistic level, evidence is accumulating that their protein products act together in complexes that direct changes in histone methylation patterns. We discuss recent studies that give clues as to how these epigenetic changes are propagated through mitosis, how they are interpreted, and how they might be reset.


[Personal factors influencing daytime sleepiness].
During the first corona wave public life largely came to a standstill. Many employees started to work from home to protect themselves from infection. The purpose of this study was to investigate changes in sleep behavior and daytime sleepiness when people changed from working in the office to mobile working from home. Office workers were asked about their chronotype, their usual sleep routine and the occurrence of daytime sleepiness on office workdays and during mobile working. Data collection took place between 15 July 2020 and 7 August 2020. An anonymized online survey tool was used. The composite scale of morningness (CSM) in the German language version was used to determine the chronotype. The association of age, gender, chronotype, sleep quality and sleep duration with self-rated daytime sleepiness was examined using multivariable logistic regression analyses. The data of n = 228 individuals could be analyzed. Sleep duration increased while working from home. The proportion of persons with less than 7.5 h time in bed decreased from 56.6% to 33.4% and the proportion of those with more than 8 h time in bed increased from 43.4% on office workdays to 66.6% when working from home. The percentage of people who always or often felt sleepy at work decreased from 47% on office workdays to 15% when working from home. The chronotype showed a significant association with daytime sleepiness on office workdays but not when working from home. The reduction of daytime sleepiness could be explained by longer sleep duration and higher satisfaction with sleep quality. Late chronotypes seem to benefit particularly when working from home. A flexible start of work, the consideration of the chronotype and measures for health-promoting sleep could reduce daytime sleepiness and thus improve occupational safety and health.


Effect of the App-Based Video Guidance on Prenatal Pelvic Floor Muscle Training Combined with Global Postural Re-education for Stress Urinary Incontinence Prevention: A Protocol for a Multicenter, Randomized Controlled Trial.
As the effectiveness on stress urinary incontinence (SUI) prevention of pelvic floor muscle training (PFMT) for pregnant women has been inconclusive, we are planning to conduct a trial to evaluate a video program designed for prevention of SUI developed through combining PFMT with global postural reeducation (GPR). As a randomized controlled trial, eligible participants will be randomized (1:1) into an exercise group and a control group to perform PFMT regularly following video guidance or with no intervention, respectively. The experimental stage will be from the 16th gestation week (GW) to the 12th month postpartum, with eight appointments at the 16th, 28th, 37th GW, delivery, the 6th week and the 3rd, 6th, and 12th month postpartum. Data will be collected regarding urinary leakage symptoms, the stress test, the modified Oxford Scale, pelvic floor ultrasound, perineal laceration classification at delivery, neonatal Apgar score, and questionnaires (PISQ-12, ICIQ-UI SF, I-QOL, OABSS). The primary outcome is the occurrence of the symptomatic SUI and positive stress test at the 6th week postpartum. This protocol is anticipated to evaluate the efficacy of the intervention via video app for the design of a future randomized control trial (RCT). The trial has been registered at Chinese Clinical Trial Registry (registration number: ChiCTR2000029618).


Application of a diazepam milligram equivalency algorithm to assess benzodiazepine dose intensity in Rhode Island in 2018.
BACKGROUND: Benzodiazepines are indicated for the treatment of many conditions, such as anxiety disorders, muscle spasms, alcohol withdrawal, agitation, movement disorders, and epilepsy, and are one of the most frequently prescribed medication classes. This class of medication has important safety considerations, including an increased risk of dependence and addiction, falls, and death from opioid overdose. Although benzodiazepine safety and prescribing encompasses a rich and important research area, there is a lack of pharmacoepidemiologic literature addressing benzodiazepine dosing intensity in real-world settings. OBJECTIVE: To develop and apply a standardized benzodiazepine milligram equivalency conversion algorithm and assess the dose intensity of benzodiazepine use in Rhode Island (RI) in 2018. METHODS: A systematic literature review was conducted to identify the most commonly used benzodiazepine equivalency values. We then conducted a cross-sectional analysis of 2018 data from the RI Prescription Drug Monitoring Program (PDMP) to calculate the mean daily diazepam milligram equivalency (DME) based on a patient's most recent dispensing. A multivariable logistic regression analysis was conducted to determine the association between higher benzodiazepine doses (≥ 15 DME/day) and recipient characteristics, including concurrent use of opioids or stimulants. RESULTS: We identified 143,026 patients who received at least 1 prescription for a benzodiazepine in RI in 2018. The mean (SD) daily DME was 10.60 (9.05), and 26.2% of individuals had a mean DME per day of at least 15. Approximately 14% (n = 20,168) of patients prescribed a benzodiazepine had concurrent use with a prescription opioid, and 6.7% (n = 9,547) had concurrent use with a prescription stimulant. Females had a 28% lower adjusted odds of receiving a benzodiazepine dose of at least 15 DME per day compared with males (adjusted odds ratio [aOR] = 0.72, 95% CI = 0.70-0.73). The adjusted odds of receiving a benzodiazepine prescription of at least 15 DME per day was lower among the younger (aged 18-34 years) and older age groups (aged 65 years and older) compared with patients aged 35-64 years. Compared with commercial insurance, all other forms of payment had significantly higher adjusted odds of a daily benzodiazepine dose of at least 15 DME per day. The adjusted odds receiving a daily DME of at least 15 was 67% higher among those who also received a concurrent pharmacy dispensing for an opioid and 84% higher among those who also received a concurrent dispensing for a stimulant drug (aOR = 1.67, 95% CI = 1.61-1.72; aOR = 1.84, 95% CI = 1.76-1.93, respectively). CONCLUSIONS: Individuals aged 35-64 years with Medicaid insurance and those aged under 65 years with Medicare were more likely to be prescribed a benzodiazepine of at least 15 DME per day. Higher benzodiazepine DMEs were also dispensed to patients who concurrently used prescription opioids or stimulants who may be at increased risk of medication-related harm. We advocate for routine measurement of benzodiazepine dose intensity as a risk reduction strategy. DISCLOSURES: No funding supported this study. The authors have no conflicts of interest to disclose. The content and results of this study are solely the responsibility of the authors and do not necessarily represent the official views of the Rhode Island Department of Health. Kogut is partially supported by Institutional Development Award Numbers U54GM115677 and P20GM125507 from the National Institute of General Medical Sciences of the National Institutes of Health, which funds Advance Clinical and Translational Research (Advance-CTR) and the RI Lifespan Center of Biomedical Research Excellence (COBRE) on Opioids and Overdose, respectively. The content of this study is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Contents of this study were presented as a poster presentation at AMCP 2019 Nexus; October 29-November 1, 2019; National Harbor, MD.