Causes of intrauterine growth restriction.
IUGR is a relatively common problem and a potential cause of significant perinatal morbidity and mortality. There are many possible causes of IUGR, and some cases may involve more than one (Table 1). Although an underlying cause may not always be identifiable, it it important to consider all of these factors because identification of the underlying cause of the IUGR may impact short-term management as well as long-term prognosis. The cornerstone of management for IUGR involves close antenatal surveillance with a well-timed delivery. Antenatal testing in the form of fetal heart rate monitoring, ultrasonographic evaluation, and, on occasion, umbilical blood sampling allows for ongoing surveillance of the growth-retarded fetus. Intrapartum management should include close fetal heart rate monitoring because the ability of the growth-restricted fetus to tolerate labor generally is low and the risk for acidosis is high. A pediatric team should attend the delivery because the risk of meconium aspiration and the frequency of low Apgar scores and metabolic disorders are high. The biochemical mediators reviewed in this article are not likely to be independent causative factors in IUGR; it is more likely they are important mediators of a pathologic process set in motion by other agents or insults. A better understanding of how these mediators contribute to the pathophysiology of IUGR will improve our understanding of this disorder and may allow for therapeutic interventions in the underlying pathophysiologic process.


Dynamics of the HIV outbreak and response in Scott County, IN, USA, 2011-15: a modelling study.
In November, 2014, a cluster of HIV infections was detected among people who inject drugs in Scott County, IN, USA, with 215 HIV infections eventually attributed to the outbreak. This study examines whether earlier implementation of a public health response could have reduced the scale of the outbreak. In this modelling study, we derived weekly case data from the HIV outbreak in Scott County, IN, and on the uptake of HIV testing, treatment, and prevention services from publicly available reports from the US Centers for Disease Control and Prevention (CDC) and researchers from Indiana. Our primary objective was to determine if an earlier response to the outbreak could have had an effect on the number of people infected. We computed upper and lower bounds for cumulative HIV incidence by digitally extracting data from published images from a CDC study using Bio-Rad avidity incidence testing to estimate the recency of each transmission event. We constructed a generalisation of the susceptible-infectious-removed model to capture the transmission dynamics of the HIV outbreak. We computed non-parametric interval estimates of the number of individuals with an undiagnosed HIV infection, the case-finding rate per undiagnosed HIV infection, and model-based bounds for the HIV transmission rate throughout the epidemic. We used these models to assess the potential effect if the same intervention had begun at two key timepoints earlier than the actual date of the initiation of efforts to control the outbreak. The upper bound for undiagnosed HIV infections in Scott County peaked at 126 around Jan 10, 2015, over 2 months before the Governor of Indiana declared a public health emergency on March 26, 2015. Applying the observed case-finding rate scale-up to earlier intervention times suggests that an earlier public health response could have substantially reduced the total number of HIV infections (estimated to have been 183-184 infections by Aug 11, 2015). Initiation of a response on Jan 1, 2013, could have suppressed the number of infections to 56 or fewer, averting at least 127 infections; whereas an intervention on April 1, 2011, could have reduced the number of infections to ten or fewer, averting at least 173 infections. Early and robust surveillance efforts and case finding alone could reduce nascent epidemics. Ensuring access to HIV services and harm-reduction interventions could further reduce the likelihood of outbreaks, and substantially mitigate their severity and scope. US National Institute on Drug Abuse, US National Institutes of Mental Health, US National Institutes of Health Big Data to Knowledge programme, and the US National Institutes of Health.


Outcome and prognostic markers of cirrhotic and non-cirrhotic patients admitted to a hepatology ICU in a tertiary care university hospital.
Patients with decompensated liver cirrhosis are not given priority for ICU admission in the settings of limited place availability. Recently, advances in medical care led to improvement in their survival. Our aim is to study the outcome of patients admitted to our hepatology ICU. We retrieved the data of patients admitted to the Endemic Medicine Department ICU at Kasr Al-Ainy Hospital in the period from November 2014 to May 2018. We included 498 patients who had complete clinical and outcome data in this analysis. The primary outcome was ICU mortality and its predictors. The overall mortality was 48.1% in the liver cirrhosis versus 52.9% in the non-cirrhosis group. The most common presentations of cirrhotic patients were hepatic encephalopathy and hypovolemic shock. The SOFA score and sepsis independently predicted mortality in the overall cohort. The mortality of cirrhotic patients admitted to ICU is not higher than non-cirrhotic patients. SOFA score is a good prognostic indicator in patients with cirrhosis.


ACE2 & TMPRSS2 Expressions in Head & Neck Tissues: A Systematic Review.
To review the data regarding the expression of angiotensin converting enzyme-2 (ACE2) and transmembrane protease serine-2 (TMPRSS2) in head and neck tissue. Scopus, Cochrane Library, Medrxiv, Google Scholar and PubMED/MEDLINE were searched by four independent investigators for studies investigating ACE2 or TMPRSS2 expressions in head and neck tissues. The following outcomes were considered: sample origin (animal versus human); detection method; anatomical location and cell types. PRISMA checklist and modified population, intervention, comparison, outcome, timing and setting (PICOTS) framework were used to perform the review. Of the 24 identified studies, 17 met our inclusion criteria. Thirteen studies were conducted during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic. ACE2 and TMPRSS2 were expressed in oral, pharyngeal, sinusonasal human mucosa. The following cell types expressed ACE2: basal, apical, goblet, minor salivary, and endothelial cells. TMPRSS2 was found in goblet and apical respiratory cells. ACE2 and TMPRSS2 were found in the olfactory region, especially in sustentacular non-neural and neural stem cells. Animal studies suggested that ACE2 expression may vary regarding age. There was an important heterogeneity between studies in the methods used to detect ACE2 and TMPRSS2, leading to a potential identification bias. The SARS-CoV-2 receptors, ACE2 and TMPRSS2, are both expressed in many head and neck tissues, enabling the viral entry into the host organism.


Novel melatonin-trientine conjugate as potential therapeutic agents for Alzheimer's disease.
Researchers continue to explore drug targets to treat the characteristic pathologies of Alzheimer's disease (AD). Some drugs relieve the pathological processes of AD to some extent, but the failed clinical trials indicate that multifunctional agents seem more likely to achieve the therapy goals for this neurodegenerative disease. Herein, a novel compound named melatonin-trientine (TM) has been covalently synthesized with the natural antioxidant compounds melatonin and the metal ion chelator trientine. After toxicological and pharmacokinetic verification, we elucidated the effects of intraperitoneal administration of TM on AD-like pathology in 6-month-old mice that express both the β-amyloid (Aβ) precursor protein and presenilin-1 (APP/PS1). We found that TM significantly decreased Aβ deposition and neuronal degeneration in the brains of the APP/PS1 double transgenic mice. This result may be due to the upregulation of iron regulatory protein-2 (IRP2), insulin degrading enzyme (IDE), and low density lipoprotein receptor related protein 1 (LRP1), which leads to decreases in APP and Aβ levels. Additionally, TM may promote APP non-amyloidogenic processing by activating the melatonin receptor-2 (MT2)-dependent signaling pathways, but not MT1. In addition, TM plays an important role in blocking γ-secretase, tau hyperphosphorylation, neuroinflammation, oxidative stress, and metal ion dyshomeostasis. Our results suggest that TM may effectively maximize the therapeutic efficacy of targeting multiple mechanisms associated with AD pathology.


Vesicle deposition and subsequent membrane-melittin interactions on different substrates: a QCM-D experiment.
Quartz crystal microbalance with dissipation (QCM-D) technique is one of the most effective methods to monitor the dynamic behaviors of a layer on a solid surface. Moreover, it has been reported recently that it is able to provide a fingerprint for the peptide-membrane interactions. In this work, QCM-D technique combined with computer simulations was employed to investigate the deposition and transformation of vesicles, as well as the subsequent membrane-melittin interactions on different substrates. A range of substrate surfaces, i.e. naked SiO2 without or with Au/polyelectrolyte coating, were produced. The nature of the substrate determined whether the adsorbed vesicles were present as a high-quality supported bilayer or an assembled vesicle matrix, which consequently influenced the membrane-melittin interactions. It was indicated by the related computer simulations that the lipid packing state of the membrane was a key factor to determine the mechanism of membrane-peptide interactions. Furthermore, this work might be a good example of the application of QCM-D for the exploration of membrane-active peptides.


The role of beta-2 agonists in foreign body aspiration.
Foreign body aspiration is a relatively common problem encountered in children during the first 3 years of life. Presentation may include a variety of symptoms and signs that may include wheezing, stridor and cough. Removal of the foreign body via rigid bronchoscopy is the main treatment. Inhaled or nebulized beta-2 agonists are sometimes used in these patients to comfort their breathing and relieve some of their symptoms but can sometimes result in relief or worsening of the obstruction. We hereby report a case of peanut aspiration that was coughed out by the patient directly after treatment with nebulized salbutamol.


