Prescription patterns of long-acting somatostatin analogues.
Acromegaly and endocrine tumors are uncommon morbidities that are currently treated with different drugs. To determine the prescription patterns of somatostatin analogues in patients affiliated with the Health System of Colombia. Retrospective cohort study of patients of any age and sex treated with octreotide or lanreotide between January 2011 and August 2015. Socio-demographic, clinical (indications) and pharmacological (comedications) variables were considered. Multivariate analysis was performed with SPSS 23.0. We identified 289 patients, with a mean age of 56.6 ± 14.0 years and female predominance (59.5%), who underwent treatment during the 56 months of monitoring. Octreotide was used in 56.1% of cases, followed by lanreotide (43.9%), both at approved doses. We found that 4.5% of subjects changed from one drug to another over the course of therapy, which was associated with being diabetic and receiving insulin (odds ratio: 4.27; 95% confidence interval: 1.23-14.84; p = 0.014). The most common indications were acromegaly (52.2% of cases) followed by neuroendocrine tumors (15.9%). The most common comorbidities were hypertension (39.4% of cases), depression (27.3%), dyslipidemia (23.3%), diabetes mellitus (23.5%) and hypothyroidism (23.5%). Being male (odds ratio: 0.57; 95% confidence interval: 0.35-0.94; p = 0.029) and belonging to the age group between 45 and 65 years (odds ratio: 0.44; 95% confidence interval: 0.21-0.90; p = 0.024) were significantly associated with a lower risk of receiving comedications. Somatostatin analogues are being used at recommended doses, especially in patients with acromegaly and neuroendocrine tumors. Variables associated with change in therapy were identified.


U-shaped relationship between iodine status and thyroid autoimmunity risk in adults.
Iodine status has long been regarded as an environmental determinant for thyroid dysfunction, but its relationship with thyroid autoimmunity (TAI) is still controversial. Our study aimed to elucidate the relationship between iodine status and TAI through both a population-based study and a dose-response meta-analysis of eligible epidemiological studies. A population-based, cross-sectional study was firstly carried out, which enrolled a total of 2808 Chinese adults. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated through logistic regression analysis. A dose-response meta-analysis of eligible epidemiological studies was also carried out. The cross-sectional study showed an U-shaped relationship between iodine intake and TAI in adults. Compared with those with more than adequate iodine status, individuals with iodine deficiency, adequate iodine status and iodine excess all had higher risk of TAI, and the adjusted ORs were 1.50 (95% CI 1.03-2.17, P = 0.032), 1.50 (95% CI 1.09-2.07, P = 0.013) and 1.68 (95% CI 1.11-2.53, P = 0.014), respectively. The dose-response meta-analysis included 22 epidemiological studies with a total of 69,987 participants and further validated the U-shaped relationship between iodine intake and TAI in adults, which proved the significantly increased risk of TAI among individuals with either iodine deficiency or iodine excess. Stratified analysis of studies with low risk of confounding bias also identified similar findings. The study suggests an U-shaped relationship between iodine intake and TAI in adults, and both iodine deficiency and iodine excess are risk factors of TAI in adults. The underlying mechanisms need to be elucidated in future studies.


A modular and flexible ESC-based mouse model of pancreatic cancer.
Genetically engineered mouse models (GEMMs) have greatly expanded our knowledge of pancreatic ductal adenocarcinoma (PDAC) and serve as a critical tool to identify and evaluate new treatment strategies. However, the cost and time required to generate conventional pancreatic cancer GEMMs limits their use for investigating novel genetic interactions in tumor development and maintenance. To address this problem, we developed flexible embryonic stem cell (ESC)-based GEMMs that facilitate the rapid generation of genetically defined multiallelic chimeric mice without further strain intercrossing. The ESCs harbor a latent Kras mutant (a nearly ubiquitous feature of pancreatic cancer), a homing cassette, and other genetic elements needed for rapid insertion and conditional expression of tetracycline-controlled transgenes, including fluorescence-coupled shRNAs capable of efficiently silencing gene function by RNAi. This system produces a disease that recapitulates the progression of pancreatic cancer in human patients and enables the study and visualization of the impact of gene perturbation at any stage of pancreas cancer progression. We describe the use of this approach to dissect temporal roles for the tumor suppressor Pten and the oncogene c-Myc in pancreatic cancer development and maintenance.


Reversible severe hereditary hemochromatotic cardiomyopathy.
Two cases of severe hereditary hemochromatotic cardiomyopathy are reported. Both patients responded remarkably well to treatment and are leading a normal life requiring no cardiac medications, following small volume phlebotomies for two years combined, in the first three and six months of treatment, with subcutaneous deferoxamine mesylate.


Cognitive ability as a factor in engagement in drug abuse treatment.
This study examined correlates of high (HCA) and low (LCA) cognitive ability among substance dependent individuals who participated in an ongoing study of early engagement strategies. Participants (55% male; 98% African American), were administered the ASI, Shipley Institute of Living Scale, Beck Hopelessness scale, and TCU Motivation Scales at intake. Analyses were limited to 416 participants whose IQs fell within the upper and lower thirds of the sample. HCA participants reported more prior treatment episodes and longer durations of voluntary abstinence than LCA participants. There were no differences in retention, although HCA participants expressed significantly greater motivation and hopefulness at intake than LCA participants. Results indicate that clients with higher cognitive ability may present with a greater capacity to engage in treatment than individuals with lower cognitive ability.


Treatment of Children Trichobezoar a Retrospective Study of 11 Cases.
The goal of this study to summarize the clinical features, treatment and prognosis of children trichobezoar, and to guide the clinical diagnosis and treatment. The clinical manifestations, auxiliary examination results, diagnosis and treatment process and family relationship of 11 cases of children with trichobezoar in our hospital were analyzed retrospectively. 11 cases were female, 4 cases were divorced single parent family, and 2 case was left behind child. Six patients were admitted to hospital with sudden exacerbation of chronic abdominal pain, and four of them had recurrent vomiting. Five patients were admitted to hospital with acute abdominal pain, and 3 of them had vomiting symptoms; The weight of 1 case was lower than -2 SD, 4 cases were between -2 SD ~ -1 SD. 6 cases had palpable left upper abdominal mass with mild tenderness, 1 case only had left upper abdominal tenderness, 4 cases had no positive abdominal signs; The results of color Doppler ultrasonography in 8 children indicated the strong echo mass in the stomach, and 3 of them showed that the hyperechoic group extended to duodenum through pylorus. 7 cases had a tail end extending into the small intestine after removing the gastrolith during the operation. Four cases were found with jejunal perforation, 2 cases were treated with intestinal resection and anastomosis, and 2 cases were treated with intestinal repair. All the children were improved and discharged after operation. For single parent families or left behind children with a history of chronic abdominal pain, vomiting and trichophilia, gastric hair stones should be highly suspected. For large hair stones in the stomach, they should be removed surgically. During the operation, the small intestine should be explored routinely to prevent the missed diagnosis of small intestinal perforation. Psychological guidance should be given to the children and their parents to prevent recurrence.


Comparisons of urban and rural heat stress conditions in a hot-humid tropical city.
In recent years the developing world, much of which is located in the tropical countries, has seen dramatic growth of its urban population associated with serious degradation of environmental quality. Climate change is producing major impacts including increasing temperatures in these countries that are considered to be most vulnerable to the impact of climate change due to inadequate public health infrastructure and low income status. However, relevant information and data for informed decision making on human health and comfort are lacking in these countries. The aim of this paper is to study and compare heat stress conditions in an urban (city centre) and rural (airport) environments in Akure, a medium-sized tropical city in south-western Nigeria during the dry harmattan season (January-March) of 2009. We analysed heat stress conditions in terms of the mean hourly values of the thermohygrometric index (THI), defined by simultaneous in situ air temperature and relative humidity measurements at both sites. The urban heat island (UHI) exists in Akure as the city centre is warmer than the rural airport throughout the day. However, the maximum UHI intensity occurs at night between 1900 and 2200 hours local time. Hot conditions were predominant at both sites, comfortable conditions were only experienced in the morning and evenings of January at both sites, but the rural area has more pleasant morning and evenings and less of very hot and torrid conditions. January has the lowest frequency of hot and torrid conditions at both sites, while March and February has the highest at the city centre and the airport, respectively. The higher frequencies of high temperatures in the city centre suggest a significant heat stress and health risk in this hot humid environment of Akure. More research is needed to achieve better understanding of the seasonal variation of indoor and outdoor heat stress and factors interacting with it in order to improve the health, safety, and productivity of Akure city dwellers.


Directing the secondary structure of polypeptides at will: from helices to amyloids and back again?
An ageing society faces an increasing number of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Creutzfeld-Jacob disease. The deposition of amyloid fibrils is a pathogenic factor causing the destruction of neuronal tissue. Amyloid-forming proteins are mainly alpha-helical in their native conformation, but undergo an alpha-helix to beta-strand conversion before or during fibril formation. Partially unfolded or misfolded beta-sheet fragments are discussed as direct precursors of amyloids. To potentially cure neurodegenerative diseases we need to understand the complex folding mechanisms that shift the equilibrium from the functional to the pathological isoform of the proteins involved. This paper describes a novel approach that allows us to study the interplay between peptide primary structure and environmental conditions for peptide and protein folding in its whole complexity on a molecular level. This de novo designed peptide system may achieve selective inhibition of fibril formation.


Assessment of the feasibility of using sunlight exposure to obtain the recommended level of vitamin D in Canada.
Endogenous vitamin D synthesis can be affected by a number of variables, including skin colour, amount of skin exposed and levels of ultraviolet radiation. The objective of this study was to assess the feasibility of using only sunlight exposure in Canada to meet the daily recommended level of vitamin D, given differences in these variables and adherence to guidelines for sun protection. Ultraviolet index data for 13 Canadian sites were obtained from Environment Canada. The sun exposure times required to synthesize 1000 IU of vitamin D in fair- and dark-skinned people who exposed either 1/4 or 1/8 of their body surface area to the sun were calculated for each hour of the year. These times were then classified according to whether the ultraviolet index was 3 or more (when sun protection is advised) or less than 3. During the fall and winter months and in the more northern sites, ultraviolet radiation levels were too low for all skin types to use sun exposure alone to obtain enough vitamin D within one time period. The required exposure time became longer when a smaller surface area was exposed. For people with darker skin, it can be difficult even in the summer to find opportunities outside of when sun protection is advised to use sunlight to obtain the recommended dose of vitamin D. Although sun exposure is an important source of vitamin D, Canadians should look to other safe sources to meet the body's vitamin D requirements throughout the year.


