Cytotoxic purine nucleoside analogues bind to A1, A2A, and A3 adenosine receptors.
Fludarabine, clofarabine, and cladribine are anticancer agents which are analogues of the purine nucleoside adenosine. These agents have been associated with cardiac and neurological toxicities. Because these agents are analogues of adenosine, they may act through adenosine receptors to elicit their toxic effects. The objective of this study was to evaluate the ability of cytotoxic nucleoside analogues to bind and activate adenosine receptor subtypes (A(1), A(2A), A(2B), and A(3)). Radioligand binding studies utilizing Chinese hamster ovary cells, stably transfected with adenosine A(1), A(2A), or A(3) receptor subtype, were used to assess the binding affinities of these compounds, whereas adenylyl cyclase activity was used to assess the binding to A(2B) receptors. Clofarabine and cladribine both bound to the A(2A) receptor with a K (i) of 17 and 15 μM, respectively. Clofarabine was the only adenosine analogue to bind to the A(3) receptor with a K (i) of 10 μM, and none of these compounds bound to the A(2B) receptor. Results show that clofarabine, cladribine, and fludarabine bind to the A(1) receptor. In addition, clofarabine, cladribine, and fludarabine were A(1) agonists (IC(50) 3.1, 30, and 30 μM, respectively). Neither pyrimidine nucleoside analogues gemcitabine nor cytarabine associated with any of the adenosine receptor subtypes (K (i) > 100μM). This is the first report of an interaction between all adenosine receptor subtypes and chemotherapeutic nucleoside analogues commonly used in the treatment of cancer. Therefore, activation of these receptors may be at least one mechanism through which fludarabine-associated toxicity occurs.


Resetting Policies to End Family Homelessness.
Homelessness is a devastating experience for children and their families. Families, the majority of whose members are children, now comprise more than one-third of the overall US homeless population. Most of these children are less than six years old. Various assumptions have driven policy and the allocation of resources to programs serving these families. Although decades of research and field experience suggest strategies for preventing and reducing this problem, perspectives differ, hindering the development of effective solutions. In this article, we explore some of these assumptions, including (a) definitions of homelessness used to count the numbers of families and determine resource allocation, (b) the needs of children and responses to the impact of adverse childhood experiences, and (c) whether services matter and should be integrated with affordable housing. We conclude by suggesting various directions to ensure that these children are protected and have the opportunity to grow and thrive.


Single anastomosis sleeve jejunal (SAS-J) bypass as a treatment for morbid obesity, technique and review of 1986 cases and 6 Years follow-up. Retrospective cohort.
Santoro's operation is a sleeve gastrectomy with transit bipartition. The operation aims to maintain passage to the duodenum to minimize nutritional deficiency. This procedure is rapidly changed to single anastomosis sleeve ileal (SASI) bypass. SAS-J bypass is a modification of SASI with a short biliary limb. This study is a retrospective study of prospectively collected data. The study includes a comprehensive review of 1986 patients who underwent SAS-J bypass over 6 years. The total number is used to evaluate the perioperative data. One- and two-year follow-up was used to evaluate weight loss and comorbidities; follow-up of more than 5 years was used to obtain long-term results. In this study, 70.4% of patients were female and 29.6% were male. The mean body mass index (BMI) was 44.7. The mean age was 42 years. Regarding comorbidities, 25.8% of the patients had type 2 diabetes, 31% were hypertensive, 14.2% had sleep apnea syndrome, 6.6% had gastroesophageal reflux disease (GERD), and 39.6% had hyperlipidemia. Of the 1294 patients who complete one-year follow up, %EWL reached 87%. Blood glucose levels were normalized in 98.5% of patients, hypertension remitted in 93%, hyperlipidemia improved in 97%, SAS is improved in all cases, and GERD improved in 89% of patients. After 5 years, 94 patients' BMI decreased from 44.3 to 28.3 without significant nutritional deficiency. Laparoscopic SAS-J bypass is an effective and simple alternative bariatric procedure at short- and long-term follow-up.


Molecular choreography of primer synthesis by the eukaryotic Pol α-primase.
The eukaryotic polymerase α (Pol α) synthesizes an RNA-DNA hybrid primer of 20-30 nucleotides. Pol α is composed of Pol1, Pol12, Primase 1 (Pri1), and Pri2. Pol1 and Pri1 contain the DNA polymerase and RNA primase activities, respectively. It has been unclear how Pol α hands over an RNA primer from Pri1 to Pol1 for DNA primer extension, and how the primer length is defined. Here we report the cryo-EM analysis of yeast Pol α in the apo, primer initiation, primer elongation, RNA primer hand-off from Pri1 to Pol1, and DNA extension states, revealing a series of very large movements. We reveal a critical point at which Pol1-core moves to take over the 3'-end of the RNA from Pri1. DNA extension is limited by a spiral motion of Pol1-core. Since both Pri1 and Pol1-core are flexibly attached to a stable platform, primer growth produces stress that limits the primer length.


[Results of animal experiments with an implantable femur distractor for operative leg lengthening (author's transl)].
A new femur distractor for operative leg lengthening has been developed. The new instrument consists of an electronically controllable distractor set including a power unit and a two-part guide rail. The whole system can be implanted totally and gives rigid fixation throughout the period of distraction. The operations "forward motion", "stop" and "backward motion" can be regulated transcutaneously by radio control. A prototype especially developed for animal experiments has been tested successfully in sheep.


Comprehensive modeling and predicting light transmission in microalgal biofilm.
Biofilm-based microalgae culture combined with wastewater treatment is a promising biotechnology for environmental management. Light availability influences the accumulation of microalgal biomass and nutrient removal. A light attenuation model which comprehensively considered microalgal biofilm structure (density and biofilm thickness), pigments content, and extracellular polymeric substances content was developed to predict the light attenuation in biofilm according to the simplification of the radiative transfer equation. The predicted results were in good overall agreement with the experiment, with an average error of less than 9.02%. These factors (biofilm density, thickness, pigments content, and extracellular polymeric substances content) all contributed to the light intensity attenuation, but biofilm thickness caused the most dramatic attenuation under the same increment of relative change in actual culture. The scattering coefficient of the biofilm (0.433 m2/g) was less than that of the suspension (1.489 m2/g) under white incident light. It suggests that the dense structure of cells allows much light to be concentrated in the forward direction when transmitting. This model could be adopted to predict the light distribution in microalgal biofilm for the further design of efficient photobioreactors and the development of light optimization strategies.


3-Amino-1-(3,4-dichloro-alpha-methyl-benzyl)-2-pyrazolin-5-one (Bay g 2821), a potent diuretic from a new substance class.
Chemistry, salidiuretic activity and mechanism of action of 3-amino-1-(3,4-dichloro-alpha-methyl-benzyl)-2-pyrazolin-5-one (Bay g 2821), a new diuretic, are described. Owing to the initial rapid onset of activity, the reserve in capacity and the additional long duration of activity, this substance represents a potent diuretic and antihypertensive agent.


Expression of human 8-oxoguanine DNA glycosylase (hOGG1) in follicular lymphoma.
The human homologue of the yeast DNA repair enzyme 8-oxoguanine DNA glycosylase (hOGG1) repairs oxidatively damaged guanosine nucleotides in DNA. This enzyme is highly expressed in reactive germinal centers, where lymphoid cells are under oxidative stress, and has been thought to protect lymphocytes from mutation. As a first step to investigate the role of hOGG1 in lymphomagenesis, we evaluated hOGG1 expression in follicular lymphoma. Immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue of 28 follicular lymphoma cases (16 grade 1, seven grade 2, and five grade 3) to evaluate the expression of hOGG1 in neoplastic follicles. Reactive germinal centers of non-neoplastic tonsil and lymph node tissue were also examined. Fluorescent-in-situ hybridization (FISH) was performed using a DNA probe from BAC clone RP11-266J6 corresponding to 3p25, where the hOGG1 gene resides, to evaluate for the presence or absence of a deletion. In reactive germinal centers, the majority of centroblasts and centrocytes were positive for hOGG1. In contrast, the majority (21 of 28 or 75%) of follicular lymphoma cases showed absent/minimal expression of hOGG1. Only four of 28 (14%) follicular lymphoma cases revealed the same levels of hOGG1 expression as reactive germinal centers. There was no correlation between hOGG1 expression and histologic grade. None of the 16 cases evaluated by FISH showed a deletion of hOGG1. Furthermore, absent/minimal hOGG1 expression was observed in four of six Bcl-2-negative follicular lymphoma cases. Our findings suggest that absent/minimal hOGG1 expression occurs in the majority of follicular lymphomas. The downregulation of hOGG1 does not appear to be due to a deletion of the hOGG1 locus. Additionally, finding absent/minimal hOGG1 expression in a subset of Bcl-2-negative follicular lymphomas suggests that hOGG1 may have utility in diagnosing Bcl-2-negative follicular lymphomas.


Conditionally unutilized proteins and their profound effects on growth and adaptation across microbial species.
Protein synthesis is an important determinant of microbial growth and response that demands a high amount of metabolic and biosynthetic resources. Despite these costs, microbial species from different taxa and habitats massively synthesize proteins that are not utilized in the conditions they currently experience. Based on resource allocation models, recent studies have begun to reconcile the costs and benefits of these conditionally unutilized proteins (CUPs) in the context of varying environmental conditions. Such massive synthesis of CUPs is crucial to consider in different areas of modern microbiology, from the systematic investigation of cell physiology, via the prediction of evolution in laboratory and natural environments, to the rational design of strains in biotechnology applications.


Linear incision and curettage vs. deroofing and drainage in subcutaneous abscess. A randomized clinical trial.
Linear incision plus curettage under antibiotic cover was compared with conventional deroofing and drainage of subcutaneous abscess in a randomized study of 50 patients. The median healing time was 9 days following linear incision and curettage and 15 days after deroofing and drainage (p less than 0.05). There was no recurrence of abscess during follow-up for 6 months. Linear incision plus curettage under single-dose antibiotic cover thus proved to be a safe method with significantly shorter healing time than after conventional deroofing an drainage.