Newborn screening for sickle cell disease in Butembo and Beni: a pilot experience in a highland region of the Democratic Republic of Congo.
sickle cell disease is an inherited autosomal recessive hemoglobin disorder resulting in acute and chronic systemic complications. Despite the high burden of sickle cell disease in the Democratic Republic of the Congo, limited data on disease prevalence is available and systematic screening is not offered to newborns. This study aimed to provide neonatal prevalence and associated factors to the phenotypic manifestation of sickle cell disease in an eastern region of the Democratic Republic of the Congo. the study was conducted from 20th April 2021 to 20th January 2022 in the cities of Beni and Butembo, involving live full-term newborns whose parents consented to participate. Blood was taken with heel pricks and analyzed using the point-of-care diagnostic tool HemoTypeSC™. We used Fisher´s exact test to compare frequencies between groups. P-value <0.05 was considered statistically significant. Results: of the 1195 newborns screened, 1122 (93.9%) were tested as having hemoglobin AA, 71 (5.9%) hemoglobin AS, 2 (0.2%) hemoglobin SS and none hemoglobin C. The mother´s ethnicity was significantly associated with the phenotypic expression of sickle cell disease. sickle cell disease prevalence is lower in Butembo and Beni than in other regions of the Democratic Republic of the Congo. However, it remains an alarming public health issue. Systematic newborn screening, parent/patient education and early management programs constitute an urgent need to be addressed by decision-makers.


Rupture of a subclavian artery aneurysm in a heroin addict. Report of a case.
A previously healthy heroin addict died suddenly and unexpectedly of hemothorax due to rupture of a subclavian artery aneurysm. He had been using the neck veins for mainlining. The pathogenesis of the aneurysm is discussed.


Neutrophil-to-Lymphocyte ratio as a prognostic biomarker in extremities undifferentiated pleomorphic sarcoma.
Neutrophil-to-lymphocyte ratio (NLR) in peripheral blood reflects the balance between systemic inflammation and immunity and has been reported as a prognostic biomarker in many neoplastic diseases, but its role in sarcomas has been poorly investigated. In this paper we analyzed the prognostic role of the neutrophil to lymphocyte ratio (NLR) in extremity undifferentiated pleomorphic sarcoma (eUPS). We performed an observational, retrospective study including all eUPS cases treated at the National Institute of Cancer in Mexico City from January 2000 to December 2018. We used a ROC analysis to find the cut-off point where the NLR had the best value in predicting death (area under the curve: 0.73, P = 0.001). When the cut-off point was set at 3.09, the sensitivity of the test was 79% and the specificity was 59%. Demographic and clinical variables using log-rank test were also analyzed. Univariate Cox regression analyses and multivariate proportional hazards regression model were carried out to identify independent prognostic factors for Overall survival (OS), Disease-free survival (DFS), Metastasis free survival (MFS) and their association with the NLR. We included 112 cases, 53.6% were women. Most cases were stage IIIA (33.9%) or IIIB (30.4%) and Grade 3 (91.1%). High NLR correlated with metastatic disease at presentation (p = 0.001), locally advanced stage (p = 0.05), worse OS (HR = 1.33, 95% CI:1.01-1.75 p = 0.041) and higher risk of specific death (HR = 4.89, 95% CI: 1.88-12.72 p = 0.001). Non-use of chemotherapy (HR: 1.33, 95% CI:1.01-1.75 p = 0.041) was also associated with worse OS. The NLR is a simple yet useful prognostic factor in patients with eUPS when using a cut-off value of 3.09. Soft tissue sarcomas lack routine biomarkers that are applied widely, therefore we propose to consider and include the NLR in prospective trials or prognostic nomograms.


Amino acid profiling as a screening and prognostic biomarker in active tuberculosis patients.
Tuberculosis (TB) is one of the world's most deadly chronic infectious diseases; early diagnosis contributes to reducing disease transmission among populations. However, discovering novel diagnostic and prognostic biomarkers is still an important topic in the field of TB. Amino acid is the basic unit of protein composition, and its structure and physicochemical characteristics are more stable. Therefore, it is a potential target for TB diagnosis and the prediction of TB development. In this study, the blood of healthy people (HC), TB patients (TB), cured TB (RxTB), and other non-TB pneumonia patients (PN) were collected to detect the levels of amino acids in whole blood and plasma using ultra-high performance liquid chromatography coupled with mass spectrometry. We detected that the amino acid levels correlated with participants status (TB, HC, RxTB, or PN) and the degree of lung damage. The results showed that phenylalanine had a good effect on the screening of TB (AUC = 0.924). We then built a TB prediction model. The model, which was based on the ratio of plasma amino acid content to whole blood amino acid content, showed good performance for the screening of TB, with 84% (95% CI = 60-97) sensitivity and 97% (95% CI = 83-100) specificity. The result of correlation between the HRCT score and amino acid level indicated that the glutamine content of plasma was significantly inversely associated with disease severity. Additionally, ornithine levels in the plasma of RxTB group reduced and four amino acids of which the ratio in plasma to whole blood showed significantly changed. Taken together, amino acid profiling can be used for TB screening, and a multiparameter profiling model is better. The profiling can also reflect the severity of lung damage. Moreover, the amino acid profile is useful for reflecting the efficacy of TB treatment.


Immunoradiometric assay of active renin versus determination of plasma renin activity in the clinical investigation of hypertension, congestive heart failure, and liver cirrhosis.
We compared the determination of plasma renin activity (PRA) and the direct immunoradiometric measurement of active renin (AR) as ways of assessing the activity of the renin-angiotensin system in normal volunteers and in patients with hypertension, heart failure, or liver failure. The levels of plasma renin substrate, angiotensinogen, and the ratio of PRA to AR concentration did not differ in the normal volunteers and the patients with essential or renovascular hypertension. However, compared to the volunteers, patients with severe heart or liver failure had markedly reduced plasma renin substrate levels, which led to a considerable underestimation of AR concentration when it was measured by PRA.


Effect of pulsatile luteinizing hormone-releasing hormone administration on pituitary-gonadal function in elderly man.
The effect of short-term pulsatile LHRH administration was studied in 8 healthy subjects ranging from 60 to 81 yr to see if the decrease of pituitary gonadal function could be in part due to changes in the discharge of LHRH from the hypothalamus. Gonadotropin and testosterone (T) secretion was evaluated two weeks before and during LHRH (122-160 ng/kg bw every 120 min sc) infusion. In addition, a bolus dosage of LHRH (50 mu iv) was given both at the beginning and at the end of pulsatile LHRH administration in order to test gonadotrophs sensitivity. A significant increase in gonadotropin levels from day 0 to day 4 was found, and was followed by a subsequent decrease from day 7 to day 14. A slight significant increase in T levels was observed during LHRH administration (p less than 0.01). LH pulses were identified in 5 out of 8 subjects on day 0. On day 14, all the exogenous LHRH pulses were followed by significant LH bursts. There was not a significant decrease in the pituitary LH responsiveness to LHRH test from day 0 to day 14. Our study seems to indicate that pituitary - gonadal unit in normal elderly men can be modulated by pulsatile administration of LHRH. A pulse frequency of LHRH which is probably similar to the physiological one, could induce a slight increase in T levels via qualitative changes in LH activity. We can assume that clinical changes in gonadal activity might also be connected to some disturbances in endogenous LHRH pulsar.


Overview of distinct 5-methylcytosine profiles of messenger RNA in human hepatocellular carcinoma and paired adjacent non-tumor tissues.
Post-transcriptional methylation modifications, including 5-methylcytosine (m5C) modification, are closely related to the tumorigenesis of cancers. However, the mRNA profile of m5C modification in hepatocellular carcinoma (HCC) is unknown. Methylated RNA immunoprecipitation sequencing was performed to identify m5C peaks on mRNA of human HCC tissues and adjacent tissues, and differences in m5C between the two groups were analyzed. In addition, we conducted a bioinformatics analysis to predict the function of specific methylated transcripts. We found that there was a noticeable difference in m5C between HCC and paired non-tumor tissues, suggesting that m5C could play a role in the pathogenesis of HCC. In addition, analyses of gene ontology and the Kyoto Encyclopedia of Genes and Genomes showed that the unique distribution pattern of mRNA m5C in HCC was associated with a wide range of cellular functions. Our results revealed different distribution patterns of m5C in HCC and adjacent tissues and provided new insights into a novel function of m5C RNA methylation of mRNA in HCC progression.


Coupling to Pam16 differentially controls the dual role of Pam18 in protein import and respiratory chain formation.
The presequence translocase (TIM23 complex) imports precursor proteins into the mitochondrial inner membrane and matrix. The presequence translocase-associated motor (PAM) provides a driving force for transport into the matrix. The J-protein Pam18 stimulates the ATPase activity of the mitochondrial Hsp70 (mtHsp70). Pam16 recruits Pam18 to the TIM23 complex to ensure protein import. The Pam16-Pam18 module also associates with components of the respiratory chain, but the function of the dual localization of Pam16-Pam18 is largely unknown. Here, we show that disruption of the Pam16-Pam18 heterodimer causes redistribution of Pam18 to the respiratory chain supercomplexes, where it forms a homodimer. Redistribution of Pam18 decreases protein import into mitochondria but stimulates mtHsp70-dependent assembly of respiratory chain complexes. We conclude that coupling to Pam16 differentially controls the dual function of Pam18. It recruits Pam18 to the TIM23 complex to promote protein import but attenuates the Pam18 function in the assembly of respiratory chain complexes.