Optimization of oxygen transport in mechanically ventilated newborns using oximetry and pulsed Doppler-derived cardiac output.
In respiratory distress syndrome (RDS), PEEP improves arterial oxygenation but may impair cardiac output. The effects of PEEP on gas exchange and hemodynamics were studied in 12 mechanically ventilated newborns in the acute phase of RDS. Stepwise increase in PEEP resulted in both a) a progressive increase in PaO2 and transcutaneous oxyhemoglobin saturation, and b) a depression of pulsed Doppler-measured cardiac output that was statistically significant at 9 cm H2O PEEP. Thus, averaged systemic oxygen delivery (DO2) was maintained with improved arterial oxygenation up to 6 cm H2O PEEP. Further increase in PEEP induced a significant fall in DO2. No variation was observed in heart rate and mean arterial pressure. The combined use of oximetry and pulsed Doppler echocardiography enables noninvasive optimization of mechanical ventilation and PEEP during the clinical course.


Cardiac External Counterpulsation Attenuates Myocardial Injury by Regulating NRF2-mediated Ferroptosisin and Oxidative stress Injury.
To explore the role of the external counterpulsation (ECP) myocardial injury by controlling NRF2-mediated ferroptosis and oxidative stress damage in acute myocardial infarction. Twenty acute myocardial infarction (AMI) participants hospitalized from January 2021 to January 2022 were enrolled. In addition, 20 healthy individuals who had a physical examination at our hospital served as normal controls. Before the AMI patients were given ECP therapy, the blood samples were collected and echocardiography was performed as the data of AMI cohort. Then, the blood samples were collected and echocardiography was performed following the ECP therapy as the data of AMI + ECP cohort. The heart function was assessed by echocardiography test. Our findings demonstrated that ECP could reduce heart damage in patients with AMI. In the current study, we found that ECP could reduce heart damage in patients with AMI through increasing the LV-EF% and enhancing LVEDV and LVESV, and the difference was statistically significant (P < 0.05). ECP could reduce the levels of oxidative stress and ferroptosis markers in blood samples of AMI patients, which was through the upregulation of NRF2 and HO-1 expression, and the difference was statistically significant (P < 0.05). Taken together, all data implied that ECP was able to attenuate myocardial injury by regulating NRF2-mediated ferroptosis and oxidative stress in AMI patients, and the difference was statistically significant (P < 0.05). Our findings in this research are that cardiac ECP is able to attenuate myocardial injury by regulating NRF2-mediated ferroptosis and oxidative stress injury in AMI patients. This certainly gives the possibility of a clinically effective treatment for AMI patients, although further clinical trials need to be validated.


Biochemical changes in lysogenic Bacillus stearothermophilus after bacteriophage induction.
Welker, N. E. (University of Illinois, Urbana), and L. Leon Campbell. Biochemical changes in lysogenic Bacillus stearothermophilus after bacteriophage induction. J. Bacteriol. 90:1129-1137. 1965.-Cultures of Bacillus stearothermophilus 1503-4R (TP-1) continued to grow at an unaltered rate after induction with mitomycin C (MC). MC-induced cultures exhibited a 2.5-fold increase in cell number before lysis occurred. Prior to lysis, cells were observed to elongate and to contain areas of lesser density. Protein synthesis was slightly inhibited in MC- or ultraviolet light (UV)-induced cultures for a period of 5 to 10 min, and then proceeded at a rate identical to that in the noninduced culture. Ribonucleic acid (RNA) synthesis was not affected by MC induction. UV induction caused RNA synthesis to occur in two stages: in the first stage, the rate of RNA synthesis was one-third that observed in the noninduced culture and lasted for a period of 15 min; the second stage of RNA synthesis then proceeded at a rate identical to that in the noninduced culture. The synthesis of deoxyribonucleic acid (DNA) in an MC- or UV-induced culture occurred in two stages. In the first stage, DNA synthesis in induced cultures occurred at a rate of one-half (MC) and one-third (UV) of that observed in the noninduced culture. The first stage of DNA synthesis in MC- or UV-induced cultures lasted for 25 to 30 min and 15 to 20 min, respectively. In the second stage, the rate of DNA synthesis in MC- or UV-induced cultures occurred at a rate three times that of the noninduced culture. UV induction appeared to have a greater inhibitory effect than MC induction on protein, RNA, and DNA synthesis as well as phage yield. The differential rate (K) of inducible and constitutive alpha-amylase synthesis was inhibited by 75 and 100%, respectively, for a period of 20 min after MC induction. After 20 min, the K values for alpha-amylase synthesis were identical to those obtained in the absence of MC induction. The synthesis of TP-1 phage DNA occurred rapidly and was complete 25 min after MC induction, whereas bacterial DNA was degraded or its rate of synthesis was decreased. During the second stage of DNA synthesis, only bacterial DNA was synthesized, but at a rate greater than that found in the noninduced culture.


Palliative care in women's cancer care: Global challenges and advances.
Women's cancer rates are increasing in low- and middle-income countries, with presentations that are often far advanced requiring intense symptom management, thus advancing the urgent need to address palliative care. Most resource settings have some options available to assist women with advanced gynecologic cancer, and a combination of leveraging these and expanding on emerging models for palliative care could lessen suffering and improve care for women with gynecologic cancers globally. Providing palliative care for women with cancer is constrained by resources (human and physical), lack of equipment, lack of access, and policy absence or barriers. There is important work to be done in advocating for appropriate infrastructure development and legislation to assure that these options are available to women and their families. Access to adequate opioid and other pain relief options for cancer-related pain is a particular concern given that availability, cost, and legislative prohibitions create barriers that cause suffering for patients and grief for their families who are unable to address their suffering. All of these require ongoing advocacy for continual advances to improve access and infrastructure for palliative care.


Graph-DTI: A New Model for Drug-Target Interaction Prediction Based on Heterogenous Network Graph Embedding.
In this study, we aimed to develop a new end-to-end learning model called Graph-Drug-Target Interaction (DTI), which integrates various types of information in the heterogeneous network data, and to explore automatic learning of the topology-maintaining representations of drugs and targets, thereby effectively contributing to the prediction of DTI. Precise predictions of DTI can guide drug discovery and development. Most machine learning algorithms integrate multiple data sources and combine them with common embedding methods. However, the relationship between the drugs and target proteins is not well reported. Although some existing studies have used heterogeneous network graphs for DTI prediction, there are many limitations in the neighborhood information between the nodes in the heterogeneous network graphs. We studied the drug-drug interaction (DDI) and DTI from DrugBank Version 3.0, protein-protein interaction (PPI) from the human protein reference database Release 9, drug structure similarity from Morgan fingerprints of radius 2 and calculated by RDKit, and protein sequence similarity from Smith-Waterman score. Our study consists of three major components. First, various drugs and target proteins were integrated, and a heterogeneous network was established based on a series of data sets. Second, the graph neural networks-inspired graph auto-encoding method was used to extract high-order structural information from the heterogeneous networks, thereby revealing the description of nodes (drugs and proteins) and their topological neighbors. Finally, potential DTI prediction was made, and the obtained samples were sent to the classifier for secondary classification. The performance of Graph-DTI and all baseline methods was evaluated using the sums of the area under the precision-recall curve (AUPR) and the area under the receiver operating characteristic curve (AUC). The results indicated that Graph-DTI outperformed the baseline methods in both performance results. Compared with other baseline DTI prediction methods, the results showed that Graph-DTI had better prediction performance. Additionally, in this study, we effectively classified drugs corresponding to different targets and vice versa. The above findings showed that Graph-DTI provided a powerful tool for drug research, development, and repositioning. Graph-DTI can serve as a drug development and repositioning tool more effectively than previous studies that did not use heterogeneous network graph embedding.


Fasting and postprandial disposition of R(-)- and S(+)-ibuprofen following oral administration of racemic drug in healthy individuals.
The effects of preceding food intake on the plasma concentrations of R(-)-ibuprofen and the pharmacologically active enantiomer S(+)-ibuprofen were investigated in healthy subjects. A single oral dose of 400 mg racemic ibuprofen was administered either fasting or following a standardized meal. As compared to fasting administration postprandial drug intake resulted in a clear reduction of R(-) and S(+)- ibuprofen plasma concentrations mainly during the initial three hours. The ratio of S(+)/R(-)-ibuprofen postprandially was increased for Cmax and AUC o-tmax as well as for AUC o-infinity. These data are compatible with a meal-induced enhancement of chiral inversion of R(-) to S(+)-ibuprofen. The significant reduction of plasma concentrations of ibuprofen mainly during the initial three hours suggests that the analgesic efficacy is diminished when the drug is taken after a meal. This may to a slight extent be compensated for by a small increase of the metabolic inversion of the R(-)-enantiomer into the active S(+)-form of the drug.


Sexual health behaviors and sexual orientation in a U.S. national sample of college students.
Many studies have examined differences in sexual behavior based on sexual orientation with results often indicating that those with same-sex partners engage in higher risk sexual behavior than people with opposite sex partners. However, few of these studies were large, national sample studies that also include those identifying as unsure. To address that gap, this study examined the relationship of sexual orientation and sexual health outcomes in a national sample of U.S. college students. The Fall 2009 American College Health Association-National College Health Assessment was used to examine sexual health related responses from heterosexual, gay, lesbian, bisexual, and unsure students (N = 25,553). Responses related to sexual behavior, safer sex behaviors, prevention and screening behaviors, and diagnosis of sexual health related conditions were examined. The findings indicated that sexual orientation was significantly associated with engaging in sexual behavior in the last 30 days. Sexual orientation was also significantly associated with the number of sexual partners in the previous 12 months, with unsure men having significantly more partners than gay, bisexual and heterosexual men and heterosexual men having significantly less partners than gay, bisexual and unsure men. Bisexual women had significantly more partners than females reporting other sexual orientations. Results examining the associations between sexual orientation and safer sex, prevention behaviors, and screening behaviors were mixed. Implications for practice, including specific programmatic ideas, were discussed.