Knowledge, practices and attitudes on antibiotics use in Cameroon: Self-medication and prescription survey among children, adolescents and adults in private pharmacies.
Benefits of antibiotics are threatened by the self-medication, people's lack of knowledge and inappropriate use of antibiotics, especially in developing countries. This study was designed to determine knowledge; attitudes and practices toward antibiotics use in an urban community, and evaluate the factors that are associated with antibiotic use. Between January and March 2015, a cross sectional and prospective study was conducted in all pharmacies within the Douala IV health district, Cameroon. Anonymous interviews including both open and closed ended questions were conducted in participants selected by convenience sampling Descriptive and logistic regression analysis were performed using StataSE11 software (version 11 SE) and R software (version 3.1.1) in data analysis. Overall 402 (33.7%) of 1,192 customers purchased antibiotics and of these, 47% bought antibiotics without a prescription. 60.7% of purchased antibiotics was for adult 'patients and around 60% of parents carried out self-medication on their children. The vast majority reported that all microbes can be treated with antibiotics (88.3%). The belief that antibiotics are appropriate for bacterial infections was more common among those with a higher level education (OR = 4.03, 95%CI:1.89-8.57, p<0.0001) and among public/private servants (OR = 2.47, 95%CI:1.21-5.08, p = 0.013). Physicians provide less explanations about antibiotics are and their potential side effects than the pharmacy auxiliaries (OR = 0.205, 95%CI = 0.09-0.46, p<0.0001), but more than pharmacists (OR = 3.692, 95%CI:1.44-9.25, p = 0.005). Indications on antibiotics use were 7 times more given to customers with a prescription compared to those without a prescription (OR = 7.37, 95% CI = 2.13-25.43, p = 0.002). Adult male (OR = 2.32, 95%CI:1.24-4.34, p = 0.009) and higher education (OR = 2.05, 95%CI:1.08-3.89, p = 0.027) were significantly associated with self-medication. Misuse, little "practical knowledge" and high self-medication confirm the unsatisfactory prescription and dispensing practices of the antibiotics in our country. These results highlight the important of the development and implementation appropriate guidelines for the responsible use of antibiotics for health care providers and health education targeting community members themselves.


How does a family history of psychosis influence the risk of methamphetamine-related psychotic symptoms: Evidence from longitudinal panel data.
To determine whether the risk of psychotic symptoms during weeks of methamphetamine use was dependent on, increased by, or independent of having a family history of psychosis. Secondary analysis of 13 contiguous 1-week periods of data (1370 weeks). A risk modification framework was used to test each scenario. Geelong, Wollongong and Melbourne, Australia. Participants in a randomized controlled trial of treatment for methamphetamine dependence (n = 148) who did not have a primary psychotic disorder on enrolment. Psychotic symptoms in the previous week were defined as a score of 3+ on any of the Brief Psychiatric Rating Scale items of hallucinations, unusual thought content or suspiciousness. Any (vs no) methamphetamine use in the previous week was assessed using the Timeline Followback method. Self-reported family history of psychosis was assessed using the Diagnostic Interview for Psychosis. The risk of psychotic symptoms in the past week was independently associated with methamphetamine use in that week (relative risk [RR] = 2.3, 95% CI = 1.3-4.3) and with having a family history of psychosis (RR = 2.4, 95% CI = 0.9-7.0); the joint risk among participants with a family history of psychosis during weeks when they were using methamphetamine was large (RR = 4.0, 95% CI = 2.0-7.9). There was no significant interaction between a family history of psychosis and methamphetamine use in predicting psychotic symptoms (interaction RR = 0.7 95% CI = 0.3-1.8), but there was a small non-significant excess risk due to the interaction (0.20 95% CI = -1.63 to 2.03). Among people dependent on methamphetamine, the relative risk of psychotic symptoms during weeks of methamphetamine use does not appear to be dependent on, or increased by, having a family history of psychosis. However, a family history of psychosis does appear to be an independent risk factor that contributes to the absolute risk of psychotic symptoms in this population.


Biotransformation of nitrosobenzene in the red cell and the role of glutathione.
1. In the red cell nitrosobenzene formed glutathione-sulphinanilide from reduced glutathione, and the corresponding sulphinanilide with the reactive cysteine residues of haemoglobin. 2. Glutathionesulphinanilide was reductively cleaved by an NADPH-linked reductase with formation of free analine half an equivalent of reduced glutathione and half of glutathione sulphinic acid. 3. About three quarters of the aniline produced from nitrosobenzene or phenylhydroxylamine was formed via this pathway within the red cell.


Postnatal dendritic development in lumbar motoneurons in mutant superoxide dismutase 1 mouse model of amyotrophic lateral sclerosis.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motoneuron (MN) degeneration and muscle paralysis. Cu/Zn superoxide dismutase (SOD1) mutant mice develop an ALS-like phenotype similar to that seen in human. Recently it has been shown in SOD1 mice that the excitability and morphology of spinal MNs are altered at postnatal age, long before overt clinical symptoms. In the present study, we examined the morphology of lumbar MNs in wild-type (WT) and SOD1(G85R) mice at two postnatal ages (P3-P4 and P8-P9) when differences in size and excitability were reported. Detailed morphological analysis was performed in MNs intracellularly labeled with Neurobiotin and 3D-reconstructed using the Neurolucida™ system. We showed that SOD1 MNs exhibited longer terminal segments than in the WT MNs at age P3-P4. This excessive elongation was followed by pathological ramification of all individual dendrites between P4 and P8. Abnormal bifurcations occurred at the terminal tips, and distance between consecutive bifurcations remained stable. Most dendrites of SOD1 MNs performed in average two successive iterations of bifurcation during this short time. Our results suggest that the SOD1 MNs switch from excessive elongation to overbranching in a few days at early postnatal life, which might be a compensatory reaction to the possible variation of synaptic input.


Precise temporal association between cortical potentials evoked by motor imagination and afference induces cortical plasticity.
In monkeys, the repeated activation of somatosensory afferents projecting onto the motor cortex (M1) has a pivotal role in motor skill learning. Here we investigate if sensory feedback that is artificially generated at specific times during imagination of a dorsiflexion task leads to reorganization of the human M1. The common peroneal nerve was stimulated to generate an afferent volley timed to arrive during specific phases of the cortical potential generated when a movement was imagined (50 repetitions). The change in the output of M1 was quantified by applying single transcranial magnetic stimuli to the area of M1 controlling the tibialis anterior muscle. The results demonstrated that the concomitance between the cognitive process of movement (motor imagination) and the ascending volley due to the peripheral nerve stimulation can lead to significant increases in cortical excitability. These increases were critically dependent on the timing between the peripherally generated afferent volley and the cortical potential generated during the imagined movement. Only if the afferent volley arrived during the peak negative deflection of the potential, were significant alterations in motor cortical output attained. These results demonstrate that an artificially generated signal (the peripheral afferent volley) can interact with a physiologically generated signal in humans leading to plastic changes within the M1, the final output stage for movement generation within the human brain. The results presented may have implications in systems for artificially inducing cortical plasticity in patients with motor impairments (neuromodulation).


A survey of FIV antibodies and FeLV antigens in free-roaming cats in the capital area of Finland.
Feline immunodeficiency virus (FIV) was first isolated and identified in 1986. Since then it has been shown to have a worldwide distribution, and the infection generally appears to have reached a state of endemicity. This is the 1st study of FIV-prevalence in Finland. Serum samples of 196 free-roaming cats were tested for antibodies to FIV and FeLV antigens (Feline leukemia virus). With a combined enzyme-linked immunosorbent assay (ELISA), 13 of the cats (6.6%) turned out to be positive for FIV and 2 for FeLV (1.0%). Adult male cats in the capital area of Finland had a FIV prevalence of 24%, a relative proportion 4.7 times higher than that for females.


Effect of cationic grafted copolymer structure on the encapsulation of bovine serum albumin.
The aim of the present study was to evaluate a library of poly-L-lysine (PLL)-graft (g)-polyethylene glycol (PEG) copolymers for the ability to encapsulate effectively a model protein, bovine serum albumin (BSA), and to characterize the stability and protein function of the resulting nanoparticle. A library of nine grafted copolymers was produced by varying PLL molecular weight and PEG grafting ratio. Electrostatic self-assembly of the protein and the grafted copolymer drove encapsulation. The formation of protein/polymer nanoparticles with a core/shell structure was confirmed using PAGE, dynamic light scattering, and electron microscopy. Encapsulation of the BSA into nanoparticles was strongly dependent on the copolymer-to-protein mass ratio, PEG grafting ratio, and PLL molecular weight. A copolymer-to-protein mass ratio of 7:1 and higher was generally required for high levels of encapsulation, and under these conditions, no loss of protein activity was observed. Copolymer characteristics also influenced nanoparticle resistance to polyanions and protease degradation. The results indicate that a copolymer of 15-30 kDa PLL, with a PEG grafting ratio of 10:1, is most promising for protein delivery.


Psychiatric Care in Acute Care Units with Locked Doors: Nursing Care Providers' Perceptions and Experiences.
Social distancing and the recent lockdown due to COVID-19 have increased the feeling of disconnection, isolation, and suffering in vulnerable individuals and have brought forward questions regarding locked acute care psychiatric units that cannot be answered by the literature. In Greece, there is no available research on how locked ward environments are perceived and experienced by mental health professionals. The aim of the present study is to illuminate nursing care providers' perceptions of psychiatric care in units with locked doors. Fifteen nursing care providers were interviewed and inductive content analysis was employed to explore their experiences of working in locked psychiatric acute care units. Negative and positive feelings about door locking did not appear to match the specific system of practice. Some participants described how locked doors influenced their professional role by placing emphasis on control rather than care while others regarded locked doors as a symbolic way of therapeutic boundary setting. Participants had positive experiences when they perceived their working environment as caring. The therapeutic benefits of locked doors were prominent when locked doors were perceived as "invisible."


Biodegradation of high di-(2-Ethylhexyl) phthalate (DEHP) concentration by food waste composting and its toxicity assessment using seed germination test.
Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer derived from phthalate ester, is used as an additive in industrial products such as plastics, paints, and medical devices. However, DEHP is known as an endocrine-disrupting chemical, causing cancers and adverse effects on human health. This study evaluated DEHP biodegradation efficiency via food waste composting during 35 days of incubation. At high DEHP concentrations (2167 mg kg-1) in food waste compost mixture, the DEHP biodegradation efficiency was 99% after 35 days. The highest degradation efficiency was recorded at the thermophilic phase (day 3 - day 11) with the biodegradation rate reached 187 mg kg-1 day-1. DEHP was metabolized to dibutyl phthalate (DBP) and dimethyl phthalate (DMP) and would be oxidized to benzyl alcohol (BA) and mineralized into CO2 and water via various metabolisms. Finally, the compost's quality with residual DEHP was evaluated using Brassica chinensis L. seeds via 96 h of germination tests. The compost (at day 35) with a trace amount of DEHP as the end product showed no significant effect on the germination rate of Brassica chinensis L. seeds (88%) compared to that without DEHP (94%), indicating that the compost can be reused as fertilizer in agricultural applications. These results provide an improved understanding of the DEHP biodegradation via food waste composting without bioaugmentation and hence facilitating its green remediation and conversion into value-added products. Nevertheless, further studies are needed on DEHP biodegradation in large-scale food waste composting or industrial applications.