Exocrine pancreatic function in dogs with denervated pancreas.
There is strong evidence that the vagus nerve plays an important role in exocrine pancreatic secretion. In the present study we examined the effect of total extrinsic denervation of the pancreas on exocrine pancreatic secretion to different stimuli in dogs. In the experiments we used the model of the orthotopic autotransplanted dog pancreas as described by Debas et al. Denervation of the gland did not significantly alter water and bicarbonate response to secretin. The dose-response curve of caerulein showed the denervated pancreas as sensitive as the intact gland. However, autotransplantation of the pancreas caused a significant decrease (p less than 0.05) in protein secretion during intraintestinal L-tryptophan in increasing doses. Furthermore, bicarbonate and protein secretion after food intake was significantly decreased in the denervated pancreas (protein: peak levels 380 mg/15 min and 135 mg/15 min; bicarbonate: 3.2 mEq/15 min and 1.4 mEq/15 min) (p less than 0.02). From our data we conclude that the denervated pancreas is as sensitive as the intact pancreas to stimulation by exogenous secretin and caerulein, whereas denervation of the pancreas causes an important influence in the intestinal phase of pancreatic secretion.


How many sentinel lymph nodes are enough during sentinel lymph node dissection for breast cancer?
: It remains unclear how many sentinel lymph nodes (SLNs) must be removed to accurately predict lymph node status during SLN dissection in breast cancer. The objective of this study was to determine how many SLNs need to be removed for accurate lymph node staging and which patient and tumor characteristics influence this number. : The authors reviewed data for all patients in their prospective database with clinical tumor, lymph node, metastasis (TNM) T1 through T3, N0, M0 breast cancer who underwent lymphatic mapping at their institution during the years 1994 through 2006. There were 777 patients who had at least 1 SLN that was positive for cancer. Simple and multiple quantile regression analyses were used to determine which patient and tumor characteristics were associated with the number of positive SLNs. The baseline number of SLNs that needed to be dissected for detection of 99% of positive SLNs in the total group of patients also was determined. : The mean number of SLNs removed in the 777 lymph node-positive patients was 2.9 (range, 1-13 SLNs). Greater than 99% of positive SLNs were identified in the first 5 lymph nodes removed. On univariate analysis, tumor histology, patient race, tumor location, and tumor size significantly affected the number of SLNs that needed to be removed to identify 99% of all positive SLNs. On multivariate analysis, mixed ductal and lobular histology, Caucasian race, inner quadrant tumor location, and T1 tumor classification significantly increased the number of SLNs that needed to be removed to achieve 99% recovery of all positive SLNs. : In general, the removal of a maximum of 5 SLNs at surgery allowed for the recovery of >99% of positive SLNs in patients with breast cancer. The current findings indicated that tumor histology, patient race, and tumor size and location may influence this number.


Interaction between visceral adiposity and ambient air pollution on LDL cholesterol level in Korean adults.
Although previous reports have found that obesity intensifies the negative impact of long-term air pollution exposure on the low-density lipoprotein-cholesterol (LDL-C) level, few studies have examined whether the type of abdominal adiposity, such as visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT), and the visceral-to-subcutaneous fat ratio (VSR) affects this relationship. We investigated the association between ambient air pollution and LDL-C in Korean adults and identified whether this association is different by the type of abdominal adiposity. A total of 2737 adults were included. Abdominal fat areas were quantified by computed tomography, and the annual average concentration of air pollutants was included in this analysis. In the total sample, none of the air pollutants was associated with LDL-C level in either the crude or adjusted model (all p > 0.05). The association was not significant even in subgroups stratified according to the obesity status defined by body mass index, and no interaction on the LDL-C level was also found (all pint > 0.05). In the subgroup analysis stratified according to adiposity level, particulate matter with an aerodynamic diameter of ≤10 μm (PM10) [β (SE) = 3.58 (1.59); p = 0.0245] and sulfur dioxide (SO2) exposures [β (SE) = 2.71 (1.27); p = 0.0330] in the high-VAT group were associated with the increased LDL-C level. Interactions on LDL-C level were also found between VAT level and ambient air pollutants such as PM10 and SO2 (both pint < 0.05). In the analysis of the VSR, PM10 exposure showed a significant interaction on LDL level (pint = 0.0032). However, the strength of these associations was not significant across all SAT subgroup (all pint > 0.05). In conclusion, we found that association between air pollution exposure and LDL-C level is different by abdominal fat distribution.


A comparison between combined open bypass revascularization and free tissue transfer versus endovascular revascularization and free tissue transfer for lower limb preservation.
Extensive defects of the lower limb as a result of diabetes and peripheral vascular disease require multidisciplinary treatment. Numerous studies with regards combining vascular bypass surgery and free tissue reconstruction of the lower limb had been published. However the trend has evolved toward a combination of endovascular revascularization and free flap reconstruction. The aim of this study was to compare the safety and efficacy of this combination of treatment to the traditional combination of bypass surgery and free tissue reconstruction. All patients who had undergone vascular bypass surgery and free tissue reconstruction of the lower limb as well as those who had undergone endovascular angioplasty with free tissue transfer for lower limb preservation, over a 10-year period was included in this study. A total of 46 patients that underwent limb preservation were included in this study, 22 patients underwent open bypass revascularization and free flap transfer and 24 patients underwent endovascular revascularization and free tissue transfer. There were no differences between the two methods with regards to age, sex, defect size, TransAtlantic InterSociety Consensus level, Wagner classification, length of hospitalization, limb preservation rate, total flap necrosis rate, and partial flap necrosis rate. More importantly, there was no significant difference in the limb preservation rate (P = 0.14). In this study we found that the safety and the success rate of lower limb preservation using a combination of endovascular revascularization and free tissue reconstruction is comparable to using a combination of bypass surgery and free tissue transfer.


Histological examination of the kidney after experimental administration of MK-801 and dexamethasone.
The aim of the research was histological assessment of the influence of MK-801 (NMDA receptor antagonist) and dexamethasone on the kidney. The experiment was carried out on adult Albino-Swiss mouse males. MK-801 was administered in the dose of 0.3 mg/kg/24 h for 8 days, dexamethasone--in the toxic dose of 120 mg/kg/24 h. Kidney slices stained with hematoxylin and eosin and with PAS method were examined with light microscope. The performed experiments revealed that MK-801 causes morphological changes in the shape of slight narrowing of the urinary spaces in renal corpuscles and narrowing of the lumen of the proximal convoluted tubules and dexamethasone administered in toxic doses causes dilatation of these spaces with kidney's hyperemia. MK-801 intensifies morphological changes of the kidney induced by toxic doses of dexamethasone.


Analysis of cardiac monitoring and safety data in patients initiating fingolimod treatment in the home or in clinic.
Fingolimod (Gilenya®) is approved for relapsing forms of multiple sclerosis in the USA. Owing to transient heart-rate effects when initiating fingolimod, eligible patients undergo precautionary baseline assessment and first-dose observation (FDO) for ≥6 h. Prior to 2014, FDO was undertaken only in clinics. As the FDO period is short, and fingolimod has accumulated evidence of a positive benefit:risk ratio, an in-home treatment-initiation program, Gilenya@Home, was developed to offer a convenient alternative. Cardiac parameters and adverse events (AEs) were recorded by healthcare professionals performing fingolimod FDOs in the US Gilenya@Home program or in US Gilenya Assessment Network clinics. Anonymized data were collated retrospectively from the first 34 months in the home setting and from 78 months in clinics; data are reported descriptively. Satisfaction with Gilenya@Home was rated by patients using a 7-item questionnaire that considered aspects such as ease of scheduling, courtesy, and competency. Data were captured as part of standard care from 5573 patients initiating fingolimod in-home (October 2014 to July 2017) and from 15,025 patients initiating in-clinic (July 2010 to December 2016). In the Gilenya@Home questionnaire, 91.7% of 1848 respondents rated their overall satisfaction as "very good," and 7.6% rated their satisfaction as "good." AEs were reported for 30.7 and 32.6% of in-home and in-clinic patients, respectively. In total, 557 in-home (10.0%) and 398 in-clinic (2.6%) patients were monitored for > 6 h; 15 (0.3%) in-home and 129 (0.9%) in-clinic patients were transferred to an emergency room for overnight monitoring. The mean (standard deviation) heart rate (HR; bpm) pre-FDO was 74.8 (12.2) in-home and 74.2 (11.3) in-clinic; reduction in HR at 6 h postdose was 10.6 (12.0) and 6.3 (9.6), respectively. New-onset first-degree atrioventricular block was experienced by 132 (2.4%) in-home and 74 (0.5%) in-clinic patients, and Wenckebach (Mobitz type I) second-degree atrioventricular block by four (0.07%) and nine (0.1%) patients, with no cases of third-degree atrioventricular block. A substantial number of patients have initiated fingolimod at home, reporting very high levels of satisfaction. Gilenya@Home was as rigorous as the clinic setting in detecting cardiovascular events. Overall, FDO safety outcomes were similar with Gilenya@Home and in-clinic.