Effect of fatty acid interaction on myoglobin oxygen affinity and triglyceride metabolism.
Recent studies have suggested myoglobin (Mb) may have other cellular functions in addition to storing and transporting O2. Indeed, NMR experiments have shown that the saturated fatty acid (FA) palmitate (PA) can interact with myoglobin (Mb) in its ligated state (MbCO and MbCN) but does not interact with Mb in its deoxygenated state. The observation has led to the hypothesis that Mb can also serve as a fatty acid transporter. The present study further investigates fatty acid interaction with the physiological states of Mb using the more soluble but unsaturated fatty acid, oleic acid (OA). OA binds to MbCO but does not bind to deoxy Mb. OA binding to Mb, however, does not alter its O2 affinity. Without any Mb, muscle has a significantly lower level of triglyceride (TG). In Mb knock-out (MbKO) mice, both heart and skeletal muscles have lower level of TG relative to the control mice. Training further decreases the relative TG in the MbKO skeletal muscle. Nevertheless, the absence of Mb and lower TG level in muscle does not impair the MbKO mouse performance as evidenced by voluntary wheel running measurements. The results support the hypothesis of a complex physiological role for Mb, especially with respect to fatty acid metabolism.


Organometallic Ru, Os, Rh and Ir half-sandwich conjugates of ispinesib - impact of the organometallic group on the antimitotic activity.
Antimitotic agents are among the most important drugs used in anticancer therapy. Kinesin spindle protein (KSP) was proposed as a promising target for new antimitotic drugs. Herein, we report the synthesis of Ru, Os, Rh, and Ir half-sandwich complexes with the KSP inhibitor ispinesib and its (S)-enantiomer. Conjugation of the organometallic moiety with ispinesib and its (S)-enantiomer resulted in a significantly increased cytotoxicity of up to 5.6-fold compared to the parent compounds, with IC50 values in the nanomolar range. The most active derivatives were the ispinesib Ru and Rh conjugates which were able to generate reactive oxygen species (ROS), which may at least partially explain their high cytotoxicity. At the same time, the Os and Ir derivatives acted as KSP inhibitors with no effects on ROS generation.


Conformational study of L-methionine and L-cysteine derivatives through quantum chemical calculations and 3JHH coupling constant analyses.
The understanding of the conformational behavior of amino acids and their derivatives is a challenging task. Here, the conformational analysis of esterified and N-acetylated derivatives of L-methionine and L-cysteine using a combination of 1H NMR and electronic structure calculations is reported. The geometries and energies of the most stable conformers in isolated phase and taking into account the implicit solvent effects, according to the integral equation formalism polarizable continuum model (IEF-PCM), were obtained at the ωB97X-D/aug-cc-pVTZ level. The conformational preferences of the compounds in solution were also determined from experimental and theoretical 3JHH coupling constants analysis in different aprotic solvents. The results showed that the conformational stability of the esterified derivatives is not very sensitive to solvent effects, whereas the conformational equilibrium of the N-acetylated derivatives changes in the presence of solvent. According to the natural bond orbital (NBO), quantum theory of atoms in molecules (QTAIM) and noncovalent interactions (NCI) methodologies, the conformational preferences for the compounds are not dictated by intramolecular hydrogen bonding, but by a joint contribution of hyperconjugative and steric effects.


The Walker Project: a longitudinal study of 48,000 children born 1952-1966 (aged 36-50 years in 2002) and their families.
The Walker cohort is a database of over 48,000 birth records that has recently become available. It contains meticulously recorded details of pregnancy, labour, birth and care before discharge for babies born in hospital in Dundee, Scotland between 1952 and 1966. These babies accounted for 75% of all births in Dundee at this time. Over 34,000 (73%) of these subjects can be identified and this presents the opportunity to link this birth information with a large number of current health-outcome databases covering both primary and secondary care. Further, it allows linkage of records across siblings and over two and, in future, three generations. The number of birth records available and linkage to current databases make this a unique birth cohort with huge potential for the investigation of the fetal origins of adult disease.


An In Vitro Evaluation of the Antibacterial Efficacy of Solanum xanthocarpum Extracts on Bacteria From Dental Plaque Biofilm.
The focus of research has recently shifted toward developing herbal-based medicines due to the emerging bacterial resistance and side effects of antibiotics. Solanum xanthocarpum (Sx) is a medicinal plant with potent pharmacological properties. This study aimed to evaluate the antibacterial activity of its crude extracts on bacteria isolated from dental plaque in patients with gingivitis. Aqueous, ethyl acetate, hexane, chloroform, and ethanolic extracts were prepared from Sx. Dental plaque samples were collected from patients with plaque-induced gingivitis. Disk diffusion assay was performed to determine the antibacterial activity of the extracts at concentrations of 25 mg/ml, 50 mg/ml, and 75 mg/ml with ampicillin 200 mg/ml as a positive control. The minimum inhibitory concentration (MIC) of the aqueous extract was also evaluated by broth dilution test against bacteria isolated from dental plaque biofilm. The antibacterial activity was estimated by measuring the zones of inhibition through the disc diffusion method. The Kruskal Wallis with Dunn post hoc test performed for intergroup comparison between the various extracts showed a statistically significant difference in inhibition of bacterial growth between 25 mg/ml and 75 mg/ml concentrations. There was no significant difference between the 75 mg/ml Sx concentration and the positive control. In addition, the MIC was elucidated to be 0.625 g/ml, at which there was maximum inhibition of bacterial growth. The Sx extract exhibited antibacterial activity against periodontal pathogens. Thus, it can be concluded that optimum concentrations of Sx could be used in therapeutic strategies to prevent and manage periodontal diseases.


Advanced Red Meat Cooking Technologies and Their Effect on Engineering and Quality Properties: A Review.
The aim of this review is to investigate the basic principles of red meat cooking technologies, including traditional and modern methods, and their effects on the physical, thermal, mechanical, sensory, and microbial characteristics of red meat. Cooking methods were categorized into two categories: traditional (cooking in the oven and frying) and modern (ohmic, sous vide, and microwave cooking). When red meat is subjected to high temperatures during food manufacturing, it undergoes changes in its engineering and quality attributes. The quality standards of meat products are associated with several attributes that are determined by food technologists and consumers based on their preferences. Cooking improves the palatability of meat in terms of tenderness, flavor, and juiciness, in addition to eliminating pathogenic microorganisms. The process of meat packaging is one of the important processes that extend the life span of meat and increase its shelf life due to non-exposure to oxygen during cooking and ease of handling without being exposed to microbial contamination. This review highlights the significance of meat cooking mathematical modeling in understanding heat and mass transfer phenomena, reducing costs, and maintaining meat quality. The critical overview considers various production aspects/quality and proposed methods, such as, but not limited to, hurdle technology, for the mass production of meat.


Improved late survival in patients with chronic aortic regurgitation by earlier operation.
Between 1970 and 1979, 156 patients with severe chronic aortic regurgitation underwent aortic valve replacement. Early mortality was 2.5%; 5 and 10 year survival rates were 85.9% and 69.2%, respectively. Early mortality decreased from 3.5% (2/56) in the period from 1970 to 1974 to 2.0% (2/100) in the period from 1975 to 1979; first-year survival rate was similar in the two periods (94.2% and 94.7%); 5 year survival rate increased from 80.1% in the period from 1970 to 1974 to 90.6% in the period from 1975 to 1979. The frequency of late death from heart failure decreased from 5/13 in the period from 1970 to 1974 to 0/9 in the period from 1975 to 1979. Preoperative NYHA class decreased from 2.7 (10 patients in class IV, none in class I) during 1970 to 1974 to 2.1 (one patient in class IV, 15 in class I) during 1975 to 1979 (p less than .001). From 1970 to 1974 preoperative cardiothoracic ratio (0.60 vs 0.57; p less than .001) and left ventricular end-diastolic pressure (33 vs 19 mm Hg; p less than .001) were higher and left ventricular ejection fraction (50% vs 54%; p less than .05) was lower than values during 1975 to 1979. The patients who died of heart failure were in a higher NYHA class before surgery, cardiothoracic ratio and left ventricular end-diastolic pressure were higher, and left ventricular ejection fraction was lower than those in patients who died suddenly. In all patients of both groups left ventricular end-diastolic volume exceeded 200 ml/m2.(ABSTRACT TRUNCATED AT 250 WORDS)


Biological minimization of excess sludge in a membrane bioreactor: Effect of plant configuration on sludge production, nutrient removal efficiency and membrane fouling tendency.
Excess sludge minimization was studied in a MBR with pre-denitrification scheme. Sludge minimization, nitrogen removal performance and membrane fouling tendency were investigated in two configurations, characterized by a different position of the sludge retention reactor (SRR). In particular, the SRR was placed: i) in the return activated sludge line (Anaerobic Side-Stream Reactor - ASSR configuration) and ii) in the mainstream between the anoxic and aerobic reactor (Anaerobic Main-Stream Reactor - AMSR configuration). The achieved results demonstrated that the ASSR enabled a higher excess sludge reduction (74% vs 32%), while achieving lower biological nitrogen removal (BNR) (TN = 63% vs 78%) and membrane fouling tendency (FR = 2.1 · 1012 m-1 d-1vs 4.0 · 1011 m-1 d-1) than the AMSR. It was found that metabolism uncoupling, destruction of EPS and endogenous decay simultaneously occurred in the ASSR. Conversely, selective enrichment of bacteria population with low biomass yield was found the main mechanism affecting sludge minimization in the AMSR.