Dynamic structure of bacterial ribosomal 5S RNA helices II and III of B. megaterium 5S RNA.
A possible switch between two conformations, previously observed in an enzymatically cleaved fragment of E. coli 5S ribosomal RNA (a Gram-negative bacterium) containing helices II and III, has been examined by means of proton nuclear magnetic resonance spectroscopy (10-15 ppm) as a function of [Mg2+] and temperature for an RNase-T1 digested fragment of Bacillus megaterium 5S rRNA (a Gram-positive bacterium) containing the same helices II and III. The conformational changes induced in the fragment are not accompanied by breakage of some base-pairs and formation of others, but rather consist simply of tightening or loosening of helices with retention of existing base-pairs. Helix III is found to be more flexible than helix II. Finally, the loop conformation is conserved over a wide range of Mg2+ concentration, suggesting that the loop may serve an important role in the biological function of 5S rRNA in ribosomes.


Dysregulation of AKT Pathway by SMYD2-Mediated Lysine Methylation on PTEN.
Phosphatase and tensin homologue (PTEN), one of the well-characterized tumor suppressor proteins, counteracts the phosphatidylinositol 3-kinase-AKT pathway through its unique lipid phosphatase activity. The functions of PTEN are regulated by a variety of posttranslational modifications such as acetylation, oxidation, ubiquitylation, phosphorylation, and SUMOylation. However, methylation of PTEN has not been reported so far. In this study, we demonstrated that the oncogenic protein lysine methyltransferase SET and MYND domain containing 2 (SMYD2) methylates PTEN at lysine 313 in vitro and in vivo. Knockdown of SMYD2 suppressed the cell growth of breast cancer cells and attenuated phosphorylation levels of AKT, indicating that SMYD2-mediated methylation negatively regulates PTEN tumor suppressor activity and results in activation of the phosphatidylinositol 3-kinase-AKT pathway. Furthermore, PTEN protein with lysine 313 substitution diminished phosphorylation of PTEN at serine 380, which is known to inactivate tumor suppressor functions of PTEN. Taken together, our findings unveil a novel mechanism of PTEN dysregulation regulated by lysine methylation in human cancer.


Dynamics of Neuropsychological Symptoms during the Training of Executive Functions in Neurological Patients.
Executive function disorder rehabilitation in neurological patients is associated with many difficulties. We investigated the effectiveness of group training, proposed by B. Wilson et al., which has the model of frontal lobes functioning by D. T. Stuss as the theoretical background. The study participants were 16 patients with executive function disorder caused by TBI, strokes, and infections. The training was shortened from 9 weeks to 3 and adopted to the conditions of the rehabilitation centre where the study was held. The evaluation of training effectiveness was carried out by the methods of neuropsychological diagnostics proposed by A. R. Luria as well as standardized quantitative tests (CWIT test, Raven test, FAB) and questionnaires (EBIQ) aimed at assessing the state of executive functions and general well-being. In result positive trends, but not reaching the level of significance, were revealed in the performance of all evaluating methods, with the exception of "arithmetic problems" and "inhibitory control" as part of the FAB test. Statistically significant result was obtained concerning such tests as "counting", "analysis of story pictures", and index of total uncorrected errors in the CWIT test. Thus, the results of eventual assessment showed positive dynamic of executive functions state.


Evaluation of the efficacy of reincubation and subsequent subculture of initially positive blood cultures in the detection of additional clinically significant isolates.
Polymicrobial bacteremias are associated with higher mortality than are unimicrobial bacteremias, and their incidence appears to be increasing. Other researchers have recently shown that the prevalence of polymicrobial bacteremias may be underestimated when blood cultures are not evaluated further after identification of an initial isolate. We investigated this possibility by reincubating and further subculturing blood cultures initially positive for a single organism. We failed to show a clinically important increase in recovery of multiple isolates.


Silibinin hemisuccinate binding to proteins in plasma and blood cell/plasma partitioning in mouse, rat, dog and man in vitro.
The determination of plasma protein binding and blood cell/plasma partitioning is important when prescribing silibinin hemisuccinate to patients concomitantly receiving other drugs and to estimate the safety margins of exposure at the no observed adverse events levels determined from toxicity studies conducted in rats and dogs. Protein binding of [3'-14C]silibinin hemisuccinate (1, 10, 100, 1000 and 4000 μM) was evaluated in human, dog, rat and mouse plasma by ultrafiltration. Blood cell/plasma partitioning in all these species was also determined. Silibinin hemisuccinate is highly bound to plasma proteins with percentage binding ranging from 94.3% to 97.8%. Its association with blood cells was negligible (<7%) in all species. The degree of protein binding was concentration independent up to the pharmacologically effective concentration of 100 μM. The blood cell/plasma partitioning indicates that distribution into blood cells is not an important feature for the disposition of silibinin hemisuccinate. No corrections for fraction unbound are needed when comparing human and preclinical pharmacokinetic and pharmacodynamic data at pharmacological doses, and it is appropriate to analyze plasma as opposed to whole blood for the determination of silibinin hemisuccinate concentrations.


Alarmingly large unemployment gap despite of above-average education in adults with ASD without intellectual disability in Germany: a cross-sectional study.
For individuals with autism spectrum disorder (ASD), both getting access to as well as staying in the labor market are very challenging. However, the detailed educational, vocational, and employment characteristics of persons with ASD without intellectual disabilities are not yet studied. We conducted a retrospective study on a sample of 232 clinically late-diagnosed adults with ASD without intellectual disabilities. Data were compared to the general German population obtained from the public database of the German Federal Employment Agency. Results showed that the majority of persons with ASD graduated from high school and obtained a university entrance qualification (ASD: 50.4%; general population: 32.5%). Also, lower rates of basic secondary education were found in the ASD sample (ASD: 16.5%, general population: 29.6%). Significantly less individuals with ASD completed vocational training (40.1%) in comparison to the German population (56.3%). Despite the above-average level of education, the unemployment rate of the sample substantially exceeds that of the general population by the factor 5 (ASD: 25.2%; general population: 5.2%). Periods of unwanted unemployment of persons with ASD lasted on average 23 months with interpersonal problems being the main reason for contract termination. A higher level of educational qualification does not protect against a higher risk of unemployment for individuals with ASD presumably due to autism-specific interpersonal difficulties. Data emphasize the necessity to develop and spread both specific employment support activities for individuals with ASD as well as adequate awareness raising strategies. Funded by a public grant of the "Landschaftsverband Rheinland (LVR)".


Prevalence and genotypes of Enterocytozoon bieneusi in pigs in southern China.
Enterocytozoon bieneusi is one of the most important causative agents of microsporidiosis, causing diarrhoea the symptoms of enteric disease in humans and animals. Although there is some information on the prevalence and genotypes of E. bieneusi in China, there is still a lack of data in pigs in southern China. In the present study, a total of 396 faecal specimens were collected from pigs in Zhejiang, Guangdong and Yunnan provinces in southern China, and were examined by nested PCR amplification of the ribosomal internal transcribed spacer (ITS) for the prevalence and genotypes of E. bieneusi. The overall prevalence of E. bieneusi in pigs was 31.57% (125/396), forming 15 genotypes, including 9 known genotypes (EbpC, EbpA, D, G, H, PigEBITS5, Henan-IV, KIN-1, CHS5) and 6 novel genotypes (GD1, ZJ1, ZJ2, YN1, YN2 and YN3), which were all clustered into Group 1. Moreover, multilocus sequence typing (MLST) showed that 6, 3, 4 and 5 types were identified in MS1, MS3, MS7 and MS4 loci, respectively, representing four multilocus genotypes (MLGs), designated as MLGs novel-1 to novel-4 in the present study. This is the first detailed study of E. bieneusi using MLST in pigs in southern China, which extended information about the distribution of E. bieneusi genotypes in China.


Short-term biological variation of serum thyroid hormones concentrations in clinically healthy cats.
Thyroid disease is common in cats, but little is known about the biologic variability of serum thyroid hormone concentrations and its impact on diagnostic utility in either healthy cats or cats with thyroid disease. The purpose of this study was to determine the biological variation, index of individuality, and reference change values for thyroid hormones and thyroid-stimulating hormone (TSH) in clinically healthy cats. Serum samples for analysis of total thyroxine (T4), triiodothyronine (T3), free T4 by dialysis, and TSH were obtained weekly for 6 wk from 10 healthy cats, then frozen until single-batch analyzed. Data were evaluated for outliers, and we determined the CV within individual cats (CVI) and between individual cats (CVG) for each hormone and the variation between duplicates or analytical variation (CVA). The index of individuality and reference change values for each hormone were then calculated. Serum concentrations of total T4, free T4, T3, and TSH all showed greater variation between cats (CVG) than within cats (CVI). Total and free T4 had an intermediate index of individuality (1.1 and 1.2, respectively), suggesting that these hormones would be best evaluated by a combination of their population-based reference intervals and reference change values. Serum TSH concentrations had high index of individuality (1.8), suggesting this hormone would be best evaluated with reference change values rather than the population-based reference interval. Total T3 also had a high calculated index of individuality (1.8); however, T3 had high ratio of analytical variation (CVA) to within cat variation (CVI), so RCV could not be accurately calculated. This study demonstrates that clinically normal cats show considerable interindividual biological variation in serum thyroid hormone and TSH concentrations, whereas the intraindividual variability in hormone concentrations is much narrower. This suggests that for all serum thyroid hormones, but especially serum TSH and T3 concentrations, comparing individual cat's hormone results to a population-based reference interval may be misleading, especially in those with early or subclinical thyroid disease. Clinicians might improve the diagnosis of feline thyroid disease by establishing baseline concentrations of T4, free T4, T3, and TSH for individual cats (ideally when healthy) and applying reference change values to subsequent measurements.


Driving simulator for speed research on two-lane rural roads.
The paper reports on a validation study of the interactive fixed-base driving simulator of Inter-University Research Center for Road Safety (CRISS) that was effectuated in order to verify the CRISS driving simulator's usefulness at a tool for speed research on two-lane rural roads. Speeds were recorded at eleven measurement sites with different alignment configurations on a two-lane rural road near Rome. The real world was reproduced in the CRISS driving simulator. Forty drivers drove the simulator. The results of the comparative and statistical analysis established the relative validity and also revealed that absolute validity was obtained in nine measurements sites. Only in two non-demanding configurations, were the speeds in simulator significantly higher than those recorded in the field. In these sites the mean speed in simulator was equal to or greater than 94 km/h. For these configurations, the higher speeds recorded in simulator appeared to stem from the different risk perception on the simulated road as opposed to that on the real road. The study's results should be considered for driving speed behavior research, in which simulator equipment with similar features of the CRISS driving simulator is used.