[High grade insulinoma detected in a patient with a 5-year history of severe hypoglycemias].
Functional endocrine tumors of the pancreas are rare. Among them insulinomas are the most common types. The majority of the patients with insulinoma are between 30 and 60 years of age and 59% of them are women. Most insulinomas are sporadic tumors while 10% of them develop in patients with multiple endocrine neoplasia (MEN). Diagnosis is based on clinical examination and laboratory tests. Preoperative imaging assessment (echo-endoscopy, CT, MRI) is essential for tumor localization in more than 80% of cases. Surgical excision is the treatment of choice. We here report the case of a 50-year old patient with high grade insulinoma developed on the anterior surface of the pancreas tail.


Parkinson's disease: From human genetics to clinical trials.
Combining genetic insights into the pathogenesis of Parkinson's disease (PD) with findings from animal and cellular models of this disorder has advanced our understanding of the pathways that lead to the characteristic degeneration of dopaminergic neurons in the brain's nigrostriatal pathway. This has fueled an increase in candidate compounds designed to modulate these pathways and to alter the processes underlying neuronal death in this disorder. Using mitochondrial quality control and the macroautophagy/lysosomal pathways as examples, we discuss the pipeline from a comprehensive genetic architecture for PD through to clinical trials for drugs targeting pathways linked to neurodegeneration in PD. We also identify opportunities and pitfalls on the road to a clinically effective disease-modifying treatment for this disease.


The effects of brainstem peribrachial stimulation on perigeniculate neurons: the blockage of spindle waves.
The mode of action of afferents arising from the brainstem peribrachial region at the midbrain-pontine junction on neurons recorded from the reticular thalamic sector adjacent to the lateral geniculate nucleus (perigeniculate cells) was investigated at the intracellular level in the cat. Experiments were performed in cats under barbiturate or urethane anaesthesia and in non-anaesthetized deafferented animals. Most cats were pretreated with reserpine (1-2 mg/kg) and were also acutely deprived of their retinal and cortical visual inputs. It was found that peribrachial stimulation produced a short train of fast-rising depolarizations followed by a long-lasting period of hyperpolarization in all perigeniculate neurons. Although the latest part of the early depolarizations preceding the hyperpolarization resulted from a parallel activation of lateral geniculate relay neurons by peribrachial afferents, those occurring at shortest latencies appear to result from a direct excitation produced by peribrachial afferents. Furthermore, these early excitatory postsynaptic potentials persisted under deep barbiturate anaesthesia, a condition that prevents activation of thalamic relay neurons by peribrachial stimulation. The evoked hyperpolarization decreased with membrane hyperpolarization, was associated with a 40-50% increase in membrane conductance and was insensitive to Cl injections. It was no longer observed within one hour after i.v. injection of scopolamine. However, the depolarizing responses were not depressed by this muscarinic antagonist. Iontophoretic applications of scopolamine also removed peribrachial-evoked inhibition of synaptic responses triggered by optic chiasma stimulation. The peribrachial input exerted a powerful control on the oscillatory behavior of perigeniculate neurons. Spindle oscillations which are generated within the reticular thalamic complex were readily blocked by peribrachial stimulation. It is then concluded that the transition from an oscillatory to a relay mode of operation in the thalamus is controlled at least in part by a muscarinic inhibition of reticular thalamic neurons. The synaptic mechanism responsible for the early depolarization remains to be elucidated.


A Novel Modified-Vista Technique With Connective Tissue Graft in the Treatment of Gingival Recession: A Case Report.
The increasing esthetic demands from patients have required that clinicians sharpen their skills and adopt newer and more novel techniques to satisfy these demands. In periodontal therapy, periodontal plastic surgery poses a substantial challenge to the clinician, both because it is technique sensitive and also because it includes a wide array of procedures and their variations. Conventional plastic procedures have provided satisfactory results in the treatment of gingival recession but there is, presently, a greater need for more advanced procedures that cause less surgical morbidity as also provide improved results. Minimally invasive surgery has been harnessed in periodontics for this purpose and has been extensively used in multiple indications, including root coverage. Modified-Vestibular Incision Supra-periosteal Tunnel Access (M-VISTA) applies the principles of minimally invasive surgery to provide satisfactory results in root coverage. A 28-year-old male patient presented with multiple Miller Class I/II buccal recession defects and associated high labial frenum on right maxillary anterior teeth. M-VISTA technique allowed coronal repositioning of gingival margin, which was then stabilized by orthodontics bracket assisted suturing technique. The V-shaped incision in the region of the frenal attachment allowed for conducting both the M-VISTA and frenectomy techniques simultaneously. Connective tissue graft was inserted in the supra-periosteal tunnel and vertical incision was sutured. Complete root coverage was achieved and maintained at 9 months with excellent esthetic outcomes. The use of connective tissue graft along with M-VISTA technique allows the clinician to successfully treat multiple recession defects.


Preparation, characterization and in vitro cytotoxicity of Fenofibrate and Nabumetone loaded solid lipid nanoparticles.
There is an increasing attention on solid lipid nanoparticles (SLNs) due to their high biocompatibility and ability to enhance bioavailability for poorly water-soluble drugs. Preparation of SLNs that are capable of high drug loading and sustained drug release through hot melt sonication method is reported here. SLNs of palmitic acid and stearic acid loaded with poorly water-soluble drugs, viz. fenofibrate (FF) and nabumetone (NBT) having spherical morphology and average particle size below 200 nm were prepared. Poloxamer 407 and pluronic® F-127 were used as surfactants. Particle size and spherical morphology was confirmed by dynamic light scattering, field emission scanning electron microscopy, transmission electron microscopy, and atomic force microscopy. The chemical, crystal, and thermal properties of SLNs were studied by Fourier transform infrared spectroscopy, X-ray diffraction, and differential scanning calorimetry, respectively. The palmitic acid-poloxamer 407 SLNs could entrap upto 13.8% FF with 80% entrapment efficiency while the stearic acid-pluronic® F-127 SLNs entrapped 13.6% NBT with 89% entrapment efficiency. The drug loaded in SLNs showed controlled release up to 3 days as confirmed by in-vitro drug release profile. Moreover, the drug loaded SLNs did not show any toxicity on macrophage cell line proving the use of these formulations as control drug delivery vehicles for the studied drugs.


An access deficit or a deficit in the phonological representations themselves: What can we learn from naming errors?
Anomic aphasia is characterized by good comprehension and non-word repetition but poor naming. Two sub-types of deficits might be hypothesized: faulty access to preserved phonological representations or preserved access to impaired representations. Phonological errors may occur only when representations are impaired or in post-lexical deficits (conduction aphasia). We analysed the incidence of phonological naming errors of 30 individuals, 25 with anomic aphasia based on poor naming but good repetition and comprehension, and five with conduction aphasia based on poor naming and poor repetition. Individuals with anomic aphasia produced very few phonological errors compared to individuals with conduction aphasia (0-19.1% versus 42-66%). However, six individuals with anomia produced more than 11% phonological errors, suggesting two patterns of deficit: either impaired lexical representations or impaired access to them. The lack of phonological errors in most individuals with anomic aphasia suggests that access to the phonological output lexicon is semantically, not phonologically driven.


Psychostimulant addiction treatment.
Treatment of psychostimulant addiction has been a major, and not fully met, challenge. For opioid addiction, there is strong evidence for the effectiveness of several medications. For psychostimulants, there is no corresponding form of agonist maintenance that has met criteria for regulatory approval or generally accepted use. Stimulant-use disorders remain prevalent and can result in both short-term and long-term adverse consequences. The mainstay of treatment remains behavioral interventions. In this paper, we discuss those interventions and some promising candidates in the search for pharmacological interventions. This article is part of the Special Issue entitled 'CNS Stimulants'.


Neurobehavioral deficits in neonatal rhesus monkeys exposed to cocaine in utero.
In spite of significant efforts, the neurobehavioral deficits in infants born from cocaine-abusing mothers have not been clearly defined. In the present study, we examined the presence of these abnormalities in a rhesus monkey model of prenatal cocaine exposure using a nonhuman primate adaptation of the Neonatal Behavioral Assessment Scale (NBAS). Pregnant monkeys (n = 14) received 10 mg/kg cocaine twice a day orally (in fruit treats) from the 40th through 102nd postconception days (PCD40-PCD102), which is the period of cerebral cortical neuronogenesis (approximately second trimester). The control consisted of pregnant monkeys (n = 14) receiving fruit treats only. The animals were allowed to deliver vaginally at term (approximately PCD165). The first testing session was conducted on PCD171 (within the first week after birth); the second testing session was conducted on PCD177 (within the second week after birth); the third test was conducted on PCD183 (within the third week after birth); and the fourth testing session was conducted on PCD189 (within the fourth week after birth). The prenatally cocaine-exposed infants showed deficits in orientation, state control, and motor maturity, which were detectable during the second, third, and fourth testing sessions. The same testing sessions also revealed a significant reduction in the time devoted to toy manipulation, which points to impaired attention. None of these abnormalities were seen during the first testing session. The first session, however, revealed increased tremulousness (one of the indicators of autonomic stability) in the prenatally cocaine-exposed infants. This impairment disappeared by the third testing session. The present findings demonstrate the potential of prenatal cocaine exposure to induce neurobehavioral deficits detectable by NBAS-like testing in primate infants.