Dietary restrictions in healing among speakers of Iquito, an endangered language of the Peruvian Amazon.
Ethno botanical research was carried out with speakers of Iquitos, a critically endangered Amazonian language of the Zaparoan family. The study focused on the concept of "dieting" (siyan++ni in Iquitos), a practice involving prohibitions considered necessary to the healing process. These restrictions include: 1) foods and activities that can exacerbate illness, 2) environmental influences that conflict with some methods of healing (e.g. steam baths or enemas) and 3) foods and activities forbidden by the spirits of certain powerful medicinal plants. The study tested the following hypotheses: H1--Each restriction will correlate with specific elements in illness explanatory models and H2--Illnesses whose explanatory models have personality elements will show a greater number and variety of restrictions than those based on naturalistic reasoning. The work was carried out in 2009 and 2010 in the Alto Nanay region of Peru. In structured interviews, informants gave explanatory models for illness categories, including etiologies, pathophysiologies, treatments and dietary restrictions necessary for 49 illnesses. Seventeen botanical vouchers for species said to have powerful spirits that require diets were also collected. All restrictions found correspond to some aspect of illness explanatory models. Thirty-five percent match up with specific illness etiologies, 53% correspond to particular pathophysiologies, 18% correspond with overall seriousness of the illness and 18% are only found with particular forms of treatment. Diets based on personalistic reasoning have a significantly higher average number of restrictions than those based on naturalistic reasoning. Dieting plays a central role in healing among Iquitos speakers. Specific prohibitions can be explained in terms of specific aspects of illness etiologies, pathophysiologies and treatments. Although the Amazonian literature contains few studies focusing on dietary proscriptions over a wide range of illnesses, some specific restrictions reported here do correspond with trends seen in other Amazonian societies, particularly those related to sympathetic reasoning and for magical and spiritual uses of plants.


Creatine measurement in serum and urine with an automated enzymatic method.
I describe an automated enzymatic procedure to quantitate creatine in both serum and urine. In this assay, which requires no pretreatment of the sample, creatine kinase (CK; EC 184.108.40.206) and pyruvate kinase (EC 184.108.40.206) are used as auxiliary enzymes and lactate dehydrogenase (EC 184.108.40.206) is used in the indicator reaction. CK is also used as the starting reagent. Data obtained with the present method for creatine measurement in serum were compared with those from the Jaffé method and an enzymatic method: y = 1.13x - 7.58, SE = 4.48, and r = 0.925 (Jaffé); and y = 1.17x + 2.73, SE = 5.06, and r = 0.962 (enzymatic); for creatine measurement in urine: y = 0.63x + 39.74, SE = 296.7 and r = 0.719 (Jaffé). The present method provides improved precision: the total CVs for serum, determined by the present and comparative methods, respectively, were 3.5-8.9%, 8.2-43.0%, and 5.3-16%; for urine, the CVs were 3.3-5.1% and 9.6-21.2% for the present and comparative method, respectively. I established the normal reference interval as 13-74 and 13-89 mumol/L for creatine in serum, and as 175-700 and 150-1200 mumol/24 h for creatine in urine for men and women, respectively.


Determining Cell-surface Expression and Endocytic Rate of Proteins in Primary Astrocyte Cultures Using Biotinylation.
Cell-surface proteins mediate a wide array of functions. In many cases, their activity is regulated by endocytic processes that modulate their levels at the plasma membrane. Here, we present detailed protocols for 2 methods that facilitate the study of such processes, both of which are based on the principle of the biotinylation of cell-surface proteins. The first is designed to allow for the semi-quantitative determination of the relative levels of a particular protein at the cell-surface. In it, the lysine residues of the plasma membrane proteins of cells are first labeled with a biotin moiety. Once the cells are lysed, these proteins may then be specifically precipitated via the use of agarose-immobilized streptavidin by exploiting the natural affinity of the latter for biotin. The proteins isolated in such a manner may then be analyzed via a standard western blotting approach. The second method provides a means of determining the endocytic rate of a particular cell-surface target over a period of time. Cell-surface proteins are first modified with a biotin derivative containing a cleavable disulfide bond. The cells are then shifted back to normal culture conditions, which causes the endocytic uptake of a proportion of biotinylated proteins. Next, the disulfide bonds of non-internalized biotin groups are reduced using the membrane-impermeable reducing agent glutathione. Via this approach, endocytosed proteins may thus be isolated and quantified with a high degree of specificity.


Risk of disability among adult leprosy cases and determinants of delay in diagnosis in five states of India: A case-control study.
A high proportion of grade 2 disability (visible deformity) is indicative of delay in detection of leprosy and leprosy is one of the major causes of preventable disability. We conducted this study to determine the risk factors associated with disability (G2D and G1D) among adult new leprosy cases and to measure their strength of association. A multi-centric case-control study was undertaken in five states of India i.e. Andhra Pradesh, Delhi, Gujarat, Maharashtra and West Bengal). Among new adult patients, cases were defined as those with disability (G2D and G1D) at the time of diagnosis and controls were defined as those without any disability (G0D). Delays were quantified based on patient recall across a timeline. Patient delay defined as the time period between first noticed symptom by the patient and the first visit to any health care provider (HCP); HCP delay defined as the time period between patient's first visit to any HCP and the confirmation of diagnosis of leprosy; and total delay defined as the sum of both patient and HCP delays. A total of 1400 new leprosy patients (700 G2D/G1D and 700 G0D) across five states were interviewed. Among G2D/G1D, the median patient delay was 8 months compared with 4 months among G0D. The median HCP delay was 2 months for G2D/G1D and 1 month for G0D. The median total delay was 14 months for G2D/G1D and 6.2 months for G0D; observed median difference between groups was statistically significant (p<0.001). When patient delay was more than 3 months, odds of G2D/G1D at diagnosis were 1.6 times higher compared to when patient delay was less than 3 months. When the HCP delay was more than one month, the odds of G2D/G1D were 1.4 times higher compared to when the HCP delay was less than one month. When the patient had multi-bacillary type leprosy the odds of G2D/G1D at the time of diagnosis was nine times higher compared to pauci-bacillary type leprosy. Patient delay is the major reason for risk of disability (G2D/G1D) among adult leprosy patients. A patient delay of more than 3 months from the notice of first symptom is a significant indicator for the disabilities among adult leprosy patients. Early case detection campaigns like active surveys in endemic spots should be done periodically as this can reduce delays and promote early diagnosis. Additionally, the program should lay greater emphasis on raising community awareness regarding the disease. Also, health care provider delay of more than 1 month have been significant risk factors for disability among adult leprosy cases. Hence, periodical capacitation of all HCPs including private practitioners would significantly contribute to reduce diagnostic delay and promote timely referral and early detection.


Prenatal diagnosis of cloacal anomaly.
The authors present a case of prenatal diagnosis of cloacal anomaly, characterized by the presence of oligohydramnios and cystic pelvic mass with changing features during observation. Postnatal study confirmed the presence of a recto-cloacal fistula, with a high confluence of the urinary, genital and intestinal systems. Both parents had a chromosome 9 inversion (p11q13), but the child was chromosomally normal.


Study of 700 Referrals to a Lymphedema Program.
Background: Lymphedema results from inadequate lymphatic function due to failure of lymphatic development or injury to a functioning lymphatic system. Patients suffer enlargement of the affected area, psychosocial morbidity, infection, and functional disability. The purpose of this study was to characterize the disease in a cohort of patients referred to a specialized center. Methods and Results: Our Lymphedema Program database was reviewed for all referrals between 2009 and 2019. Diagnosis was determined based on history, physical examination, and lymphoscintigraphy. Lymphedema type (primary, secondary, and obesity-induced), location of swelling, morbidity, previous management, accuracy of referral diagnosis, the geographic origin of the patients, and treatment in our center were analyzed. Seven hundred patients were referred with a diagnosis of "lymphedema"; 71% were female and 38% were children. Lymphedema was confirmed in 71% of the cohort: primary (62%), secondary (22%), and obesity-induced (16%). Twenty-nine percent of individuals labeled with "lymphedema" had another condition. One-half of patients had not received treatment, and 36% resided outside of our local referral area. One-third of subjects with lymphedema had an infection and 30% had >1 visit to the center. Patients with confirmed lymphedema were managed with compression stockings (100%), pneumatic compression (69%), and/or an excisional procedure (6%). Conclusions: Patients with lymphedema typically are adequately managed with conservative compression therapies and rarely require excisional operations. Diagnostic confusion is common and individuals with possible lymphedema are best managed by physicians focused on the disease.


Improved Open-Circuit Voltage and Repeatability of Perovskite Cells Based on Double-Layer Lead Halide Precursors Fabricated by a Vapor-Assisted Method.
Highly repeatable fabrication of compact perovskite films is crucial for large-area perovskite cells (PSCs) in commercial applications. In this work, a vapor-assisted method with the combination of spin-coating and thermal evaporation is employed to fabricate the double-layer PbI2/PbIxBr(2-x) precursor. It is found that surface morphologies of perovskite films could be tailored through tuning the spin-coating speed (the first precursor layer) and chemical compositions (the second precursor layer). The continuous pinhole-free perovskite films are successfully fabricated by double-layer PbI2/PbBr2 precursors. The open-circuit voltages of all the corresponding cells exceed 1.00 V, showing an average value of 1.02 V. The high mean voltage and small variation reveals high repeatability of this method. This work provides a potential method to achieve large-area and high-efficiency PSCs.


Cardiomyocyte mitochondria as targets of humoral factors released by remote ischemic preconditioning.
Remote ischemic preconditioning (RIPC) reduces myocardial infarct size, and protection can be transferred with plasma to other individuals, even across species. Mitochondria are the end-effectors of cardioprotection by local ischemic conditioning maneuvers. We have now analyzed mitochondrial function in response to RIPC. Plasma from pigs undergoing placebo or RIPC (infarct size reduction by 67% in RIPC pigs compared to placebo) was transferred to isolated perfused rat hearts subjected to 30 min global ischemia followed by 120 min reperfusion for infarct size measurement. Additional experiments were terminated at 10 min reperfusion to isolate mitochondria for functional measurements. Effects of RIPC pig plasma were compared to local ischemic preconditioning (IPC) or to infusion of tumor necrosis factor α (TNF-α). Ischemia/reperfusion (I/R) induced an infarct of 41 ±2% of total ventricular mass. Placebo pig plasma did not affect infarct size (38 ±1, p = 0.13). The RIPC pig plasma reduced infarct size (27 ±2, p < 0.001), as did IPC (20 ±1, p < 0.001) and TNF-α (28 ±2, p < 0.001). Associated with cardioprotection, reductions of mitochondrial adenosine diphosphate (ADP)-stimulated respiration, adenosine triphosphate (ATP) production and calcium retention capacity (CRC) by I/R and placebo pig plasma were prevented by RIPC pig plasma, as they were by IPC and TNF-α. Mitochondrial reactive oxygen species production (nmol H2O2/100 µg protein) induced by I/R (272 ±34) was comparable in response to placebo pig plasma (234 ±28, p = 0.37) and was reduced by RIPC pig plasma (83 ±15, p < 0.001) as well as by IPC (78 ±21, p < 0.001) and TNF-α (125 ±42, p = 0.002). In rat myocardium, mitochondria are an intracellular target of protection induced by humoral factors retrieved from pigs undergoing RIPC.