Bone marrow-derived IFN-producing killer dendritic cells account for the tumoricidal activity of unpulsed dendritic cells.
The CD11c(int)B220(+)NK1.1(+)CD49(+) subset of cells has recently been described as IFN-producing killer dendritic cells (IKDC), which share phenotypic and functional properties of dendritic cells and NK cells. Herein we show that bone marrow-derived murine dendritic cell preparations contain abundant CD11c(int)B220(+)NK1.1(+)CD49(+) cells, the removal of which results in loss of tumoricidal activity of unpulsed dendritic cells in vivo. Moreover, following s.c. injection, as few as 5 x 10(3) highly pure bone marrow-derived IKDC cells are capable of shrinking small contralateral syngeneic tumors in C57BL/6 mice, but not in immunodeficient mice, implying the obligate involvement of host effector cells in tumor rejection. Our data suggest that bone marrow-derived IKDC represent a population that has powerful tumoricidal activity in vivo.


Significant Histologic Changes Are Not Rare in Treatment-naive Hepatitis B Patients with Normal Alanine Aminotransferase Level: A Meta-analysis.
Chronic hepatitis B is the main cause of liver cancer. However, the most neglected group has been treatment-naive chronic hepatitis B patients with normal alanine aminotransferase (ALT). People have tended to subjectively assume that the liver lesions of these patients are not serious and do not need antiviral treatment. However, the truth is not as optimistic as we thought. We aimed in this study to analyze the proportion of significant inflammation or fibrosis in aforementioned patients. Medline, Embase, and Cochrane Library were searched up to January 10th 2020, to identify studies of these patients with liver biopsy. The double arcsine method was used with a random-effect model to combine the proportion of significant inflammation or fibrosis. Potential heterogeneity was explored by subgroup analysis and meta-regression. Outcome of interests included the proportion of significant inflammation or fibrosis and cirrhosis. The secondary outcome was to find the risk factors of significant histological changes. Nineteen eligible studies, with 2,771 participants, were included. The pooled proportion of significant inflammation or fibrosis was 35% [95% confidence interval (CI): 27 to 43] and 30% (95% CI: 25 to 36), respectively. The pooled proportion of cirrhosis was 3% [95% CI: 1 to 5, (12 studies; 1,755 participants)]. In subgroup analysis, old age [vs. young (<40 years-old), 44% vs. 26%, p=0.012] was significantly associated with higher fibrosis stage as well as cirrhosis [vs. young (<40 years-old), 4.8% vs. 1.8%, p<0.001]. About 1/3 of the treatment-naive chronic hepatitis B patients with normal ALT show significant histological changes, and some even have cirrhosis.


Multiple myeloma cells are exceptionally sensitive to heat shock, which overwhelms their proteostasis network and induces apoptosis.
Proteasome inhibitors, such as bortezomib (BTZ), are highly effective and widely used treatments for multiple myeloma. One proposed reason for myeloma cells' exceptional sensitivity to proteasome inhibition is that they produce and continually degrade unusually large amounts of abnormal immunoglobulins. We, therefore, hypothesized that, heat shock may also be especially toxic to myeloma cells by causing protein unfolding, increasing further the substrate load on proteasomes, and, thus, putting further stress on their capacity for protein homeostasis. After a shift from 37 to 43 °C, all four myeloma lines studied underwent extensive apoptosis in 4 h, unlike 13 nonmyeloma cell lines, even though the myeloma cells induced heat-shock proteins and increased protein degradation similar to other cells. Furthermore, two myeloma lines resistant to proteasome inhibitors were also more resistant to 43 °C. Shifting myeloma cells to 43, 41, or 39 °C (which was not cytotoxic) dramatically increased their killing by proteasome inhibitors and inhibitors of ubiquitination or p97/VCP. Combining increased temperature with BTZ increased the accumulation of misfolded proteins and substrate load on the 26S proteasome. The apoptosis seen at 43 °C and at 39 °C with BTZ was mediated by caspase-9 and was linked to an accumulation of the proapoptotic Bcl-2-family member Noxa. Thus, myeloma cells are exceptionally sensitive to increased temperatures, which greatly increase substrate load on the ubiquitin-proteasome system and eventually activate the intrinsic apoptotic pathway. Consequently, for myeloma, mild hyperthermia may be a beneficial approach to enhance the therapeutic efficacy of proteasome inhibitors.


Evoked bursting in injured Aβ dorsal root ganglion neurons: a mechanism underlying tactile allodynia.
Chronic compression of rat dorsal root ganglion (CCD) produced tactile allodynia accompanied with hyperexcitability of the myelinated Aβ dorsal root ganglion (DRG) neurons. The Aβ DRG neuron hyperexcitability exhibits as bursting discharges in response to peripherally evoked action potentials (evoked bursting [EB]). The incidence of EB was significantly increased after chronic compression of DRG (CCD) (43.3%) vs control (13.3%). EB was maintained by oscillation of the membrane potential, and its duration was increased when the membrane potential was depolarized. EB was found to coexist in some neurons with spontaneous bursting (SB), but EB always occurred at a more negative membrane potential than SB. Afterdischarges of the wide dynamic range neurons of the dorsal horn in the spinal cord in response to electrical stimulation of Aβ afferent nerve fibers were suppressed by blocking EB of the DRG neurons. CCD neurons with EB exhibited increased current density of persistent sodium current (I(Nap)) and hyperpolarization-activated cation current (I(h)) and decreased α-dendrotoxin (α-DTX) sensitive current (I(DTX)). The increased I(h) activated by afterhyperpolarization of peripheral afferent action potential was necessary for EB generation and a balance between I(DTX) and I(Nap) might be necessary for EB maintenance. This study may suggest a role of EB of myelinated DRG neurons in development of allodynia after nerve injury and a potential pharmaceutical therapy in treating neuropathic allodynia.


Altered linkage values in phage P22--mediated transduction caused by distant deletions or insertions in donor chromosomes.
The effects of distant deletions or insertions in the Salmonella typhimurium donor strains on P22--mediated cotransducibility of genetic markers was studied. We found that deletions of histidine operon, unit 44 of the chromosome map, changed the linkage of markers purF and aroC (unit 49) and pyrF and trpA (unit 34). They did not change the linkage of more distant markers pyrE and cysE. The effect of three types of insertions was examined. The donor strains carried F factor, Tn10 transposon or pi-his duplication inserted close to histidine operon. These insertions caused alteration of purF-aroC linkage while pyrF-trpA cotransduction values were not affected. These data show that the effect of the chromosome rearrangements extends to at least 5% of S. typhimurium chromosome length and may reach as much as 10% of it. Our results are in agreement with the model of Chelala and Margolin (1974) concerning formation of transduction particles. They indicate that the cotransducibility changes caused by deletions or insertions extent further than it might have been expected from previous reports.


"Tailoring the TiO2 phases through microwave-assisted hydrothermal synthesis: Comparative assessment of bactericidal activity".
Nanocrystalline titania (TiO2) is one of the most investigated crystalline nanostructured systems in the field of materials science. The technological applications of this material are related to its optoelectronic and photocatalytic properties, which in turn are strongly dependent on the crystal phase (i.e., anatase, brookite, and rutile), particle size, and surface structure. However, systematic comparative studies of all its crystal phases are scarce in literature due to difficulties in providing a controlled synthesis, which is primarily important in obtaining the brookite phase. In this report, the synthesis of TiO2 nanoparticles in the anatase, brookite, and rutile structures was explored, using amorphous TiO2 as a common precursor under microwave-assisted hydrothermal conditions. The influence of parameters such as temperature, acidity, and precursor concentration on phase crystallization were investigated. The TiO2 materials (amorphous and crystalline phases as well as commercial Degussa P25) were systematically characterized using Raman spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, scanning electron microscopy, UV-visible reflectance spectroscopy, and dynamic and electrophoretic light scattering. The bactericidal activity and photocatalytic antibacterial effectiveness of each material were evaluated through the determination of the minimum inhibitory and bactericidal concentrations, and via the mortality kinetic method under ultraviolet (UV) illumination under similar conditions with two bacterial groups of unique cellular structures: Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus aureus (S. aureus). The results are discussed with particular emphasis on the relationship between the synthesis parameters (acidity, precursor concentration, temperature and reaction time) and the bactericidal properties.


Epidemiology and control of bovine ostertagiasis in South America.
Gastrointestinal parasitism has been recognized by practitioners as the most common disease in beef cattle, mainly in weaning calves and fattening steers. Among the different genera, Ostertagia ostertagi is the predominant parasite in the temperate climate, in which the major beef and dairy cattle area of South America is situated. Outbreaks of Type I ostertagiasis are usually seen after weaning time (autumn-winter) when larvae counts are high and food availability is low. The development of the disease is rapidly established and 15-30 kg are lost in 30-50 days. Epidemiological studies have demonstrated a fast evolution of parasite eggs to larvae (L3) in summer (1 week or less), evolution being 30-45 days during winter. Inhibition O. ostertagi occurs during spring (September-December) and development resumes in late summer and early autumn. The production effect is seen as a significant reduction in body weight gain and occasionally clinical Type II ostertagiasis appears. A similar epidemiological pattern of inhibition of Ostertagia sp. has been recorded in Uruguay and temperate areas in southern Brazil.


'Let there be light' or life in the dark? Vital geographies of mental healthcare.
This paper explores the relations between light and dark/white and black disclosed in a study of Gartnavel Royal Hospital in Glasgow, Scotland, where an old Victorian lunatic asylum remains, if becoming ruined, on the same site as a modern mental healthcare campus. In-depth interview work recovering the 'spatial stories' of patients and staff, past and present, reveals a complex mixture of positive and negative memories and interpretations prompted by both the 'darkened spaces' of Old Gartnavel and the liveliness associated with both sets of spaces. These findings are framed by (a) a reading of Badiou's short monograph on Black (Badiou, 2017) and (b) an engagement with light and dark studies, both of which suggest a rebalancing of the normal valuations whereby dark/black is cast as the realm of death, everything that deadens and threatens life, whereas light/white is cast as that of life, liveliness and vitality. The scholarship here speaks to work on vitalist health geographies, agreeing that vital health-worlds can surface almost anywhere, but reminding that the fragility of such worlds can always be threatened by too much over-ordering.