Application of advanced magnetic resonance imaging techniques in evaluation of the lower extremity.
This article reviews current magnetic resonance imaging (MR imaging) techniques for imaging the lower extremity, focusing on imaging of the knee, ankle, and hip joints. Recent advancements in MR imaging include imaging at 7 T, using multiple receiver channels, T2* imaging, and metal suppression techniques, allowing more detailed visualization of complex anatomy, evaluation of morphologic changes within articular cartilage, and imaging around orthopedic hardware.


Engineering fluorescent proteins.
Green fluorescent protein from the jellyfish Aequorea victora (GFP) and GFP-like proteins from Anthozoa species encode light-absorbing chromophores intrinsically within their respective protein sequences. Recent studies have made progress in obtaining bright variants of these proteins which develop chromophores quickly and efficiently, as well as novel fluorescent proteins that photoactivate or photoconvert, i.e., become fluorescent or change colors upon illumination at specific wavelengths. Also, monomeric versions of these proteins have been engineered for fusion protein applications. Simple GFP variants and circularly permuted GFP variants have been used to develop fluorescent probes that sense physiological signals such as membrane potential and concentrations of free calcium. Further molecular characterization of the structure and maturation of these proteins is in progress, aimed at providing information for rational design of variants with desired fluorescence properties.


Impact of graft size and resuspension level of the commissures on aortic insufficiency after reimplantation of the aortic valve.
In addition to the size of the graft, the resuspension of the commissures has been described as important for valve function in valve-sparing aortic root replacement procedures. This study describes the influence of a stepwise reduction of the fixation level of the commissures within the graft as well as a stepwise reduction of graft size on valve insufficiency. Porcine aortic valves were reimplanted into a tubular graft and the height of the commissures was reduced in a stepwise manner. In a second series of experiments, the diameter of the grafts was reduced by 30 % and 50 %. A reduction of the commissure heights by 10 % and 20 % caused a significant increase in reflux water. Using the criteria of homograft preparation, a 10 %, but not a 20 %, reduction was tolerated. The coaptation level of the valve became increasingly lower, indicating a higher risk for late valve incompetence. A reduction of the prosthesis diameter by 30 % and 50 % did not result in insufficiency of the valve but it lowered the coaptation level. Resuspension of the commissures within the graft has a more important impact on early failure rates than the choice of graft size.


Follicle structure-dependency of thyroglobulin and thyroxin staining in the thyroid glands of Graves' disease.
H.E. morphology of the thyroid glands from 170 patients with Graves' disease was studied, and the thyroid follicles were classified into two main groups: (1) F pattern, in which the follicles show circle/ellipse on cut sections; (2) P pattern, in which the follicular epithelium protrudes into the lumen or a follicle, is accompanied by proliferation of tubular or microfollicular structures. Studies on three serial sections of 88 thyroid glands stained with hematoxylin and eosin, thyroglobulin (TG), and thyroxin (T4), respectively, revealed the followings: (i) TG/T4 staining is dependent on the follicle structure (i.e., F or P); while the epithelium and colloid including scalloped vesicles in F follicles generally exhibited a direct relationship between TG and T4 staining, those in P follicles often showed an intense TG, but negative T4 staining. (ii) The results of morphological and immunohistochemical studies of P follicles among the cases are consistent with the view that P follicles are in the process of proliferation of immature daughter follicles from a main follicle and of their maturation. (iii) P follicles of Graves' thyroid glands were evaluated as possible non-neoplastic counterparts of well-differentiated follicular and papillary tumors.


Influence of hypercapnia and hypoxia on rabbit platelet aggregation.
The influence of changes in pCO2, pH and pO2 on the aggregation of rabbit blood platelets was studied in vitro, with emphasis on hypercapnia, acidosis and hypoxia. Hypercapnia combined with acidosis caused a reduction in rabbit platelet aggregation, as induced by collagen, thrombin and ADP; the effect being most pronounced with collagen and smallest with ADP. Hypoxia reduced thrombin induced platelet aggregation, but had no effect on ADP and collagen induced aggregation. Synergistic activation of rabbit platelets, as induced by the addition of serotonin to platelet rich plasma together with collagen or ADP, seemed to be equally sensitive to changes in pCO2 and pH as activation by the individual agents, and insensitive to changes in pO2.


The interaction of peptide-tethered platinum(II) complexes with DNA.
The sequence specificity and intensity of DNA damage induced by six peptide-tethered platinum complexes was compared to cisplatin and Pt(en)Cl(2). DNA damage was investigated in pUC19 plasmid and in intact HeLa cells, and quantitatively analyzed using a Taq DNA polymerase/linear amplification assay. The DNA sequence specificity of the peptide-platinum compounds was found to be very similar to cisplatin and Pt(en)Cl(2), with runs of consecutive guanines being the most intensely damaged sites. The observed reactivity of the peptide-platinum complexes towards plasmid DNA was lower compared to cisplatin and Pt(en)Cl(2), with the glycine-tethered complex 3 and the phenylalanine-tethered complex 4 producing the highest relative damage intensity, followed by (in decreasing order) lysine-tethered (5), arginine-tethered (6), serine-tethered (7) and glutamate-tethered (8). The reactivity of the peptide-platinum complexes towards cellular DNA was also lower compared to cisplatin and Pt(en)Cl(2). For most investigated complexes, the relative damage intensities were found to be similar in cells compared to plasmid DNA, but were greatly reduced for 3 and 4. The lysine-tethered 5 complex produced the highest DNA damage intensity in cells followed by (in decreasing order) 6, 7, 3, 4 and 8.


A randomized study comparing the effectiveness of microwave ablation radioimmunotherapy and postoperative adjuvant chemoradiation in the treatment of non-small cell lung cancer.
To evaluate the differences in the outcomes of patients with stage II and IIIa non-small cell lung cancer (NSCLC) treated with either 131I-labeled mouse/human chimeric monoclonal antibody against intracellular DNA exposed in necrotic and degenerating regions of tumors (131I-chTNT-mediated radioimmunotherapy) combined with percutaneous microwave coagulation therapy (PMCT) guided by computed tomography (CT) or with postoperative adjuvant chemoradiation. Ninety-six patients with stage II and IIIa NSCLC were randomized into two groups. Group A included 49 patients who were treated with chemotherapy with docetaxel and cisplatin and three-dimensional conformal radiotherapy 3-4 weeks after surgery. Group B included 47 patients treated with 131I-chTNT and PMCT sequentially, with follow-up chemotherapy. The survival rates of patients in group A for the first and second years were 79.59% and 48.98%, respectively. The median survival was 23.0 months. Survival rates at 1 and 2 years for group B were 82.98% and 53.19%, respectively and the median survival was 29.1 months. The survival rate of group B patients for the first and second years was better compared with group A, and the difference in median survival between the groups was statistically significant (p<0.05). However, median survival and the incidence of adverse events were not significantly different between the two groups. 131I-chTNT radioimmunotherapy with PMCT has a complementary effect in NSCLC, which can effectively improve therapeutic ratio and survival of patients effectively and has the same effect as that of post-operative adjuvant chemoradiation.


Metabolism of cis-12-octadecenoic acid and trans-9,trans-12-octadecadienoic acid and their influence on lipogenic enzyme activities in mouse liver.
High carbohydrate (65% glucose) diets containing cis-12-octadecenoic acid (12c-18:1) or trans-9,trans-12-octadecadienoic acid (9t,12t-18:2) were fed to weanling mice to investigate the influence of fatty acid structure on six hepatic enzyme activities involved in lipid metabolism. Results with these diets were compared to those with diets containing no fatty acids, saturated fatty acids; cis-9-octadecenoic acid (9c-18:1) and cis-9,cis-12-octadecadienoic acid (9c,12c-18:2). These comparisons show saturated fatty acids, 9c-18:1, 12c-18:1, and 9t,12t-18:2, had little or no influence on the activity levels of fatty acid synthetase, malic enzyme (EC 184.108.40.206)citrate cleavage enzyme (EC 18.104.22.168), glucose-6-phosphate dehydrogenase (EC 18.104.22.168), 6-phosphogluconate dehydrogenase (EC 18.104.22.168) and acetyl-CoA carboxylase (EC 126.96.36.199). Neither 12c-18:1 nor 9t,12t-18:2 produced the dramatic enzyme-lowering effect exhibited by the diet containing 9c,12c-18:2 when compared to the diet devoid of fat. Thus, both the 9 and 12 bonds must be present in the same molecule. Also, at least one and probably both bonds must be in the cis configuration to depress liver enzyme activities. Capillary gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS) were both used for analysis of the methyl esters derived from the hepatic lipids. The GC and GC-MS data provided (a) direct evidence for incorporation of both isomers into hepatic lipids and (b) indirect evidence that 9t,12t-18:2 lowered liver delta 9-desaturase activity. In addition, since these products were found in the complex liver lipids, there is no doubt that the various enzymes concerned with activation and acylation utilize both of these isomeric fatty acids as substrates.