Classification of EEG Single Trial Microstates Using Local Global Graphs and Discrete Hidden Markov Models.
We present a novel synergistic methodology for the spatio-temporal analysis of single Electroencephalogram (EEG) trials. This new methodology is based on the novel synergy of Local Global Graph (LG graph) to characterize define the structural features of the EEG topography as a global descriptor for robust comparison of dominant topographies (microstates) and Hidden Markov Models (HMM) to model the topographic sequence in a unique way. In particular, the LG graph descriptor defines similarity and distance measures that can be successfully used for the difficult comparison of the extracted LG graphs in the presence of noise. In addition, hidden states represent periods of stationary distribution of topographies that constitute the equivalent of the microstates in the model. The transitions between the different microstates and the formed syntactic patterns can reveal differences in the processing of the input stimulus between different pathologies. We train the HMM model to learn the transitions between the different microstates and express the syntactic patterns that appear in the single trials in a compact and efficient way. We applied this methodology in single trials consisting of normal subjects and patients with Progressive Mild Cognitive Impairment (PMCI) to discriminate these two groups. The classification results show that this approach is capable to efficiently discriminate between control and Progressive MCI single trials. Results indicate that HMMs provide physiologically meaningful results that can be used in the syntactic analysis of Event Related Potentials.


In vitro protein digestibility and biochemical characteristics of soaked, boiled and fermented soybeans.
Protein digestibility of soybean obtained from the main manufacturing steps for natto, such as soaking (soaked soybeans 'S'), boiling (boiled soybeans 'B'), and fermentation (fermented soybeans 'F'), was examined in this study. Biochemical indices for the processed soybeans from each manufacturing step and those digested fractions by simulated in vitro gastrointestinal digestion were also evaluated. The result showed a significant (P < 0.05) increase in the protein digestibility of B (48.71 ± 0.04%) and F (50.21 ± 0.45%) compared to that of S (20.58 ± 0.25%), accompanying the accumulation of small protein sub-fractions and essential amino acids. Besides, antioxidant activity indices of all digested fractions increased around two to fourfold at the end of the simulated digestion. F showed a consistently increasing trend when the digestion stage progressed and maximum values overall at the final digestion stage. Soybeans from fermentation step showed higher protein digestibility and indispensable amino acids as well as potential bioactivities than those from boiling and soaking step. The results demonstrated that manufacturing steps improved nutritional values of soybean protein, such as bioavailability of amino acids and certain bioactivities.


[Neuropsychiatry in the Islamic world of the Middle Ages].
The distinction between neurology and psychiatry, which represents a prevailing tendency in contemporary medicine, did not exist in the medieval Moslim world. Moslim doctors, linking their research to the Hippocratic and Galenic heritage, thought of the brain as the origin of psychic and neurological diseases. The article analyzes the history of neuropsychiatry in the Moslim medioeval world and its fundamental contribution in a dark age for the western world, through texts written by famous doctors and scientists. Special attention is devoted to pharmacology and therapeutics: many simple and composed drugs were used to cure mental diseases, together with medical rules for a correct way of life.


Effect of maxillary protraction with alternating rapid palatal expansion and constriction vs expansion alone in maxillary retrusive patients: a single-center, randomized controlled trial.
The objective of this randomized controlled trial was to investigate the effects of facemask protraction combined with alternating rapid palatal expansion and constriction (RPE/C) vs rapid palatal expansion (RPE) alone in the early treatment of maxillary retrusive patients. Patients with a midface deficiency were recruited and randomly allocated into either the control group (RPE) or the intervention group (RPE/C). Eligibility criteria included the following: age 7 to 13 years old, Class III malocclusion, anterior crossbite, ANB less than 0°, Wits appraisal less than -2 mm, A-Np less than 0 mm, and no cleft of lip or palate. The primary outcome was the degree of maxillary forward movement after treatment. The secondary outcomes were the changes of the other cephalometric variables after treatment and the treatment time. Simple randomization was carried out using a random number table at the beginning of the study. Envelopes containing the grouping information were used to ensure allocation concealment from the researchers. Blinding was applicable for cephalometric analysis only. Hyrax palatal expanders and facemask maxillary protraction were used in all patients. Patients in the RPE group were treated with rapid palatal expansion for 1 week. Patients in the RPE/C group were treated with RPE/C for 7 weeks. The expansion or constriction rate was 1 mm per day. Cephalometric analysis with traditional cephalometric measurements and an x-y coordinate system were used to compare the pretreatment and posttreatment cephalometric radiographs. Independent t tests were used to compare the data between the 2 groups. A total of 44 patients were randomized to either the RPE group or the RPE/C group in a 1:1 ratio. One subject in the RPE group was lost to follow-up during the treatment. Per-protocol analysis was used. All the other 43 patients reached the treatment completion criteria and were analyzed (RPE group: n = 21; RPE/C group: n = 22). The average protraction time was 10.84 months in the RPE group, which was significantly longer than that in the RPE/C group (9.06 months) (effect size [ES], 1.78 [95% CI, 0.15, 3.42; P = 0.033]). Maxillary forward movement increased by 3.04 mm in the RPE/C group, which was significantly greater than that in the RPE group (2.11 mm) (ES, -0.93 [95% CI, -1.65, -0.20; P = 0.013]). The counterclockwise rotation of the palatal plane was 1.73° in the RPE/C group, which was significantly greater than that in the RPE group (0.83°) (ES, 0.90 [95% CI, 0.08, 1.73; P = 0.033]). The degree of mandibular downward and backward rotation was significantly smaller in the RPE/C group (P <0.05). No serious harm was observed during treatment and research. Facemask maxillary protraction with RPE/C might positively affect the forward movement of the maxilla compared with facemask protraction with RPE alone in the early treatment of maxillary retrusive patients. Although the differences between the groups were statistically significant for forward movement of the maxilla and rotation of the palatal and mandibular planes, these may not be clinically relevant, since the differences were less than 1 mm and 1°, respectively. This trial was not registered. The protocol was not published before trial commencement. This research was supported by Peking University Research Fund. No conflict of interest is declared.


Role of Brain-Gut-Microbiota Axis in Depression: Emerging Therapeutic Avenues.
The human gut microbiota plays a significant role in the pathophysiology of central nervous system-related diseases. Recent studies suggest correlations between the altered gut microbiota and major depressive disorder (MDD). It is proposed that normalization of the gut microbiota alleviates MDD. The imbalance of brain-gut-microbiota axis also results in dysregulation of the hypothalamicpituitary- adrenal (HPA) axis. This imbalance has a crucial role in the pathogenesis of depression. Treatment strategies with certain antibiotics lead to the depletion of useful microbes and thereby induce depression like effects in subjects. Microbiota is also involved in the synthesis of various neurotransmitters (NTs) like 5-hydroxy tryptamine (5-HT; serotonin), norepinephrine (NE) and dopamine (DA). In addition to NTs, the gut microbiota also has an influence on brain derived neurotrophic factor (BDNF) levels. Recent research findings have exhibited that transfer of stress prone microbiota in mice is also responsible for depression and anxiety-like behaviour in animals. The use of probiotics, prebiotics, synbiotics and proper diet have shown beneficial effects in the regulation of depression pathogenesis. Moreover, transplantation of fecal microbiota from depressed individuals to normal subjects also induces depression-like symptoms. With the precedence of limited therapeutic benefits from monoamine targeting drugs, the regulation of brain-gut microbiota is emerging as a new treatment modality for MDDs. In this review, we elaborate on the significance of brain-gut-microbiota axis in the progression of MDD, particularly focusing on the modulation of the gut microbiota as a mode of treating MDD.


Multiple hematopoietic growth factors signal through tyrosine phosphorylation.
The role of tyrosine phosphorylation in the signal transduction of four hematopoietic colony-stimulating factors (IL-3, IL-4, G-CSF, and GM-CSF) in myeloid cells was investigated. In DA-3 cells, both IL-3 and GM-CSF stimulated, within 10 min, the tyrosine phosphorylation of similar proteins with molecular masses of 70, 56, 51, 42, and 38 kD, as well as two different 140-kD proteins, one being the IL-3 receptor. Both of these growth factors were able to increase the transcription, within 1 hr, of two IL-3-inducible genes--c-myc and the gamma chain of the T-cell receptor. In NFS-60 cells, tyrosine phosphorylation on a common 56-kD protein occurred within 10 min in response to either G-CSF or IL-3. In addition, IL-3 stimulation increased the phosphorylation of the 140-kD IL-3 receptor. Both growth factors were able to increase transcription of the c-myc gene within 1 hr. Finally, in NFS-107 cells, IL-3 and IL-4 stimulated the tyrosine phosphorylation, within 10 min, of two different 140-kD proteins, one of which was the IL-3 receptor. Both growth factors were able, within 1 hr, to increase the transcription of the c-myc and gamma chain of the T-cell receptor genes.


Plant structural and storage glucans trigger distinct transcriptional responses that modulate the motility of Xanthomonas pathogens.
Some phytopathogens are outfitted with a broad and diverse repertoire of enzymatic systems that enable the breakdown and utilization of host polysaccharides as a source of carbon, energy, and stimuli. However, the functional assignment of these enzymatic systems and the influence of their products on modulating pathogen behavior during host colonization are yet poorly comprehended. In this study, we performed RNA-seq analyses to provide a comprehensive, genome-wide view of the transcriptional response of the model phytopathogen Xanthomonas citri pv. citri 306 (known as X. citri 306) to cellobiose, a component of structural β-1,4-glucans (majorly cellulose), and storage α-glucans, seeking to better understand how they are assimilated and the impacts of their sensing on bacterial behavior and physiology. Structural β-1,4-glucans and storage α-glucans (starch) are spatially discretized in the plant cell, therefore representing spatiotemporal references for the bacterium during host colonization. Combining transcriptional and genome mining analyses with gene knockout and cell motility assays, we show that X. citri 306 harbors molecular systems for the breakdown and assimilation of these carbohydrates, revealing that cellobiose upregulates genes related to flagellum assembly and type IV pili, inducing a higher motility state. In contrast, starch suppresses genes related to chemotaxis, flagellum assembly, and biofilm dispersion, decreasing motility. Taken together, these results unravel that, besides using structural β-glucans and storage α-glucans as sources of carbon and energy, Xanthomonas bacteria also sense them, adapting their metabolism and controlling transitions between higher and lower motility states for successful host colonization. IMPORTANCE Pathogenic Xanthomonas bacteria can affect a variety of economically relevant crops causing losses in productivity, limiting commercialization and requiring phytosanitary measures. These plant pathogens exhibit high level of host and tissue specificity through multiple molecular strategies including several secretion systems, effector proteins, and a broad repertoire of carbohydrate-active enzymes (CAZymes). Many of these CAZymes act on the plant cell wall and storage carbohydrates, such as cellulose and starch, releasing products used as nutrients and modulators of transcriptional responses to support host colonization by mechanisms yet poorly understood. Here, we reveal that structural and storage β-glucans from the plant cell function as spatial markers, providing distinct chemical stimuli that modulate the transition between higher and lower motility states in Xanthomonas citri, a key virulence trait for many bacterial pathogens.