A phase II study of first-line chemotherapy with weekly carboplatin plus gemcitabine in advanced non-small cell lung cancer.
The efficacy and safety of weekly carboplatin (CBDCA) and gemcitabine (GEM) was evaluated as first-line chemotherapy with advanced non-small cell lung cancer (NSCLC). 46 chemotherapy-naive patients with measurable NSCLC were enrolled. Patients underwent a combination chemotherapy of GEM 1,000 mg/m2 plus CBDCA at an area under the curve of 2 on days 1 and 8 every 3 weeks. Response rate was 30% (14/46; 95% confidence interval: 17.7-45.8%). The median number of treatment cycles was 3 (range 1-2). Time to progressive disease was 19.4 weeks and the median survival was 46.3 weeks. The 1-year survival rate was 46.9%. The major toxicity was hematotoxicity: grade 3 or 4 neutropenia (58.7%) and thrombocytopenia (45.7%). There were no other severe toxicities. Weekly chemotherapy with CBDCA plus GEM is a well-tolerated and promising regimen as first-line treatment of advanced NSCLC.


Space-Confined seeding and growth of ordered arrays of TiO2 hierarchical nanostructures.
Here, we report a facile approach to fabricate large area ordered arrays of TiO2 hierarchical nanostructures through space-confined seeding and growth on inverted pyramid templates. The mechanisms of space-confined seeding and growth have been systematically explored and studied. The drying TiO2 seed precursor solution prefers to accumulate on the narrow structures including the centre and edges of the inverted pyramid structures, which facilitates to reduce the free energy of the precursor solution surface and form crystal seeds. Followed by hydrothermal treatment, selective growth of TiO2 hierarchical nanostructures on desirable locations, such as only on the centre, only on the edges, or on the entire surface of the inverted pyramid templates, can be achieved. In addition, the growth temperature, duration and solvents affect the morphology of TiO2 hierarchical nanostructures. This work may provide a universal approach to obtain ordered arrays of metal oxide (e.g. ZnO and MnO2, etc.) nanostructures for applications in optics, electrics, energy, and catalysis.


Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy.
Oxaliplatin, a platinum-based chemotherapeutic agent, is effective in the treatment of solid tumors, particularly colorectal cancer. During and immediately following oxaliplatin infusion, patients may experience cold-induced paresthesias, throat and jaw tightness, and occasionally focal weakness. We assessed nerve conduction studies and findings on needle electromyography of patients with metastatic colorectal cancer before and during treatment with oxaliplatin. Twenty-two patients had follow-up studies within 48 h following oxaliplatin infusions, and 14 patients had follow-up studies after 3-9 treatment cycles. Repetitive compound muscle action potentials and neuromyotonic discharges were observed in the first 24-48 h following oxaliplatin infusion, but resolved by 3 weeks. After 8-9 treatment cycles, sensory nerve action potential amplitudes declined, without conduction velocity changes or neuromyotonic discharges. The acute neurological symptoms reflect a state of peripheral nerve hyperexcitability that likely represents a transient oxaliplatin-induced channelopathy. Chronic treatment causes an axonal neuropathy similar to other platinum-based chemotherapeutic agents.


Global distribution, trends, and drivers of flash drought occurrence.
Flash drought is characterized by a period of rapid drought intensification with impacts on agriculture, water resources, ecosystems, and the human environment. Addressing these challenges requires a fundamental understanding of flash drought occurrence. This study identifies global hotspots for flash drought from 1980-2015 via anomalies in evaporative stress and the standardized evaporative stress ratio. Flash drought hotspots exist over Brazil, the Sahel, the Great Rift Valley, and India, with notable local hotspots over the central United States, southwestern Russia, and northeastern China. Six of the fifteen study regions experienced a statistically significant increase in flash drought during 1980-2015. In contrast, three study regions witnessed a significant decline in flash drought frequency. Finally, the results illustrate that multiple pathways of research are needed to further our understanding of the regional drivers of flash drought and the complex interactions between flash drought and socioeconomic impacts.


Voltammetric studies on the electrochemical determination of methylmercury in chloride medium at carbon microelectrodes.
Electroanalytical techniques have been used to determine methylmercury at low levels in environmental matrices. The electrochemical behaviour of methylmercury at carbon microelectrodes in a hydrochloric acid medium using cyclic, square wave and fast-scan linear-sweep voltammetric techniques has been investigated. The analytical utility of the methylmercury reoxidation peak has been explored, but the recorded peak currents were found to be poorly reproducible. This is ascribed to two factors: the adsorption of insoluble chloromercury compounds on the electrode surface, which appears to be an important contribution to hinder the voltammetric signal of methylmercury; and the competition between the reoxidation of the methylmercury radical and its dimerization reaction, which limits the reproducibility of the methylmercury peak. These problems were successfully overcome by adopting the appropriate experimental conditions. Fast-scan rates were employed and an efficient electrochemical regeneration procedure of the electrode surface was achieved, under potentiostatic conditions in a mercury-free solution containing potassium thiocyanate--a strong complexing agent. The influence of chloride ion concentration was analysed. Interference by metals, such as lead and cadmium, was considered. Calibration plots were obtained in the micromolar and submicromolar concentration ranges, allowing the electrochemical determination of methylmercury in trace amounts. An estuarine water sample was analysed using the new method with a glassy carbon microelectrode.


Wear Compliance and Activity in Children Wearing Wrist- and Hip-Mounted Accelerometers.
This study aimed to 1) explore children's compliance to wearing wrist- and hip-mounted accelerometers, 2) compare children's physical activity (PA) derived from raw accelerations of wrist and hip, and 3) examine differences in raw and counts PA measured by hip-worn accelerometry. One hundred and twenty-nine 9- to 10-yr-old children wore a wrist-mounted GENEActiv accelerometer (GAwrist) and a hip-mounted ActiGraph GT3X+ accelerometer (AGhip) for 7 d. Both devices measured raw accelerations, and the AGhip also provided count-based data. More children wore the GAwrist than those from the AGhip regardless of wear time criteria applied (P < 0.001-0.035). Raw data signal vector magnitude (r = 0.68), moderate PA (MPA) (r = 0.81), vigorous PA (VPA) (r = 0.85), and moderate-to-vigorous PA (MVPA) (r = 0.83) were strongly associated between devices (P < 0.001). GAwrist signal vector magnitude (P = 0.001), MPA (P = 0.037), VPA (P = 0.002), and MVPA (P = 0.016) were significantly greater than those from the AGhip. According to GAwrist raw data, 86.9% of children engaged in at least 60 min · d(-1) of MVPA, compared with 19% for AGhip. ActiGraph MPA (raw) was 42.00 ± 1.61 min · d(-1) compared with 35.05 ± 0.99 min · d(-1) (counts) (P = 0.02). ActiGraph VPA was 7.59 ± 0.46 min · d(-1) (raw) and 37.06 ± 1.85 min · d(-1) (counts; P = 0.19). In children, accelerometer wrist placement promotes superior compliance than the hip. Raw accelerations were significantly higher for GAwrist compared with those for AGhip possibly because of placement location and technical differences between devices. AGhip PA calculated from raw accelerations and counts differed substantially, demonstrating that PA outcomes derived from cut points for raw output and counts cannot be directly compared.


Long-term patient perception of pain control experience after participating in a trial between patient-controlled analgesia and epidural after pectus excavatum repair with bar placement.
Pain control is the dominant management issue after bar placement for pectus excavatum. We previously conducted a prospective, randomized trial comparing patient-controlled analgesia (PCA) to thoracic epidural (EPI) documenting similar objective outcomes. Our impression is that the subjective cognitive experience differs between the groups, which impacts trial results interpretation. Therefore, we conducted a survey to ascertain patient recollection and impression of their experience. By telephone questionnaire, yes/no questions included early course recall, anxiety, if they would choose the same arm, do the operation again, or recommend it to friends. Qualitative questions included description, location, and time of peak pain. The graded question addressed severity of pain (1-5). We contacted 27 EPI and 38 PCA patients with a median follow-up of 3.2 y. The majority (~/= 85%) of both groups remembered the first 2 d. Mean pain severity was 3.0 in both groups (3 = bad, but tolerable). Description, location, and time of peak pain responses did not differ. Anxiety was reported by 30% of EPI group and 18% of PCA group (P = 0.37). Approximately 15% of both groups still think about the pain. No differences were seen in nausea, emesis, constipation, itching, or sleepiness. Most patients would choose the same group (87% PCA, 81% EPI, P = 0.73), have the operation again (87% PCA, 74% EPI, P = 0.21), and recommend the operation to friends (100% PCA, 96% EPI, P = 0.42). Long-term recall after repair of pectus excavatum with bar placement does not substantially differ between those managed with an epidural or PCA.


Effect of Nutritional Restriction on the Hair Follicles Development and Skin Transcriptome of Chinese Merino Sheep.
The high concentration of secondary branched wool follicles is a distinctive feature of the Merino sheep. At present, the molecular control of the development and branching of secondary wool follicles (SF) remains elusive. To reveal the potential genes associated with the development of hair follicles, we investigated the characteristics of prenatal and postnatal development of wool follicles, and the transcriptional expression profile in fetuses/lambs from dams under either maternal maintenance or sub-maintenance (75% maintenance) nutrition. The density of SF and the ratio of SF to primary wool follicles (PF) were reduced (p < 0.05) in fetuses from day 105 to 135 of gestation under sub-maintenance nutrition. Differentially expressed genes were enriched in the binding, single-organism process, cellular process, cell and cell part Gene Ontology (GO) functional categories and metabolism, apoptosis, and ribosome pathways. Four candidate genes, SFRP4, PITX1, BAMBI, and KRT16, which were involved in secondary wool follicles branching and development, were identified. Our results indicate that nutritional intervention imposed on pregnant ewes by short-term sub-maintenance nutrition could provide a strategy for the study of wool follicle development. Overall insight into the global gene expression associated with SF development can be used to investigate the underlying mechanisms of SF branching in Merino sheep.


Actions of ORG 5222 as a novel psychotropic agent.
ORG 5222 is a tetracyclic compound with high affinity for dopamine and 5-HT2 receptors. ORG 5222 was compared to fluphenazine in behavioural tests and was shown to be less potent to cause catalepsy on peripheral administration or to induce asymmetric body posturing following intrastriatal injection. On injection into the nucleus accumbens, ORG 5222 antagonised spontaneous and amphetamine-induced hyperactivity. The peripheral administration of ORG 5222 antagonised the hyperactivity induced by infusion of dopamine into the nucleus accumbens of rat or ventral striatum of the marmoset and, unlike the use of fluphenazine, there was no evidence of a 'rebound' hyperactivity after discontinuation of treatment. Furthermore, ORG 5222 prevented changes in responsiveness to dopamine agonist challenge following dopamine infusion. In a mouse black and white test box and the rat elevated plus maze ORG 5222 released exploratory behaviour suppressed by the aversive white or elevated environments. It is concluded that ORG 5222 is effective to antagonise mesolimbic dopamine function in the rodent and primate and an aversive behaviour in rodent tests. Such effects reveal a novel profile of action of ORG 5222 in behavioural paradigms predictive of antipsychotic and anxiolytic potential and may relate to a dopamine and 5-HT receptor antagonism.