Isolation of prostrate turfgrass mutants via screening of dwarf phenotype and characterization of a perennial ryegrass prostrate mutant.
Prostrate turf varieties are desirable because of their increased low mowing tolerance, heat resistance, traffic resistance and ground coverage compared with upright varieties. Mutation breeding may provide a powerful tool to create prostrate varieties, but there are no simple, straightforward methods to screen for such mutants. Elucidation of the molecular basis of the major 'green revolution' traits, dwarfism and semi-dwarfism, guided us to design a simple strategy for isolating dwarf mutants of perennial ryegrass (Lolium perenne L.). We have shown that gamma-ray-mediated dominant dwarf mutants can be easily screened for at the three-leaf stage. About 10% of dwarf mutant lines also displayed a prostrate phenotype at mature stages (>10 tillers). One prostrate line, Lowboy I, has been characterized in detail. Lowboy I had significantly shorter canopy, leaf blade and internode lengths compared with wild type. Lowboy I also exhibited greater tolerance to low mowing stress than wild type. Exogenous gibberellic acid (GA) restored Lowboy I to a wild-type phenotype, indicating that the dwarf and prostrate phenotypes were both due to GA deficiency. We further showed that phenotypes of Lowboy I were dominant and stably inherited through sexual reproduction. Prostrate turfgrass mutants are difficult to screen for because the phenotype is not observed at young seedling stages, therefore our method represents a simple strategy for easily isolating prostrate mutants. Furthermore, Lowboy I may provide an outstanding germplasm for breeding novel prostrate perennial ryegrass cultivars.


Health-related quality of life and the burden of prolonged seizures in noninstitutionalized children with epilepsy.
This study aimed to provide information on the burden of illness and health-related quality of life (HRQoL) in children with epilepsy who experience prolonged acute convulsive seizures (PACS) in the community setting, and to investigate factors that may predict poor HRQoL in this population. Noninstitutionalized children (aged 3-16 years) who had experienced at least one PACS within the past year and had currently prescribed PACS rescue medication were enrolled in a cross-sectional study in Germany, Italy, Spain, and the United Kingdom (Practices in Emergency and Rescue medication For Epilepsy managed with Community-administered Therapy 3 [PERFECT-3]). Clinicians, parents/guardians, and patients completed web-based questionnaires regarding clinical characteristics, PACS frequency, and day-to-day impairment. Patients' HRQoL was rated by clinicians, parents/guardians, and patients themselves using the 5-dimension EuroQol questionnaire (EQ-5D) and summarized as a utility score. Potential predictors of poor HRQoL were tested in individual univariate generalized linear models and a global multivariable model. Enrolled children (N = 286) had experienced 1-400 PACS (median: 4) in the past year. Clinicians reported that 216/281 patients (76.9%) had learning disabilities of varying severity. Mean EQ-5D utility scores rated by clinicians (n = 279), parents (n = 277), and patients (n = 85) were 0.52 (standard deviation: 0.41), 0.51 (0.39), and 0.74 (0.29), respectively. Increasing PACS frequency, increasing severity of learning disability, and specialist school attendance were significantly associated with decreasing EQ-5D utility score. In the multivariable model, having learning disabilities was the best predictor of poor HRQoL. Health-related quality of life was very poor in many children with epilepsy whose PACS were managed with rescue medication in the community, with learning disability being the most powerful predictor of patients' HRQoL. Mean EQ-5D utility scores were lower (worse) than published values for many other chronic disorders, indicating that optimal treatment should involve helping children and their families to manage learning disabilities and day-to-day impairments, in addition to preventing seizures.


A comparison of attitudes towards end-of-life decisions: survey among the Dutch general public and physicians.
In The Netherlands, there has been a continuing public debate about the acceptability and regulatory system for medical decision-making concerning the end of life. We studied attitudes of the Dutch general public towards different types of end-of-life decisions in various situations and compared them to attitudes of physicians. Questionnaires were mailed to 1777 members of the Dutch general public (response: 78%). A total of 391 Dutch physicians, including general practitioners, nursing home physicians and clinical specialists, were interviewed in person (response: 81%). In both the survey and physician interviews, questions were asked about attitudes towards active ending of life, terminal sedation, and increasing morphine with premature death as a likely consequence, using hypothetical cases of different patients. By logistic regression analysis, the differences between public and physicians' attitudes were assessed, as well as the associations between attitudes of the general public and their personal characteristics. Acceptance of active ending of life at the request of a terminally ill cancer patient was higher among the general public (85%) than among physicians (64%). For physicians, acceptance decreased to 36% for an incompetent adult, 11% for a patient without a serious disease, and 6% for a patient with dementia. For the general public, these percentages were 63%, 37%, and 62%, respectively. Between both groups, no differences were found in acceptance of terminal sedation and increasing morphine. For the general public, determinants of support for active ending of life were being non-religious, lower education, and having a single household. Acknowledging the observed differences in appreciation of end-of-life decision-making between the general public and physicians is important in doctor-patient communication and in public debate and policymaking. Continued monitoring of practices and informing the general public and policymakers about the clinical and ethical consequences of different types of end-of-life decisions is important.


Association of Admission Hyperglycemia with Clinical Outcomes in Japanese Patients with Acute Large Vessel Occlusion Stroke: A post hoc Analysis of the Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism Japan Registry 2.
Admission hyperglycemia is an indicator of poor functional prognosis in acute stroke, but investigations of its prevalence and effects on the outcomes of acute large vessel occlusion in real-world, large-scale studies are limited, especially in Asian population. We aimed to elucidate the relationship between admission hyperglycemia and outcomes in a prospective multicenter registry in Japan. We analyzed data from the Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism (RESCUE) Japan Registry 2, which was a prospective, multicenter registry that enrolled patients from 46 centers in Japan. Admission hyperglycemia was defined as blood glucose level >140 mg/dL. The relationships between clinical outcomes and admission hyperglycemia were analyzed in all 1,932 assessable patients. A favorable functional outcome, defined as a modified Rankin Scale score of 0-2 at day 90, as well as mortality within 90 days and symptomatic intracranial hemorrhage (SICH) within 72 h, was analyzed. We performed subgroup analyses of the adjusted variables to investigate the association between hyperglycemia and favorable outcome in relation to each variable. Admission hyperglycemia was present in 687 (35.6%) of the assessable patients and in 420 (26.9%) of the 1,561 patients without diabetes. A favorable outcome was significantly less frequent in the hyperglycemia group than in the no-hyperglycemia group (33.2% vs. 47.6%, adjusted odds ratio [OR]: 0.60, 95% confidence interval [CI]: 0.47-0.76). The mortality rates were 12.8% and 6.8% in the hyperglycemia and no-hyperglycemia groups, respectively. The incidence of SICH within 72 h was higher in the hyperglycemia group than in the no-hyperglycemia group (4.4% vs. 1.9%, adjusted OR: 2.54, 95% CI: 1.36-4.82). Hyperglycemia was associated with unfavorable outcomes in almost all subgroups. Admission hyperglycemia in Japanese patients with large vessel occlusion stroke is associated with an unfavorable functional outcome at 90 days, mortality within 90 days, and the occurrence of SICH within 72 h.


Metastatic prostate cancer mimicking primary osteosarcoma of the jaw: an infrequent clinical case.
Prostate cancer metastasizing to the mandible is a rare occurrence. This case describes a patient whose presenting symptom was a painless swelling of the left mandible. Radiological investigation demonstrated a lesion within the left mandibular ramus, and subsequent biopsy confirmed the diagnosis of metastatic prostate cancer.


Nonviral retrograde gene transfer of human hepatocyte growth factor improves neuropathic pain-related phenomena in rats.
Peripheral nerve injury occasionally causes chronic neuropathic pain with hyperalgesia and allodynia. However, its treatment is difficult. Here, we used a chronic constriction injury (CCI) model in rats to investigate the effects on experimental neuropathic pain of the human hepatocyte growth factor (HGF) gene delivered into the nervous system by retrograde axonal transport following its repeated intramuscular transfer, using liposomes containing the hemagglutinating virus of Japan (HVJ). CCI (control) rats exhibited marked mechanical allodynia and thermal hyperalgesia, and decreased blood flow in sciatic nerve and hind paw. All these changes were significantly reversed by HGF gene transfer. In the sciatic nerve in HGF-treated rats, the size-frequency distributions for myelinated and unmyelinated axons each showed a rightward shift, the number of myelinated axons >5 microm in diameter was significantly increased, and the mean diameter of unmyelinated axons was significantly increased (versus CCI rats). Levels of P2X3, P2X4, and P2Y1 receptor mRNAs, and of interleukin-6 (IL-6) and activating transcription factor 3 (ATF3) mRNAs, were elevated in the ipsilateral dorsal root ganglia and/or sciatic nerve by CCI, and these levels were decreased by HGF gene transfer. These results may point toward a potential new treatment strategy for chronic neuropathic pain in this model.