Impact of the Pattern of Atrial Fibrillation on Stroke Risk and Mortality.
Thromboembolism is the most serious complication of AF, and oral anticoagulation is the mainstay therapy. Current guidelines place all AF types together in terms of anticoagulation with the major determinants being associated comorbidities translated into risk marker. Among patients in large clinical trials, those with non-paroxysmal AF appear to be at higher risk of stroke than those with paroxysmal AF. Higher complexity of the AF pattern is also associated with higher risk of mortality. Moreover, continuous monitoring of AF through cardiac implantable devices provided us with the concept of 'AF burden'. Usually, the larger the AF burden, the higher the risk of stroke; however, the relationship is not well characterised with respect to the threshold value above which the risk increases. The picture is more complex than it appears: AF and underlying disorders must act synergically respecting the magnitude of its own characteristics, which are the amount of time a patient stays in AF and the severity of associated comorbidities.


Spontaneous Emergence of Space Stems Ahead of Negative Leaders in Lightning and Long Sparks.
We investigate the emergence of space stems ahead of negative leaders. These are luminous spots that appear ahead of an advancing leader mediating the leader's stepped propagation. We show that space stems start as regions of locally depleted conductivity that form in the streamers of the corona around the leader. An attachment instability enhances the electric field leading to strongly inhomogeneous, bright, and locally warmer regions ahead of the leader that explain the existing observations. Since the attachment instability is only triggered by fields above 10 kV/cm and internal electric fields are lower in positive than in negative streamers, our results explain why, although common in negative leaders, space stems, and stepping are hardly observed if not absent in positive leaders. Further work is required to fully explain the streamer to leader transition, which requires an electric current persisting for timescales longer than the typical attachment time of electrons, around 100 ns.


Polymorphisms in CLEC16A and CIITA at 16p13 are associated with primary adrenal insufficiency.
It is known that different autoimmune diseases often share the same susceptibility genes. In this study we aimed to investigate if loci found associated with common autoimmune diseases in recent genome-wide association studies also could be susceptibility loci for autoimmune Addison's disease (primary adrenal insufficiency). A total of 139 tagging single nucleotide polymorphisms (SNPs) in 11 candidate genes (IL2, IL21, IL2RA, CLEC2D, CD69, ERBB3, PTPN11, SH2B3, CLEC16A, CIITA, and PTPN2) were genotyped in a case/control study design consisting of Norwegian Addison's disease patients (n = 332) and Norwegian healthy control individuals (n = 1029). Five SNPs were subsequently selected for analysis in a United Kingdom sample set consisting of Addison's disease patients (n = 210) and controls (n = 191). Polymorphisms in CLEC16A and CIITA remained significantly associated with Addison's disease in the Norwegian sample set at the 0.05 level, even after correction for multiple testing. CLEC16A and CIITA are both located at 16p13, but linkage disequilibrium patterns and logistical regression analyses suggest that SNPs in these two genes are independently associated with Addison's disease. We were not able to confirm these associations in the United Kingdom material, however, this may well be due to the limited sample size and lack of statistical power. Two alleles at 16p13 are independently associated with the risk of Addison's disease in the Norwegian population, suggesting this chromosomal region to harbor common autoimmunity gene(s), CLEC16A and CIITA being possible independent candidates.


Promising approaches to circumvent the blood-brain barrier: progress, pitfalls and clinical prospects in brain cancer.
Brain drug delivery is a major challenge for therapy of central nervous system (CNS) diseases. Biochemical modifications of drugs or drug nanocarriers, methods of local delivery, and blood-brain barrier (BBB) disruption with focused ultrasound and microbubbles are promising approaches which enhance transport or bypass the BBB. These approaches are discussed in the context of brain cancer as an example in CNS drug development. Targeting to receptors enabling transport across the BBB offers noninvasive delivery of small molecule and biological cancer therapeutics. Local delivery methods enable high dose delivery while avoiding systemic exposure. BBB disruption with focused ultrasound and microbubbles offers local and noninvasive treatment. Clinical trials show the prospects of these technologies and point to challenges for the future.


Assessing the visual vertical: how many trials are required?
The visual vertical (VV) consists of repeated adjustments of a luminous rod to the earth vertical. How many trials are required to reach consistency in this measure? This question has never been addressed despite the widespread clinical use of the measurement in stroke rehabilitation. VV perception was assessed (10 trials) in 117 patients undergoing rehabilitation after a first hemisphere stroke. The intraclass correlation coefficient (ICC) and standard error of measurement (SEM) were calculated for each patient category: with contralesional VV bias (n = 48), ipsilesional VV bias (n = 17) and normal VV (n = 52). For patients with VV biases, 6 trials were required to reach high inter-trial reliability (contralesional: ICC = 0.9, SEM = 1.36°; ipsilesional: ICC = 0.896, SEM = 0.96°). For patients with normal VV, a minimum of 10 trials was required (ICC = .728, SEM = 1.13°). A set of 6 trials correctly classified 96 % of patients. In the literature, 10 is the most frequently used number of trials used to assess VV orientation. Our study shows that 10 trials are required to adequately measure VV orientation in non-selected subacute stroke patients. For complex protocols imposing a decrease in the number of trials in each condition, 6 trials are needed to identify VV biases in most patients.


Blast wave energy diagnostic.
The distance radiation waves that supersonically propagate in optically thick, diffusive media are energy sensitive. A blast wave can form in a material when the initially diffusive, supersonic radiation wave becomes transonic. Under specific conditions, the blast wave is visible with radiography as a density perturbation. [Peterson et al., Phys. Plasmas 13, 056901 (2006)] showed that the time-integrated drive energy can be measured using blast wave positions with uncertainties less than 10% at the Z Facility. In some cases, direct measurements of energy loss through diagnostic holes are not possible with bolometric and x-ray radiometric diagnostics. Thus, radiography of high compression blast waves can serve as a complementary technique that provides time-integrated energy loss through apertures. In this paper, we use blast waves to characterize the energy emerging through a 2.4 mm aperture and show experimental results in comparison to simulations.


Single-cell transcriptome conservation in cryopreserved cells and tissues.
A variety of single-cell RNA preparation procedures have been described. So far, protocols require fresh material, which hinders complex study designs. We describe a sample preservation method that maintains transcripts in viable single cells, allowing one to disconnect time and place of sampling from subsequent processing steps. We sequence single-cell transcriptomes from >1000 fresh and cryopreserved cells using 3'-end and full-length RNA preparation methods. Our results confirm that the conservation process did not alter transcriptional profiles. This substantially broadens the scope of applications in single-cell transcriptomics and could lead to a paradigm shift in future study designs.


Creatinase: Using Increased Entropy to Improve the Activity and Thermostability.
Improving protein thermostability in mutagenesis-based enzyme engineering was often achieved by enhancing interresidue interactions via mutation to increase the enthalpy penalty of unfolding. However, this approach may trade off the functional activity due to the loss of structural flexibility of the biomolecule. Here, by performing X-ray crystallography, enzymatic kinetic experiments, neutron scattering, and thermodynamical measurements, we compared the structures, catalytic behaviors, dynamics, and thermostability between a wild-type creatinase and its four-point mutant. We found that the mutant is an entropy-driven thermostable protein with higher structural flexibility, i.e., higher conformational entropy, in the folded state compared to the wild type. The increased conformational entropy of the mutant in the folded state can reduce the entropy gain during unfolding and thus renders it greater thermostability. Moreover, the increased structural flexibility, particularly around the catalytic site, can broaden the mutant's working temperature range and considerably improve its activity at ambient conditions, which is crucial for its application in diagnosing kidney diseases. Complementary all-atom molecular dynamics simulations indicated that the four mutations replaced several of the strong interresidue interactions (electrostatic interactions and hydrogen bonds) with weak hydrophobic interactions. These substitutions not only release the structural flexibility to promote the thermostability and enzymatic activity of the protein but they also preserve the protein structure from collapsing. Our findings may pave a route for the entropy-driven strategy to design proteins with high thermostability and activity.


Venlafaxine in the treatment of children and adolescents with attention-deficit/hyperactivity disorder.
The objectives of this pilot study were to explore the changes in symptom severity, tolerability, and the pharmacodynamics of venlafaxine treatment in youths with attention-deficit/hyperactivity disorder (ADHD). This was a 2-week, open-label, outpatient trial of venlafaxine in children and adolescents, ages 5-17 years, with ADHD. Three dosing strata, 0.5, 1.0, and 2.0 mg/kg per day, were examined. ADHD symptom severity and improvement assessments included the ADHD Rating Scale (ARS-IV) and the Clinical Global Impressions Scale (CGI). During this study, venlafaxine, O-desmethylvenlafaxine (ODV), norepinephrine, and serotonin concentrations were obtained. Thirty-eight participants (33 males) were treated in this trial. Overall, parent-completed and teacher-completed ARS-IV total scores showed a statistically significant positive change at the end of the study when compared to baseline (p < 0.05). Significant increases in plasma venlafaxine concentrations were observed at day 15 when compared to day 8 (p = 0.04). In addition, plasma norepinephrine and serotonin concentrations were found to be significantly decreased from baseline at end of study (p < 0.05). Four patients ended participation in the study prematurely: lost to follow up (n = 2), withdrawal of consent (n = 1), and worsening of ADHD symptoms after 8 days of treatment (n = 1). There were no discontinuations due to other adverse events. Venlafaxine appeared to offer some benefit and appears to be relatively safe for the short-term treatment of ADHD in this open-label trial. The pharmacodynamics of venlafaxine in youths are consistent with serotonergic and neuradrenergic modulation.