Non-uniformity of regional vasomotor activity indicating the existence of 2 different systems in the sympathetic cardiovascular outflow.
In rabbits, 2 populations of sympathetic postganglionic fibres innervating the skin, heart, muscle and kidney could be classified by their different spike heights and their different susceptibility to noradrenaline and angiotensin amide. The ability of the 2 populations to respond to physiological stimuli in a highly differentiated manner leads to the assumption that 2 different systems in the cardiovascular sympathetic outflow exist.


[The role of the microbiome in lupus and antiphospholipid syndrome].
Systemic lupus erythematosus (SLE) and antiphospholipid syndrome are related, systemic autoimmune diseases of unclear etiology. Genetically predisposing factors are known; however, these alone cannot be decisive for the onset and severity of these diseases. This article explains the role of the bacterial microbiome in the origin and progression of these rheumatic diseases. The most recent knowledge in the field of microbiome research based on animal experimental approaches, patient cohorts and human samples is summarized. Various commensal bacteria that promote autoimmunity, so-called pathobionts, which originate from the gut, the skin and the oral cavity, are described. Additionally, their different mechanisms of action are described: Enterococcus gallinarum and Limosilactobacillus reuteri induce adaptive autoimmunity and innate type I interferon pathways via translocation from the small intestine to the liver and spleen; Bacteroides thetaiotaomicron, Actinomyces massiliensis, Pseudopropionibacterium propionicum, Corynebacterium amycolatum, Ruminococcus gnavus and Roseburia intestinalis lead to the formation of pathogenic T‑cell and autoantibody responses via the cross-reactivity with autoantigens (Ro60, dsDNA and ß2 glycoprotein I). Finally, potential future treatment approaches are also discussed, such as immunization against certain pathobionts or the targeted modulation of the microbiome via dietary approaches, which can successfully reduce autoimmune pathologies in animal models.


Effects of mTOR and calcineurin inhibitors combined therapy in Epstein-Barr virus positive and negative Burkitt lymphoma cells.
Post-transplant lymphoproliferative disorder is a severe complication in solid organ transplant recipients, which is highly associated with Epstein-Barr virus infection in pediatric patients and occasionally presents as Burkitt- or Burkitt-like lymphoma. The mammalian target of rapamycin (mTOR) pathway has been described as a possible antitumor target whose inhibition may influence lymphoma development and proliferation after pediatric transplantation. We treated Epstein-Barr virus positive (Raji and Daudi) and negative (Ramos) human Burkitt lymphoma derived cells with mTOR inhibitor everolimus alone and in combination with clinically relevant immunosuppressive calcineurin inhibitors (tacrolimus or cyclosporin A). Cell proliferation, toxicity, and mitochondrial metabolic activity were analyzed. The effect on mTOR Complex 1 downstream targets p70 S6 kinase, eukaryotic initiation factor 4G, and S6 ribosomal protein activation was also investigated. We observed that treatment with everolimus alone significantly decreased Burkitt lymphoma cell proliferation and mitochondrial metabolic activity. Everolimus in combination with cyclosporin A had a stronger suppressive effect in Epstein-Barr virus negative but not in Epstein-Barr virus positive cells. In contrast, tacrolimus completely abolished the everolimus-mediated suppressive effects. Moreover, we showed a significant decrease in activation of mTOR Complex 1 downstream targets after treatment with everolimus that was attenuated when combined with tacrolimus, but not with cyclosporin A. For the first time we showed the competitive effect between everolimus and tacrolimus when used as combination therapy on Burkitt lymphoma derived cells. Thus, according to our in vitro data, the combination of calcineurin inhibitor cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus.


Kraepelin and manic-depressive insanity: an historical perspective.
Since the time of the ancient Greeks, physicians have recognized a certain relatedness between the mental states of depression and mania. In the mid-Nineteenth century, French alienists proposed a 'double' or 'circular' illness consisting of alternating depressed and manic episodes and at the beginning of the twentieth century, Emil Kraepelin introduced the term 'manic-depressive insanity.' Kraepelin's broad clinical experience resulted in compelling descriptions of the symptoms of mood disorders that have arguably never been surpassed. The Kraepelinian nosology continues to provide a touchstone for modern classification systems of the mood disorders.


The effects of wireless devices on male reproductive health: A literature overview.
The aim of this study was to summarize the evidence of radiofrequency electromagnetic radiation (RF-EMR) exposure from wireless devices on total motile sperm count (TMSC) and identify gaps in the literature that could help clarify this link. A literature search was conducted using PubMed/MEDLINE to find relevant studies examining the effects of EMR on male fertility, with a specific focus on TMSC, published from 2000 to 2019. R was used for data analyses. Motility was identified as the parameter linked to TMSC that was most negatively impacted by EMR exposure. Many gaps were found including geographic and lack of standardization with EMR factors such as exposure time and operating frequency. The EMR emitted by wireless devices may negatively affect TMSC, which is one of the better predictors of achieving pregnancies and impairs male fertility. Our findings highlight the need for clinicians to explore wireless device usage to help guide treatment decisions in men or couples with subfertility concerns.


Intracranial Hemorrhage in Patients with Durable Mechanical Circulatory Support Devices: Institutional Review and Proposed Treatment Algorithm.
Spontaneous intracranial hemorrhage (ICH) is frequently managed in neurosurgery. Patients with durable mechanical circulatory support devices, including total artificial heart (TAH) and left ventricular assist device (LVAD), are often encountered in the setting of ICH. Although durable mechanical circulatory support devices have improved survival and quality of life for patients with advanced heart failure, ICH is one of the most feared complications following LVAD and TAH implantation. Owing to anticoagulation and clinically relevant acquired coagulopathies, ICH should be treated promptly by neurosurgeons and cardiac critical care providers. We provide an analysis of ICH in patients with mechanical circulatory support and propose a treatment algorithm. We retrospectively reviewed medical records from 2013-2016 for patients with a durable mechanical circulatory device at Banner-University of Arizona Medical Center Tucson. All patients with suspected ICH underwent computed tomography scan of the brain. Anticoagulation was managed by the cardiothoracic surgeon. In 58 patients, an LVAD (n = 49), TAH (n = 10), or both (n = 1) were implanted. Both acquired von Willebrand disease and spontaneous ICH were diagnosed in 5 patients (8.6%) who underwent LVAD implantation. Seven neurosurgical procedures were performed in 2 patients. The overall mortality rate was 60%. Two patients had little or no deficits after treatment with modified Rankin Scale score of 1 and 2, respectively. We propose a novel treatment algorithm to manage patients with a LVAD or TAH and ICH, implemented in a multidisciplinary manner to best avoid neurologic and cardiovascular complications.


Inactivation of uptake hydrogenase leads to enhanced and sustained hydrogen production with high nitrogenase activity under high light exposure in the cyanobacterium Anabaena siamensis TISTR 8012.
Biohydrogen from cyanobacteria has attracted public interest due to its potential as a renewable energy carrier produced from solar energy and water. Anabaena siamensis TISTR 8012, a novel strain isolated from rice paddy field in Thailand, has been identified as a promising cyanobacterial strain for use as a high-yield hydrogen producer attributed to the activities of two enzymes, nitrogenase and bidirectional hydrogenase. One main obstacle for high hydrogen production by A. siamensis is a light-driven hydrogen consumption catalyzed by the uptake hydrogenase. To overcome this and in order to enhance the potential for nitrogenase based hydrogen production, we engineered a hydrogen uptake deficient strain by interrupting hupS encoding the small subunit of the uptake hydrogenase. An engineered strain lacking a functional uptake hydrogenase (∆hupS) produced about 4-folds more hydrogen than the wild type strain. Moreover, the ∆hupS strain showed long term, sustained hydrogen production under light exposure with 2-3 folds higher nitrogenase activity compared to the wild type. In addition, HupS inactivation had no major effects on cell growth and heterocyst differentiation. Gene expression analysis using RT-PCR indicates that electrons and ATP molecules required for hydrogen production in the ∆hupS strain may be obtained from the electron transport chain associated with the photosynthetic oxidation of water in the vegetative cells. The ∆hupS strain was found to compete well with the wild type up to 50 h in a mixed culture, thereafter the wild type started to grow on the relative expense of the ∆hupS strain. Inactivation of hupS is an effective strategy for improving biohydrogen production, in rates and specifically in total yield, in nitrogen-fixing cultures of the cyanobacterium Anabaena siamensis TISTR 8012.


Primary HIV infection diagnosed in South Africa masquerading as another tropical disease.
Eleven patients referred to a hospital in South Africa with suspected tropical diseases such as malaria, typhoid fever and South African tick bite fever were found to be suffering from primary human immunodeficiency virus (HIV) infection. Hospital records were reviewed retrospectively in those acutely ill, febrile patients where a clinical suspicion of HIV seroconversion existed and no other diagnosis could be found. A history of recent travel, particularly to malarious areas, was given by most of these patients. The clinical presentation was dominated by high fevers and headaches. The most helpful pointers to primary HIV infection included a characteristic palatal enanthem, leucopenia and thrombocytopenia. Ironically, the history of recent travel appeared to have confounded the diagnosis despite the fact that travel has often been associated with the acquisition of HIV in Africa. Recognition of primary HIV infection masquerading as a tropical disease may result in more frequent diagnosis of this serious condition.


Biomimetic scaffolds with three-dimensional undulated microtopographies.
Many human and animal tissues naturally possess three-dimensional (3D) micro-scale geometries enabling certain physiological functions. Absence of these microgeometries in engineered tissues may undermine the effectiveness of corresponding tissue repair and regeneration. This paper introduces a novel approach to create tissue scaffolds with biomimetic 3D undulated microtopographies. The mechanical micromilling technology is used for precise and reproducible fabrication of poly(methyl methacrylate) (PMMA) master molds with 3D undulated microtopographies. Poly(dimethylsiloxane) (PDMS) production molds are then created using the master molds through elastomer molding. Next, gelatin-chondroitin-6-sulfate-hyaluronic acid (Gel-C6S-HA) is filled into the PDMS molds, lyophilized to obtain solid porous scaffolds, and covalently cross-linked to control biodegradability. The utility of the final porous scaffolds with undulated microtopographies mimicking dermal papillae of skin is demonstrated in vitro by culturing neonatal human fibroblasts (NHFs) on the scaffold surfaces for up to 7 days. The assessment of the mold and scaffold geometries demonstrates high accuracy and reproducibility of the PMMA mold fabrication, as well as well-controlled undulated microtopographies and porous microstructures of the final scaffolds. The analysis of cell responses to the undulated microtopographies shows the biocompatibility and effectiveness of the final scaffolds, as well as unique cellular response to these biomimetic topographies at the macroscopic level.