A review and synthesis of frameworks for engagement in health research to identify concepts of knowledge user engagement.
Engaging those who influence, administer and/or who are active users ("knowledge users") of health care systems, as co-producers of health research, can help to ensure that research products will better address real world needs. Our aim was to identify and review frameworks of knowledge user engagement in health research in a systematic manner, and to describe the concepts comprising these frameworks. An international team sharing a common interest in knowledge user engagement in health research used a consensus-building process to: 1) agree upon criteria to identify articles, 2) screen articles to identify existing frameworks, 3) extract, analyze data, and 4) synthesize and report the concepts of knowledge user engagement described in health research frameworks. We utilized the Patient Centered Outcomes Research Institute Engagement in Health Research Literature Explorer (PCORI Explorer) as a source of articles related to engagement in health research. The search includes articles from May 1995 to December 2017. We identified 54 articles about frameworks for knowledge user engagement in health research and report on 15 concepts. The average number of concepts reported in the 54 articles is n = 7, and ranges from n = 1 to n = 13 concepts. The most commonly reported concepts are: knowledge user - prepare, support (n = 44), relational process (n = 39), research agenda (n = 38). The least commonly reported concepts are: methodology (n = 8), methods (n = 10) and analysis (n = 18). In a comparison of articles that report how research was done (n = 26) versus how research should be done (n = 28), articles about how research was done report concepts more often and have a higher average number of concepts (n = 8 of 15) in comparison to articles about how research should be done (n = 6 of 15). The exception is the concept "evaluate" and that is more often reported in articles that describe how research should be done. We propose that research teams 1) consider engagement with the 15 concepts as fluid, and 2) consider a form of partnered negotiation that takes place through all phases of research to identify and use concepts appropriate to their team needs. There is a need for further work to understand concepts for knowledge user engagement.


Mice: the initiation and maintenance of pregnancy-induced aggression following thelectomy.
Two experiments were conducted in order to assess the effects of thelectomy (i.e., nipple removal) on the display of pregnancy-induced aggression in Rockland-Swiss (R-S) albino mice. Pregnant animals, thelectomized on Gestation Day (GD) 12, exhibit a high incidence and intensity of aggression toward adult R-S male intruders during tests conducted on GDs 14, 16, and 18 (i.e., during the last third of gestation in this species). Since thelectomized dams display levels of aggression (i.e., 63% incidence) equivalent to those of sham-operated and nonoperated animals (53 and 67% incidence, respectively), it would appear that nipple presence is not a critical factor for the maintenance of pregnancy-induced aggression in mice (Experiment 1). To examine the effects of nipple deprivation on the initiation of pregnancy-induced aggression, virgin animals were thelectomized prior to mating, then repeatedly tested for aggression at 2-day intervals of gestation. Unlike nipple-intact dams, pregnant mice, deprived of nipples prior to conception, rarely exhibit (less than 17% incidence) agonistic behaviors toward intruder males (Experiment 2). These findings suggest that the development and self-stimulation of nipples early in pregnancy may be important conditions for the display of heightened aggression with advancing pregnancy in mice.


Neuroscientific Psychophysiology: The International Organization of Psychophysiology (I.O.P.) associated with the United Nations (New York) in the 21st Century.
This Presidential Address 2004 emphasizes the pivotal role of Psychophysiology as an integrated neuroscience with a panoply of electrophysiological and neuroimaging technologies for the establishment of methodologically crucial conceptual links for the understanding and mapping of brain functions pertaining to cognitive, emotional and motivational processes. Moreover, Psychophysiology's unique neuroscientific perspective by integrating functions of central and autonomic nervous systems with behavior in health and disease is underlined. Based on these developments, the progress of rigorous neuroscientific Clinical Psychophysiology offers possibilities for diagnosis, treatment and objective evaluation of therapeutic outcome in various pathological conditions.


Cell differentiation and p38(MAPK) cascade are inhibited in human osteoblasts cultured in a three-dimensional clinostat.
A three-dimensional (3D) clinostat is a device for multidirectional G force generation. By controlled rotation of two axes, a 3D clinostat cancels the cumulative gravity vector at the center of the device and produces an environment with an average of 10(-3) G over time. We cultured a human osteoblast cell line in a 3D clinostat and examined the growth properties and differentiation of the cells, including morphology, histological detection of calcification, and mitogen-activated protein kinase (MAPK) cascades. In a normal 1 G condition, alkaline phosphatase (AlPase) activity was detected on day 7 of culture, bone nodules were formed on day 12, and calcium deposits were seen on day 20. In the 3D clinostat, the cells looked larger and bulged. AlPase activity was detected on day 10 of culture. However, neither bone nodules nor calcification was found in the 3D clinostat up to day 21. The expression levels of core-binding factor A1 (a transcription factor for bone formation) and osteocalcin (a bone matrix protein) increased in the control culture but decreased in culture in 3D clinostat. Phosphorylation of p38(MAPK) (p38) was repressed in culture in 3D clinostat, whereas total p38 as well as total and phosphorylated forms of extracellular signal-regulated kinases and stress-activated protein kinase/jun N-terminal kinase were not changed in the 3D clinostat. When a p38 inhibitor, SB 203580, was added to the culture medium in a normal 1 G environment, AlPase activity and formation of bone nodules and calcium deposits were strongly inhibited. On the other hand, they were inhibited only partially by a MAPK kinase inhibitor, U-0126. On the basis of these results, it is concluded that (1) osteoblast differentiation is inhibited in culture in a 3D clinostat and (2) this inhibition is mainly due to the suppression of p38 phosphorylation.


[Local population of Eritrichium caucasicum as an object of mathematical modelling. I. Life cycle graph and a nonautonomous matrix model].
For the plant species, which is considered a short-lived perennial, we have composed a scale of ontogenetic stages and the life cycle graph (LCG) according to annual observations on permanent sample plots in an Alpine lichen heath during the 2009-2014 period. The LCG that reflects seed reproduction has been reduced to the one that avoids the stage of soil seed bank, yet preserves the arcs of annual recruitment. The corresponding matrix model of stage-structured population dynamics has four stages: juvenile plants (including seedlings), virginal, generative, and 'terminally generative' (the plants die after seed production). Model calibration reduces to directly calculating the rates of transition between stages and those of delays within stages from the data of only one time step, while keeping the two reproduction rates uncertain, yet confined to the quantitative bounds of observed recruitment. This has enabled us to determine a feasible range for the dominant eigenvalue of the model matrix, i.e., the quantitative bounds for the measure of how the local population adapts to its environment, at each of the five time steps, resulting in aformally nonautonomous model. To obtain 'age-specific parameters' from a stage-classified model, we have applied the technique that constructs a virtual absorbing Markov chain and calculates its fundamental matrix. In a nonautonomous model, the estimates of life expectancy also depend on the time of observation (that fixes certain environmental conditions), and vary from two to nearly seven years. The estimates reveal how specifically short lives the short-lived perennial, while their range motivates the task to average the model matrices over the whole period of observation. The model indicates that Eritrichium caucasicum plants spend the most part of their life span in the virginal stage under each of the environment conditions observed, thus revealing the place retention strategy by C. K6rner (2003), or the delayed-development strategy by L.A. Zhukova (1995). We discuss the prospects of model experiments with a logically nonautonomous model to forecast the long-term dynamics of E. caucasicum under a scenario of climate changes.


Bosentan, a drug used in the treatment of pulmonary hypertension, can prevent development of osteoporosis.
We examined the antiosteoporotic effect of bosentan (Bose) by radiographic, histopathological, and molecular methods. Rats were divided into 4 groups of 8 rats each: one control (Sham), one osteoporosis only (OP), and two osteoporosis groups treated with Bose doses of 50 and 100 mg/kg (OP+Bose50, OP+Bose100). Six weeks later, Bose was administered for eight weeks to animals undergoing ovariectomy. The left femoral bone of the rats was evaluated in vitro after surgical removal. Bone mineral density (BMD) was analyzed by Dual-energy X-ray absorptiometry (DEXA). Endothelin 1 (ET-1), ET-A, and ET-B expressions were examined by real-time polymerase chain reaction (real time-PCR). In addition, bone tissue was evaluated histopathologically. Compared with the osteoporosıs group, Bose significantly increased BMD values at both 50 and 100 mg/kg doses. ET-1 mRNA levels were significantly higher in the OP group than in the Sham group, while ET-1 mRNA levels were significantly lower in Bose treatment groups. ET-A mRNA levels were significantly lower in the OP group than in the Sham group, while ET-A mRNA levels were significantly higher in Bose treatment groups. Histopathological results supported the molecular results. Our study is the first to demonstrate the molecular, radiological, and histopathological effects of Bose in preventing osteoporosis in rats.