Sorptive sample preparation -- a review.
Most sample-enrichment procedures currently available rely on adsorption of the analytes of interest by a suitable adsorbent material. Although good performance can be obtained for many practical problems, in some cases the applicability of adsorptive sample preparation falls short, particularly for the enrichment of polar and/or high-molecular-weight compounds, especially in combination with thermal desorption. Because of the very strong retention of adsorbent materials, undesired effects such as incomplete desorption and artifact formation are observed. Polar solutes are easily adsorbed but readily undergo surface-catalyzed reactions and on desorption yield compounds different than those originally sampled. High-molecular-weight compounds cannot be desorbed because of extremely strong interactions with the adsorbent and their low volatility. To overcome some of these problems sample-preparation techniques based on polydimethylsiloxane sorption have been developed over the past 15 years. In contrast with adsorptive trapping, sorption is based on dissolution of the analytes in a liquid polymeric material. This is a much more inert means of solute retention which overcomes some of the limitations encountered when working with adsorbents. In this contribution, the basic principles of sorption, the different instrumentation used, and applications of the technique will be reviewed. The review covers the sorptive sample-preparation techniques, open-tubular trapping (OTT), solid-phase microextraction (SPME), gum-phase extraction (GPE), equilibrium gum-phase extraction (EGPE), and stir-bar-sorptive extraction (SBSE). Because of the nature of sorptive sample-preparation techniques, which perform particularly well in combination with thermal desorption, this review focuses strongly on gas chromatography as the means of chemical analysis.


Acute beta-blockade changes the extracellular distribution of thyroid hormones.
The acute (within hours) changes in the concentrations of T4, T3, reverse-T3 (rT3) and T3 resin uptake test (T3RU) were studied in 31 hyperthyroid patients for 4 h after po treatment with either acebutolol, oxprenolol, pindolol or timolol. In 21 of the patients, the changes were compared to changes in the serum concentrations of alpha 2-macroglobulin (a macromolecule) and two middle-sized molecules; thyroid hormone-binding globulin (TBG) and albumin in order to calculate the changes in extracellular distribution of the thyroid hormones and to distinguish between changes due to a changed metabolism and changes due to a changed distribution of the thyroid hormones. Acebutolol, oxprenolol and timolol caused a decrease in serum T3 after 1/2 h, and acebutolol and oxprenolol also a decrease in rT3 after 1/2 - 1 h, the changes reversed within 2 h. A concomitant decrease in serum albumin and TBG suggests a change in the extracellular distribution of middle-sized molecules to which thyroid hormones are attached, as an explanation of the acute decrease (1 h) of the thyroid hormones. The small and insignificant change in alpha 2-macroglobulin indicates that the changes are mainly extravascular, but the difference of alpha 2-macroglobulin changes between the drugs (acebutolol/timolol vs pindolol/oxprenolol) could depend on the intrinsic sympathomimetic activity of the drugs.


Increased postsynaptic Ca2+ reduces mini frequency at the Drosophila larval NMJ.
Repetitive stimulation of the Drosophila larval NMJ can produce a reduction in the frequency of miniature excitatory postsynaptic currents. By buffering postsynaptic Ca2+ , it was shown that the decrease in "mini" frequency was due to an increase in postsynaptic Ca2+ .


Fatigue due to mild heart failure: effects of Robuvit® in a concept, pilot registry study.
The aim of this supplement registry study was the evaluation of possible benefits of Robuvit® (oak wood extract) as a standardized supplement (in an 8-week registry) in stable, mild, heart failure patients. All subjects received the standard management (SM) for this condition. Otherwise healthy subjects with mild, initial symptoms (mild shortness of breath and/or angina) and slight limitation during their normal daily activity were included. This corresponds to the New York Heart Association (NYHA) Functional Classification class II. Forty subjects were included in the study. The two groups completing 8 weeks were comparable at baseline with 20 subjects managed with SM and 20 subjects supplemented with Robuvit® in addition to SM. Tolerability and compliance were optimal (with more than 95% of the capsules correctly used). The age and symptoms of the supplemented patients and the controls were comparable at baseline. There were no dropouts. At 8 weeks, systolic-diastolic pressure, heart rate, respiratory rate were minimally (non-significantly) lowered with the supplement without differences in controls. Ultrasound-derived ejection fraction was significantly increased in the supplement group (P<0.05) while there were minimal, non-significant differences in controls. Walking distance on treadmill was also significantly increased in the supplement group (P<0.05) and significantly less in controls. The microcirculation (laser Doppler parameters and transcutaneous PO2, PCO2) improved significantly in the Robuvit® group (P<0.05) in comparison with the non-supplemented controls. Oxidative stress was significantly decreased (P<0.05) with the supplement while there were minimal, non-significant changes in controls. In conclusion in this pilot, supplement registry Robuvit® seems to help and improve patients with mild heart failure and should be considered for larger studies.


Effects of Neuromuscular Training on the Rear-foot Angle Kinematics in Elite Women Field Hockey Players with Chronic Ankle Instability.
The aims of this study were to investigate the ankle position, the changes and persistence of ankle kinematics after neuromuscular training in athletes with chronic ankle instability (CAI). A total of 21 national women's field hockey players participated (CAI = 12, control = 9). Ankle position at heel strike (HS), midstance (MS), and toe touch (TT) in the frontal plane during walking, running and landing were measured using 3D motion analysis. A 6-week neuromuscular training program was undertaken by the CAI group. Measurements of kinematic data for both groups were measured at baseline and the changes in kinematic data for CAI group were measured at 6 and 24 weeks. The kinematic data at HS during walking and running demonstrated that the magnitude of the eversion in the CAI group (-5.00° and -4.21°) was less than in the control group (-13.45°and -9.62°). The kinematic data at MS also exhibited less ankle eversion in the CAI group (-9.36° and -8.18°) than in the control group (-18.52° and -15.88°). Ankle positions at TT during landing were comparable between groups. Following the 6-week training, the CAI participants demonstrated a less everted ankle at HS during walking and running (-1.77° and -1.76°) compared to the previous positions. They also showed less ankle eversion at MS (-5.14° and -4.19°). Ankle orientation at TT changed significantly to an inverted ankle position (from -0.26° to 4.11°). The ankle kinematics were restored back to the previous positions at 24 weeks except for landing. It appeared that athletes with unstable ankle had a relatively inverted ankle position, and that 6-week neuromuscular training had an immediate effect on changing ankle orientation toward a less everted direction. The changed ankle kinematics seemed to persist during landing but not during walking and running.


Genetic architecture of wild soybean (Glycine soja) response to soybean cyst nematode (Heterodera glycines).
The soybean cyst nematode (SCN) is one of the most destructive pathogens of soybean plants worldwide. Host-plant resistance is an environmentally friendly method to mitigate SCN damage. To date, the resistant soybean cultivars harbor limited genetic variation, and some are losing resistance. Thus, a better understanding of the genetic mechanisms of the SCN resistance, as well as developing diverse resistant soybean cultivars, is urgently needed. In this study, a genome-wide association study (GWAS) was conducted using 1032 wild soybean (Glycine soja) accessions with over 42,000 single-nucleotide polymorphisms (SNPs) to understand the genetic architecture of G. soja resistance to SCN race 1. Ten SNPs were significantly associated with the response to race 1. Three SNPs on chromosome 18 were localized within the previously identified quantitative trait loci (QTLs), and two of which were localized within a strong linkage disequilibrium block encompassing a nucleotide-binding (NB)-ARC disease resistance gene (Glyma.18G102600). Genes encoding methyltransferases, the calcium-dependent signaling protein, the leucine-rich repeat kinase family protein, and the NB-ARC disease resistance protein, were identified as promising candidate genes. The identified SNPs and candidate genes can not only shed light on the molecular mechanisms underlying SCN resistance, but also can facilitate soybean improvement employing wild genetic resources.


The developing Drosophila eye - a new model to study centriole reduction.
In the developing Drosophila eye, the centrioles of the differentiating retinal cells are not surrounded by the microtubule-nucleating γ-tubulin, suggesting that they are unable to organize functional microtubule-organizing centers. Consistent with this idea, Cnn and Spd-2, which are involved in γ-tubulin recruitment, and the scaffold protein Plp, which plays a role in the organization of the pericentriolar material, are lost in the third-instar larval stage. However, the centrioles maintain their structural integrity, and both the parent centrioles accumulate Asl and Ana1. Although the loading of Asl points to the acquisition of the motherhood condition, the daughter centrioles fail to recruit Plk4 and do not duplicate. However, it is surprising that the mother centrioles that accumulate Plk4 also never duplicate. This suggests that the loading of Plk4 is not sufficient, in this system, to allow centriole duplication. By halfway through pupal life, the centriole number decreases and structural defects, ranging from being incomplete or lacking B-tubules, are detected. Asl, Ana1 and Sas-4 are still present, suggesting that the centriole integrity does not depend on these proteins.


Preoperative planning for revision total hip arthroplasty.
Similar to total hip arthroplasty (THA), preoperative planning is more important for revision THA and includes a thorough clinical evaluation (ie, patient history, physical examination, and laboratory tests, including aspiration and culture) as well as radiographic assessment (ie, for changes in bone loss and quality, for leg length, and for templating to choose the correct components). Similar to primary THA, preoperative planning for revision THA must include the inherent possibility of failure. Careful planning of the current technology and expertise to perform THA will help minimize potential problems. The essence of preoperative planning in revision THA can be summed up simply: Be prepared.