The distinguishing anthropometric features of the Saudi Arabian eyes.
Identifying the peri-ocular anthropometric measurements characteristic of Saudi Arabian eyes. A prospective, cohort, hospital-based study. Measurements were made on 668 subjects (mean age 33.8 years; 58.7% female). The horizontal palpebral aperture was 30.1 ± 2.9 mm (mean ± SD), vertical palpebral aperture was 10.1 ± 0.85 mm, upper lid skin fold height was 3.6 ± 1.9 mm, upper lid crease height was 9.6 ± 0.8 mm, eyebrow height was 10.2 ± 2.7 mm, and intercanthal distance was 32 ± 2.7 mm. There was a statistically significant correlation between gender and eyebrow height (P = 0.001) and gender and horizontal palpebral aperture (P = 0.016), but no significant correlations were noted between any measurement and age. Saudi Arabian eyes are unique in exhibiting a higher upper lid skin fold, higher lid crease.


Ornithine decarboxylase lability in 2 transplantable highly deviated rat hepatomas.
A strong ornithine decarboxylase (ODC)-inactivating capacity has been previously shown (M.F. Zuretti and E. Gravela (1983) Biochim. Biophys. Acta, 742, 269-277) to be bound to rat liver microsomes. Present results show that in 2 fast-growing transplantable tumors, the 3924A Morris hepatoma and the AH 130 Yoshida ascites hepatoma, microsomes are endowed with a greatly enhanced ODC-inactivating capacity, and, concurrently, ODC displays an extreme in vitro liability and an unusual thiol-dependency (most of the activity requires dithiothreitol supply to be determined). These data are at variance with those previously obtained in hepatomas induced by N-2-fluorenylacetamide (E. Gravela et al., (1983) Cancer Res., 42, 2298-2300). The possibility that ODC liability in the 2 hepatomas here studied may result from in vivo exposure to a strong microsomal activity is considered.


Label-free fluorescence turn-on detection of microRNA based on duplex-specific nuclease and a perylene probe.
A novel fluorescence turn-on microRNA (miRNA) detection method based on duplex-specific nuclease (DSN) and a perylene probe is presented in this study. A positively charged perylene derivative (compound 1) was used as the fluorescent probe. Compound 1 exhibits strong monomer fluorescence in an aqueous buffer solution. It is well known that single-stranded DNA is a polyanion in nature. Thus, it can induce the aggregation of compound 1 through strong electrostatic, hydrophobic and π-π stacking interactions. As a result, the fluorescence of compound 1 was efficiently quenched. When the target miRNA was added, the formation of DNA-RNA hybridized duplex initiated the cleavage of the DNA strand by DSN cycle reaction, which resulted in disaggregation of compound 1. A fluorescence turn-on signal was detected, and a novel miRNA sensing method was therefore established. The presented method is label-free, simple, cost effective, sensitive and selective.


A review on sterilization methods of environmental decontamination to prevent the coronavirus SARS-CoV-2 (COVID-19 virus): A new challenge towards eco-friendly solutions.
In recent years, the COVID-19 pandemic is currently wreaking havoc on the planet. SARS-CoV-2, the Severe Acute Respiratory Syndrome Coronavirus, is the current term for this outbreak. Reports about this novel coronavirus have been presented since the pandemic's breakout, and they have demonstrated that it transmits rapidly from person to person, primarily by droplets in the air. Findings have illustrated that SARS-CoV-2 can survive on surfaces from hours to days. Therefore, it is essential to find practical solutions to reduce the virus's impact on human health and the environment. This work evaluated common sterilization methods that can decontaminate the environment and items. The goal is that healthcare facilities, disease prevention organizations, and local communities can overcome the new challenge of finding eco-friendly solutions. Further, a foundation of information encompassing various sterilization procedures and highlighting their limits to choose the most appropriate method to stop disease-causing viruses in the new context has been presented. The findings of this crucial investigation contribute to gaining insight into the comprehensive sterilization approaches against the coronavirus for human health protection and sustainable environmental development.


Deep brain stimulation therapy for a persistent vegetative state.
Twenty cases of a persistent vegetative state (PVS) caused by various kinds of brain damage were neurologically and electrophysiologically evaluated at 3 months after persistence of the PVS, and were treated by deep brain stimulation (DBS) therapy. The stimulation sites were the mesencephalic reticular formation (2 cases) and CM-pf complex (18 cases). Seven of the patients emerged from the PVS, and became able to obey verbal commands. However, they remained in a bedridden state. These 7 cases revealed a desynchronization or slight desynchronization pattern on continuous EEG frequency analysis. The Vth wave of ABR and N20 of SEP could be recorded even with a prolonged latency, and the pain-related P250 was recorded with an amplitude of over 7 microV. We conclude that chronic DBS therapy may be useful for allowing the patient to emerge from a PVS, if the candidates are selected according to the neurophysiological criteria. In view of the severely disabled state of the patients who emerged from the PVS, a special rehabilitation program which includes neurostimulation therapy may be necessary for treatment of the PVS.


Generation and analysis of biosensors to measure mechanical forces within cells.
The inability to measure mechanical forces within cells has been limiting our understanding of how mechanical information is processed on the molecular level. In this chapter, we describe a method that allows the analysis of force propagation across distinct proteins within living cells using Förster resonance energy transfer (FRET)-based biosensors.


Characteristics of normal and waxy corn: physicochemical, protein secondary structure, dough rheology and chapatti making properties.
The physicochemical, protein secondary structure, dough rheological and chapatti making properties of normal and waxy corn types were evaluated. Waxy corn grains showed the highest L* and b* value, while red-pigmented corn grains had the highest a* value. Higher accumulation of K, Mg, Na and Ca minerals in corn was recorded, while Cu, Mn, Fe and Zn were present in trace. Meal prepared from waxy corn had higher L*, a* and b* values as well as ash, protein and fat content. A significant decrease in various mixograph parameters was observed with increase in water level during dough development. A decrease in dynamic rheological parameters (G', G'' and tan δ) of dough from all corn types was recorded with increase in water level. Dough developed from waxy corn meal had lower G' and G'' as compared to that from normal corn types. FTIR spectra of dough from different corn types at different water levels showed various peaks in amide-I region with most prominent peak at about 1650 cm-1 followed by 1640-1645 and 1610-1620 cm-1 regions. The peak intensities increased with increase in water level which was an indicative of the increase in intermolecular and antiparallel (IM + AP) β-sheet as well as α-helix and β-sheet structures. Dough developed from waxy corn showed change in peak intensities at high moisture level only. The chapatti made from normal (yellow) corn showed higher consumers' acceptability score, while that from waxy corn was poor.


Highly antiproliferative, low-calcemic, side-chain ketone analogs of the hormone 1alpha,25-dihydroxyvitamin D3.
A series 2a-4b of seven new side-chain ketone analogs of calcitriol (1) have been prepared. Unexpectedly, several of these 24- and 25-tert-butyl ketones, even though lacking the classical side-chain tertiary hydroxyl group, are considerably more antiproliferative in vitro than the hormone calcitriol (1) even at physiologically relevant low nanomolar concentrations and are less calcemic than calcitriol (1) in vivo. In addition, ketone analog 19-nor-2a is not significantly less calcemic in vivo than 19-methylene analog 2a.


Bipaddled submental artery flap.
Oral cancer is a major public health problem in India. Most patients present with locally advanced disease requiring complex resection and reconstruction strategies. Costs, operating time and availability of expertise are major issues that influence efficient health delivery, especially in developing countries such as India. Technically simple and widely reproducible techniques may be used successfully where applicable, to overcome these issues. The submental artery flap is a well described and acceptable alternative to the radial artery forearm free flap in oral cavity reconstruction. Researchers have demonstrated its technical ease of performance and reproducibility amongst trainees. Here the authors describe the bipaddled submental artery flap, a modification of the standard flap, which can be used to provide lining as well as skin cover for a full thickness cheek defect. Two skin paddles are fashioned taking advantage of the vascular anatomy of the submental vessels.


[Pregnancy and pulmonary arterial hypertension].
Pulmonary hypertension in pregnant women is associated with high mortality and morbidity despite significant improvement in prognosis. Women with pulmonary arterial hypertension (PAH) should be still advised against pregnancy and advised on effective contraceptive methods. Pregnancy may be manageable in women with well controlled PAH or mild pulmonary hypertension (sPAP<50mmHg). When women with PAH choose to continue their pregnancy, they need: management by a multidisciplinary team in an expert centre; continuation or early introduction of targeted PAH therapy; early planned delivery.


[The intratesticular leiomyoma: an unusual location. Report of a case].
Intratesticular location of leiomyoma is unusual. A single case has been published in the literature. We report a case of what we consider to be an intratesticular leiomyoma, with a description of its pathology, a discussion of its differential diagnosis and histogenesis.


Accuracy of ultrasound vs. Fourier-domain optic biometry for measuring preoperative axial length in cases of rhegmatogenous retinal detachment.
To identify a method for accurately measuring preoperative axial length (AL) in cases of rhegmatogenous retinal detachment (RRD). Retrospective study. This retrospective study included 83 eyes of 83 patients who underwent vitrectomy for RRD and had both preoperative and postoperative data for AL. Preoperative AL measurements for the affected eye were obtained using ultrasound (aUS-AL) and compared with those for affected and fellow eyes measured using optical biometry (aOB-AL and fOB-AL, respectively). Absolute differences between preoperative aUS-AL, aOB-AL, or fOB-AL measurements and postoperative AL (aPost-AL) were examined. In the 41 eyes without macular detachment, the absolute difference between aOB-AL and aPost-AL (0.06±0.07 mm) was significantly smaller than between aUS-AL and aPost-AL (0.21±0.18 mm) and that between fOB-AL and aPost-AL (0.29±0.35 mm) (P = 0.017 and P < 0.001, respectively). In the 42 eyes with macular detachment, the absolute difference between aOB-AL and aPost-AL (1.22±2.40 mm) was significantly larger than between aUS-AL and aPost-AL (0.24±0.24 mm) and between fOB-AL and aPost-AL (0.35±0.49 mm) (P = 0.006, P = 0.016, respectively). The current findings suggest that aOB-AL is more accurate than aUS-AL or fOB-AL in cases of RRD without macular detachment, while aUS-AL or fOB-AL is more accurate than aOB-AL in cases with macular detachment.