Family history of cancer as surrogate predictor for immunotherapy with anti-PD1/PD-L1 agents: preliminary report of the FAMI-L1 study.
Tumors related to hereditary susceptibility seem to have an immunosensitive phenotype. We conducted a multicenter retrospective study, to investigate if family history of cancer, multiple neoplasms and early onset of cancer could be related to clinical outcomes of anti-PD-1/PD-L1 therapy. Activity and efficacy data of 211 advanced cancer patients (kidney, non-small-cell lung cancer, melanoma, urothelium, colorectal and HeN), treated at seven Italian centers with anti-PD-1/PD-L1 agents, were analyzed. In this preliminary report at multivariate analyses, positive family history of cancer showed a statistically significant relationship with a better objective response rate (p = 0.0024), disease control rate (p = 0.0161), median time to treatment failure (p = 0.0203) and median overall survival (p = 0.0221). Diagnosis of multiple neoplasms significantly correlates only to a better disease control rate, while interestingly non-early onset of cancer and sex (in favor of female patients) showed significant correlation with a better median overall survival (p = 0.0268 and p = 0.0272, respectively). This pilot study seems to individuate easily available patient's features as possible predictive surrogates of clinical benefit for anti-PD-1/PD-L1 treatments. These preliminary results need to be confirmed with a greater sample size, in prospective trials with immunotherapy.


Crystal Structures and Magnetic Properties of Nickel Chain Compounds PbM2Ni6Te3O18 (M = Mn, Cd).
The synthesis, crystal structures, and magnetic properties of the pentanary oxides PbM2Ni6Te3O18 (M = Mn and Cd) were investigated. These compounds crystallize in a hexagonal structure with space group P63/m, in which the Ni(2+) ions form a zigzag chain along the c axis. From the magnetic susceptibility and specific heat measurements, we found that the PbCd2Ni6Te3O18 behaves as a low-dimensional magnet due to the intrachain antiferromagnetic interaction between Ni(2+) ions. Both compounds show a long-range antiferromagnetic ordering at 25.7 K (M = Cd) and 86.0 K (Mn). The magnetic structure of PbMn2Ni6Te3O18 determined by neutron diffraction measurements is a collinear antiferromagnetic arrangement of Mn(2+) ions in the Mn2O9 dimeric unit and Ni(2+) ions in the zigzag chain.


Spatially modulated thermal convection of viscoelastic fluids.
The thermal convection of modulated viscoelastic flow is examined in this study. The modulation is assumed to be weak enough for a regular perturbation solution to be implemented. In addition to being more accurate, the second-order perturbation results reveal new physical phenomena that could not be predicted by the first-order analysis. Inertia was found to enhance globally the discrepancies between the first- and the second-order perturbation solution. A comparison between the Newtonian and the non-Newtonian solution is carried out and the influences of inertia, modulation amplitude, and wave number are emphasized. The present results show that elasticity has a marked effect on fluid patterns, especially regarding the roll structure and symmetry. The influence of elasticity is greater for larger Rayleigh number and aspect ratio.


Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Goals-of-care and Family/Surrogate Decision-Maker Data.
In order to facilitate comparative research, it is essential for the fields of neurocritical care and rehabilitation to establish common data elements (CDE) for disorders of consciousness (DoC). Our objective was to identify CDEs related to goals-of-care decisions and family/surrogate decision-making for patients with DoC. To achieve this, we formed nine CDE working groups as part of the Neurocritical Care Society's Curing Coma Campaign. Our working group focused on goals-of-care decisions and family/surrogate decision-makers created five subgroups: (1) clinical variables of surrogates, (2) psychological distress of surrogates, (3) decision-making quality, (4) quality of communication, and (5) quality of end-of-life care. Each subgroup searched for existing relevant CDEs in the NIH/CDE catalog and conducted an extensive literature search for additional relevant study instruments to be recommended. We classified each CDE according to the standard definitions of "core," "basic," "exploratory," or "supplemental," as well as their utility for studying the acute or chronic phase of DoC, or both. We identified 32 relevant pre-existing NIH CDEs across all subgroups. A total of 34 new instruments were added across all subgroups. Only one CDE was recommended as disease core, the "mode of death" of the patient from the clinical variables subgroup. Our findings provide valuable CDEs specific to goals-of-care decisions and family/surrogate decision-making for patients with DoC that can be used to standardize studies to generate high-quality and reproducible research in this area.


Relationship between seasonal changes in spermatogenesis in the juvenile ostrich (Stuthio camelus) and the presence of the LH receptor and 3beta-hydroxysteroid dehydrogenase.
The immunohistochemical localization of the LH receptor and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) was studied in the testis of the juvenile ostrich (Stuthio camelus) throughout a 1 year period. Spermatogenic activity of juvenile birds changed throughout the year, as has been reported previously for sexually mature birds. During the active stage of the testicular cycle, from September to January, spermatogenesis progressed up to the stage of formation of spermatozoa, although spermatozoa could not be detected in the epididymis. Leydig cells stained intensely with antibodies against the LH receptor and 3beta-HSD during the quiescent, recrudescent and active phases of the testicular cycle. During the regressive phase, there was a slight decrease in immunostaining for 3beta-HSD in these cells. These results indicate that Leydig cells in the testis of the juvenile ostrich are able to respond to LH and are capable of steroid synthesis. Furthermore, in juvenile (prepubertal) ostriches, spermatogeneic activity can be observed and, as in mature birds, spermatogenesis undergoes seasonal changes.


Iron bioavailability from commercially available iron supplements.
Iron deficiency anaemia (IDA) is a global public health problem. Treatment with the standard of care ferrous iron salts may be poorly tolerated, leading to non-compliance and ineffective correction of IDA. Employing supplements with higher bioavailability might permit lower doses of iron to be used with fewer side effects, thus improving treatment efficacy. Here, we compared the iron bioavailability of ferrous sulphate tablets with alternative commercial iron products, including three liquid-based supplements. Iron bioavailability was measured using Caco-2 cells with ferritin formation as a surrogate marker for iron uptake. Statistical analysis was performed using one-way ANOVA followed by either Dunnett's or Tukey's multiple comparisons tests. Spatone Apple(®) (a naturally iron-rich mineral water with added ascorbate) and Iron Vital F(®) (a synthetic liquid iron supplement) had the highest iron bioavailability. There was no statistical difference between iron uptake from ferrous sulphate tablets, Spatone(®) (naturally iron-rich mineral water alone) and Pregnacare Original(®) (a multimineral/multivitamin tablet). In our in vitro model, naturally iron-rich mineral waters and synthetic liquid iron formulations have equivalent or better bioavailability compared with ferrous iron sulphate tablets. If these results are confirmed in vivo, this would mean that at-risk groups of IDA could be offered a greater choice of more bioavailable and potentially better tolerated iron preparations.


Clinical efficacy of codergocrine mesylate in children with learning difficulties.
A double-blind placebo-controlled study in children showed codergocrine mesylate to be effective in improving cognitive functions and behavioural symptoms associated with learning disorders. Forty randomly grouped children of either sex were given an increasing dosage of codergocrine mesylate and followed up for 12 weeks. A significant improvement was noted in speech (acquisition of new words, comprehensibility/meaningfulness of speech), sociability, attention/concentration, comprehension and memory. Improvement in behaviour (emotional lability and cooperativeness) was also noted. Problems of assessing cognitive progress in very young children with culturally appropriate methods were encountered.


Dynamics of the alar rim graft.
The purpose of this study was to review the dynamics and frequency of the use of the alar rim graft. The recorded intraoperative information for the purpose of rhinoplasty research was reviewed to investigate the frequency of the use of alar rim grafts. Intraoperative observations were also made while inserting the alar rim graft to identify the changes that occur in the structures that could be influenced by placement of this graft. The data were tabulated in an Excel file and analyzed. Of the 1427 patients who underwent nose reconstruction or rhinoplasty in this study, 565 (39.56 percent) received alar rim grafts. This included 73 primary nose reconstructions, 20 secondary nose reconstructions, two revision nose reconstructions, 304 primary rhinoplasties, 107 secondary rhinoplasties, 43 revision operations following primary rhinoplasties, and seven revision operations following secondary rhinoplasties. However, when 100 more recent consecutive cases were reviewed, 88 percent of primary rhinoplasty patients and 67 percent of secondary rhinoplasty patients received alar rim grafts. The observed dynamic changes after insertion of each graft included (1) correction of the concavity of the ala, (2) caudal advancement of the alar rim, (3) elongation of nostril, and (4) widening of the nostril. The majority of patients who undergo rhinoplasty would benefit from the alar rim graft, and this study demonstrates a steady increase in its use. Placement of an alar rim graft results in elongation of the short nostril, correction of the alar concavity, widening of the nostril, and slight caudal transposition of the alar rim.


Microarray Noninvasive Neuronal Seizure Recordings from Intact Larval Zebrafish.
Zebrafish epilepsy models are emerging tools in experimental epilepsy. Zebrafish larvae, in particular, are advantageous because they can be easily genetically altered and used for developmental and drug studies since agents applied to the bath penetrate the organism easily. Methods for electrophysiological recordings in zebrafish are new and evolving. We present a novel multi-electrode array method to non-invasively record electrical activity from up to 61 locations of an intact larval zebrafish head. This method enables transcranial noninvasive recording of extracellular field potentials (which include multi-unit activity and EEG) to identify epileptic seizures. To record from the brains of zebrafish larvae, the dorsum of the head of an intact larva was secured onto a multi-electrode array. We recorded from individual electrodes for at least three hours and quantified neuronal firing frequency, spike patterns (continuous or bursting), and synchrony of neuronal firing. Following 15 mM potassium chloride- or pentylenetetrazole-infusion into the bath, spike and burst rate increased significantly. Additionally, synchrony of neuronal firing across channels, a hallmark of epileptic seizures, also increased. Notably, the fish survived the experiment. This non-invasive method complements present invasive zebrafish neurophysiological techniques: it affords the advantages of high spatial and temporal resolution, a capacity to measure multiregional activity and neuronal synchrony in seizures, and fish survival for future experiments, such as studies of epileptogenesis and development.


Effect of protein aggregation on murine splenic prostaglandin F2 alpha levels.
Intravenous injection of deaggregated human gamma globulin and deaggregated keyhole limpet hemocyanin into C57Bl/6 mice does not result in an increase in splenic prostaglandin F2 alpha. However, when aggregated human gamma globulin or aggregated keyhole limpet hemocyanin were injected, significant increases in splenic PGF2 alpha were observed. Mice which had been rendered immunologically tolerant to human gamma globulin (HGG) also demonstrated increases in splenic PGF2 alpha and PGE2 5 min after boosting with aggregated HGG with no increases in antibody against HGG. These results imply that the property of protein aggregation will engender increases in splenic prostaglandin levels and that these increases don't appear to affect the tolerant state.