The occurrence of small, intensely fluorescent (SIF) cells in human sympathetic ganglia.
Small, intensely fluorescent (SIF) cells were found histochemically in lumbar sympathetic ganglia (L2) obtained from sympathectomy of 3 patients suffering from chronic occlusive diseases of leg arteries. 3 types of SIF cells were distinguished. These cells will probably contain dopamine.


Functional variation in phyllogen, a phyllody-inducing phytoplasma effector family, attributable to a single amino acid polymorphism.
Flower malformation represented by phyllody is a common symptom of phytoplasma infection induced by a novel family of phytoplasma effectors called phyllogens. Despite the accumulation of functional and structural phyllogen information, the molecular mechanisms of phyllody have not yet been integrated with their evolutionary aspects due to the limited data on their homologs across diverse phytoplasma lineages. Here, we developed a novel universal PCR-based approach to identify 25 phytoplasma phyllogens related to nine "Candidatus Phytoplasma" species, including four species whose phyllogens have not yet been identified. Phylogenetic analyses showed that the phyllogen family consists of four groups (phyl-A, -B, -C, and -D) and that the evolutionary relationships of phyllogens were significantly distinct from those of phytoplasmas, suggesting that phyllogens were transferred horizontally among phytoplasma strains and species. Although phyllogens belonging to the phyl-A, -C, and -D groups induced phyllody, the phyl-B group lacked the ability to induce phyllody. Comparative functional analyses of phyllogens revealed that a single amino acid polymorphism in phyl-B group phyllogens prevented interactions between phyllogens and A- and E-class MADS domain transcription factors (MTFs), resulting in the inability to degrade several MTFs and induce phyllody. Our finding of natural variation in the function of phytoplasma effectors provides new insights into molecular mechanisms underlying the aetiology of phytoplasma diseases.


Calreticulin discriminates the proximal region at the N-glycosylation site of Glc1Man9GlcNAc2 ligand.
Calreticulin (CRT) is well known as a lectin-like chaperone that recognizes Glc1Man9GlcNAc2 (G1M9)-glycoproteins in the endoplasmic reticulum (ER). However, whether CRT can directly interact with the aglycone moiety (protein portion) of the glycoprotein remains controversial. To improve our understanding of CRT interactions, structure-defined G1M9-derivatives with different aglycones (-OH, -Gly-NH2, and -Gly-Glu-(t)Bu) were used as CRT ligands, and their interactions with recombinant CRT were analyzed using thermal shift analysis. The results showed that CRT binds strongly to a G1M9-ligand in the order -Gly-Glu-(t)Bu > -Gly-NH2 > -OH, which is the same as that of the reglucosylation of Man9GlcNAc2 (M9)-derivatives by the folding sensor enzyme UGGT (UDP-glucose: glycoprotein glucosyltransferase). Our results indicate that, similar to UGGT, CRT discriminates the proximal region at the N-glycosylation site, suggesting a similar mechanism mediating the recognition of aglycone moieties in the ER glycoprotein quality control system.


Uterine prostaglandin levels following stimulation of the decidual cell reaction: effects of indomethacin and tranylcypromine.
Prostaglandin E (PGE) and F (PGF) levels were measured in mouse uteri at various times after either trauma (hemostat crusing) or oil stimulation of the decidual cell reaction (DCR). The oil induced DCR led to an early increase (within 5 min) in both PGE and PGF levels. Both returned to baseline by 1 h after stimulation. A second peak in PGF levels was observed at 120 min after oil stimulation. This study demonstrates a distinct difference between the pattern of PGE and PGF changes in the uterus following oil stimulation of the DCR. Indomethacin pretreatment completely blocked the oil stimulated DCR as well as all prostaglandin increases following either stimulus. The trauma stimulated DCR was not completely blocked by indomethacin pretreatment. Pretreatment with tranylcypromine, an inhibitor of prostacyclin biosynthesis, did not block the prostaglandin E and F increases, but did block the oil stimulated DCR. These findings suggest that prostacyclin may be an early mediator of the DCR.


pH dependence of histidine affinity for blood-brain barrier carrier transport systems for neutral and cationic amino acids.
The effects of pH (3.5-7.5) on the brain uptake of histidine by the blood-brain barrier (BBB) carriers for neutral and cationic amino acids were tested, in competition with unlabeled histidine, arginine, or phenylalanine, with the single-pass carotid injection technique. Cationic amino acid ( [14C]arginine) uptake was increasingly inhibited by unlabeled histidine as the pH of the injection solution decreased. In contrast, the inhibitory effect of unlabeled histidine on neutral amino acid ( [14C]phenylalanine) uptake decreased with decreasing pH. Brain uptake indices with varying histidine concentrations indicated that the neutral form of histidine inhibited phenylalanine uptake whereas the cationic form competed with arginine uptake. Since phenylalanine decreased [14C]histidine uptake at all pH values whereas arginine did not, it was concluded that the cationic form of histidine had an affinity for the cationic carrier, but was not transported by it. We propose that the saturable entry of histidine into brain is, under normal physiological circumstances, mediated solely by the carrier for neutral amino acids.


Peroral endoscopic myotomy for esophageal achalasia: outcomes of the first over 100 patients with short-term follow-up.
POEM is a recently developed achalasia treatment method, which combines the efficacy of surgical myotomy with the benefits of endoscopic procedures. Very few studies have focussed on the efficacy and usefulness of POEM in over 100 cases. The first 100 adult patients treated according to standard POEM technique in a single center and followed up for 3 months were identified and included in this study (men 42; women 58; mean age 48.2 ± 18.8; range 9-91 years) The pre- and postoperative assessments included Eckardt scores, manometry, endoscopy, and monitoring pH. Mean operative time was 150.8 ± 49.3 min (75-370 min). Adverse events over Grade IIIb by the Clavien-Dindo classification were not encountered. The mean preoperative and postoperative lower esophageal sphincter pressures were 43.6 ± 26.2 and 20.9 ± 12.7 mmHg, respectively, indicating a statistically significant decrease after POEM (P < 0.05). The mean preoperative and postoperative integrated relaxation pressure values were 33.5 ± 15.2 and 15.3 ± 6.5 mmHg (P < 0.05). Furthermore, the Eckardt score significantly decreased from 5.9 ± 2.5 preoperatively to 0.8 ± 0.9 postoperatively (P < 0.05). Clinical success was documented in 99 % of the patients. Short-term outcomes after POEM were extremely good and independent of the age, type of achalasia, and previous treatment method. The percent of monitoring time with a pH < 4 was 25.6 % (22/86) in patients not on proton-pump inhibitors. Nine patients were diagnosed with symptomatic gastroesophageal reflux disease (GERD); patients with reflux esophagitis and symptomatic GERD improved with PPI treatment. Our results confirm the efficacy of POEM in a large patient series and support POEM as one of the first-line achalasia therapies in the near future.


Personality, smoking and suicide: a prospective study.
From a random sample of Swiss army conscripts, 28 cases of suicide, 36 deaths due to accident and 2754 controls were analyzed for social and psychological features, in particular for personality factors at age 19 years; further information was collected during a follow-up study to age 36 years. Among the subjects who committed suicide low school achievement, smoking, and psychiatric disorders were overrepresented. In both groups of deaths aggressiveness (excitability, reactive aggression, spontaneous aggression) and depression scores were higher than among controls. The findings are compatible with those of other studies and biological theories about the role of impulsiveness in suicide.


Kimidinomycin, a new antibiotic against Mycobacterium avium complex, produced by Streptomyces sp. KKTA-0263.
During our screening for antibiotics against Mycobacterium avium complex (MAC) with a mass spectrometry network-based indexing approach, a new compound named kimidinomycin was isolated from the culture broth of Streptomyces sp. KKTA-0263 by solvent extraction, HP20 column chromatography, and preparative HPLC. From the structural elucidation, the compound possesses a 38-membered macrolide structure with an N-methylguanidyl group at the terminal side chain. The compound exhibited antimycobacterial activity against M. avium, M. intracellulare, M. smegmatis, and M. bovis BCG with respective MIC values of 12.5, 0.78, 12.5, and 25.0 µg ml-1.


Intracranial capillary hemangioma: extra-axial tumorous lesions closely mimicking meningioma.
Capillary hemangiomas are common tumorous lesions of the skin and soft tissue in infants. These lesions often involve internal organs and rarely develop in the intracranial space. Because of their rarity, clinical descriptions of intracranial capillary hemangioma have been anecdotal and have not provided a coherent understanding of these lesions. We report four cases of intracranial capillary hemangioma. Review of these 4 cases and 14 cases reported in the literature was undertaken to assess the influence of age, sex, location, clinical manifestation, treatment, and outcome. A significant difference was observed in age at diagnosis between sexes. The median age for male patients was 4.8 years (range 6 weeks to 20 years), and the median age for female patients was 22.5 years (range 4 months to 44 years). Approximately two-thirds of intracranial capillary hemangioma lesions develop in the vicinity of major venous sinuses, such as the cavernous/sphenoparietal sinus and the transverse sinus/torcular/superior sagittal sinus. This propensity for specific locations appears to be responsible for the symptom manifestation. The majority of the lesions also seem to be extra-axial in imaging and operative findings. Complete surgical resection provided excellent outcome, but incomplete resection led to recurrence. Capillary hemangioma should be considered in the diagnosis of extra-axial, contrast-enhancing lesions, especially in children and adolescents.


Statistical Genetic Terminology.
Common terms used in statistical genetics with multiple meanings are explained and the terminology used in subsequent chapters is defined. Statistical human genetics has existed as a discipline for over a century, and during that time the meanings of many of the terms used have evolved, largely driven by molecular discoveries, to the point that molecular geneticists, statistical geneticists, and statisticians often have difficulty understanding each other. It is therefore imperative, now that so much of molecular genetics is becoming an in silico and statistical science, that we have a well-defined, common terminology.


Analysis of Social Media Interactions Between Pharmaceutical Companies and Consumers: The Power of the "Like".
The way in which pharmaceutical companies are using social media is vitally important in staying competitive, but the way social media users respond is equally if not more important. This study aimed to evaluate the use of social media by the top 20 pharmaceutical companies and to determine how much consumers interacted with these posts. The top 20 pharmaceutical companies included in this study were present in varying degrees on Twitter, YouTube, and Facebook (90%, 70%, and 50%, respectively). A linear regression analysis between pharmaceutical company interactions and corresponding consumer interactions for each social media platform did not find a statistically significant association ( r2 = 0.44, 0.49, and 0.22, respectively). In a descriptive review of the social media posts analyzed, this study found pharmaceutical company posts to relate to disease state awareness, business updates, and community outreach projects.