Gene regulatory network inference resources: A practical overview.
Transcriptional regulation is a fundamental molecular mechanism involved in almost every aspect of life, from homeostasis to development, from metabolism to behavior, from reaction to stimuli to disease progression. In recent years, the concept of Gene Regulatory Networks (GRNs) has grown popular as an effective applied biology approach for describing the complex and highly dynamic set of transcriptional interactions, due to its easy-to-interpret features. Since cataloguing, predicting and understanding every GRN connection in all species and cellular contexts remains a great challenge for biology, researchers have developed numerous tools and methods to infer regulatory processes. In this review, we catalogue these methods in six major areas, based on the dominant underlying information leveraged to infer GRNs: Coexpression, Sequence Motifs, Chromatin Immunoprecipitation (ChIP), Orthology, Literature and Protein-Protein Interaction (PPI) specifically focused on transcriptional complexes. The methods described here cover a wide range of user-friendliness: from web tools that require no prior computational expertise to command line programs and algorithms for large scale GRN inferences. Each method for GRN inference described herein effectively illustrates a type of transcriptional relationship, with many methods being complementary to others. While a truly holistic approach for inferring and displaying GRNs remains one of the greatest challenges in the field of systems biology, we believe that the integration of multiple methods described herein provides an effective means with which experimental and computational biologists alike may obtain the most complete pictures of transcriptional relationships. This article is part of a Special Issue entitled: Transcriptional Profiles and Regulatory Gene Networks edited by Dr. Federico Manuel Giorgi and Dr. Shaun Mahony.


Relation between C-reactive protein, treadmill exercise testing, and inducible myocardial ischemia.
This study examined the relation between high-sensitivity C-reactive protein (CRP), exercise-induced myocardial ischemia, and exercise tolerance in 288 stable patients who underwent maximal treadmill stress testing. CRP was correlated with peak exercise workload, which was consistent with the long-term predictive value of peak workload and CRP for outcome events. There was no correlation of high-sensitivity CRP with stress-induced ischemia, which is consistent with a lack of correlation between CRP and the degree of chronic luminal coronary arterial narrowing.


Examining Sex Differences in Markers of Cognition and Neurodegeneration in Autosomal Dominant Alzheimer's Disease: Preliminary Findings from the Colombian Alzheimer's Prevention Initiative Biomarker Study.
Growing evidence suggests that there may be a sex-specific biological risk for Alzheimer's disease (AD). Individuals with autosomal dominant AD due to a mutation (E280A) in Presenilin-1 (PSEN1) are genetically determined to develop early-onset dementia and thus, have few age-related risk factors for AD that are known to vary by sex (i.e., cardiovascular disease, menopause, life expectancy). Investigate sex differences in markers of cognition and neurodegeneration in autosomal dominant AD. We conducted a retrospective study in 19 cognitively-unimpaired PSEN1 mutation carriers (age range 20-44; 11 females), 11 symptomatic carriers (age range 42-56; 8 females), and 23 matched non-carriers family members (age range 20-50; 13 females). We examined hippocampal volume ratio, CERAD Total Score, and CERAD Word List (i.e., Learning, Delayed Recall, and Recognition). Mann-Whitney U tests, Spearman correlations and regression models were conducted. There were no differential associations between age, CERAD Total Score, CERAD Word List-Learning, Delayed Recall, Recognition, and hippocampal volume ratio in male and female carriers and non-carriers. Cognitively-unimpaired female carriers showed better CERAD Total scores and CERAD Word List-Learning than cognitively-unimpaired male carriers, despite having similar hippocampal volume ratios. The interaction of sex and hippocampal volume ratio did not predict cognitive performance across groups. Our preliminary findings suggest that cognitively-unimpaired female carriers showed a verbal memory reserve, and as disease progresses, female carriers did not exhibit a cognitive susceptibility to AD-related neurodegeneration. Future studies with larger samples of autosomal dominant AD are warranted to further understand sex differences in AD-related clinical and pathological markers.


TRPM7 transactivates the FOSL1 gene through STAT3 and enhances glioma stemness.
We previously reported that TRPM7 regulates glioma cells' stemness through STAT3. In addition, we demonstrated that FOSL1 is a response gene for TRPM7, and the FOSL1 gene serves as an oncogene to promote glioma proliferation and invasion. In the present study, we determined the effects of FOSL1 on glioma stem cell (GSC) markers CD133 and ALDH1 by flow cytometry, and the maintenance of stem cell activity by extreme limiting dilution assays (ELDA). To further gain insight into the mechanism by which TRPM7 activates transcription of the FOSL1 gene to contribute to glioma stemness, we constructed a FOSL1 promoter and its GAS mutants followed by luciferase reporter assays and ChIP-qPCR in a glioma cell line and glioma patient-derived xenoline. We further examined GSC markers ALDH1 and TRPM7 as well as FOSL1 by immunohistochemistry staining (IHC) in brain tissue microarray (TMA) of glioma patients. We revealed that FOSL1 knockdown reduces the expression of GSC markers CD133 and ALDH1, and FOSL1 is required to maintain stem cell activity in glioma cells. The experiments also showed that mutations of - 328 to - 336 and - 378 to - 386 GAS elements markedly reduced FOSL1 promoter activity. Constitutively active STAT3 increased while dominant-negative STAT3 decreased FOSL1 promoter activity. Furthermore, overexpression of TRPM7 enhanced while silencing of TRPM7 reduced FOSL1 promoter activity. ChIP-qPCR assays revealed that STAT3, present in nuclear lysates of glioma cells stimulated by constitutively activated STAT3, can bind to two GAS elements, respectively. We demonstrated that deacetylation of FOSL1 at the Lys-116 residue located within its DNA binding domain led to an increase in FOSL1 transcriptional activity. We found that the expression of TRPM7, ALDH1, and FOSL1 protein is associated with grades of malignant glioma, and TRPM7 protein expression correlates to the expression of ALDH1 and FOSL1 in glioma patients. These combined results demonstrated that TRPM7 induced FOSL1 transcriptional activation, which is mediated by the action of STAT3, a mechanism shown to be important in glioma stemness. These results indicated that FOSL1, similar to GSC markers ALDH1 and TRPM7, is a diagnostic marker and potential drug target for glioma patients.


All non-real worlds provide exploration: Evidence from developmental psychology.
While Dubourg and Baumard argue that predisposition toward exploration draws us to fictional environments, they fail to answer their titular question: "Why Imaginary Worlds?" Research in pretend play, psychological distancing, and theatre shows that being "imaginary" (i.e., any type of unreal, rather than only fantastically unreal) makes exploration of any fictional world profoundly different than that of real-life unfamiliar environments.


Isolation of a nitrogen response regulator gene (nrr1) from Metarhizium anisopliae.
Attempts to improve the effectiveness of entomopathogenic fungi as biological control agents require a clear understanding of the pathogenicity determinants at both the biochemical and molecular level. Proteases play a key role in entomopathogenicity, allowing the fungus to penetrate the insect cuticle and rapidly invade the host. The most extensively studied of these protease activities, PR1A and PR2, are both subject to nitrogen derepression. The Metarhizium anisopliae nrr1 (nitrogen response regulator 1) gene was identified using a PCR-based strategy; it encodes a putative DNA-binding protein with a single zinc finger motif defined by the C-X2-C-X17-C-X2-C sequence. M. anisopliae NRR1 shows a significant sequence similarity to Neurospora crassa NIT2. Sequence analysis identified the presence of two introns, suggesting a greater degree of similarity to N. crassa nit2 than to the areA-like genes that have been identified. However, functional equivalence of nrr1 to areA was demonstrated, by co-transformation and complementation of an A. nidulans areA loss-of-function mutant (areA18 argB2 pabaA1 inoB2) with the M. anisopliae nrr1 gene. The areA-/nrr1+ Aspergillus transformants were able to grow on media with nitrate and glutamate as the sole nitrogen source, whereas the areA- strain is unable to grow under these conditions. The possible relevance of nitrogen regulation to pathogenicity is discussed.


Evaluation of a functional index and an articular index in ankylosing spondylitis.
We describe an index of functional impairment and a system of scoring joint tenderness for use in the assessment of ankylosing spondylitis. The functional index consists of 20 questions and the articular index is based on the scoring of a total of 10 joint responses after movement or firm digital pressure. These indices are simple to establish and not time consuming. They have a high degree of intra- and interobserver reproducibility. The indices showed changes in short term clinical trials of antiinflammatory drugs; these changes were highly correlated with the patient's overall assessment of his own clinical condition.


Exosomes from ovarian cancer cells induce adipose tissue-derived mesenchymal stem cells to acquire the physical and functional characteristics of tumor-supporting myofibroblasts.
Most tumor tissue is composed of parenchymal tumor cells and tumor stroma. Mesenchymal stem cells (MSCs) can function as precursors for tumor stromal cells, including myofibroblasts, which provide a favorable environment for tumor progression. A close relationship between tumor cells and MSCs in a tumor microenvironment has been described. Exosomes are small membrane vesicles that are enriched with a discrete set of cellular proteins, and are therefore expected to exert diverse biological functions according to cell origin. In the current study, we determined the biological effect of exosomes from two ovarian cancer cell lines (SK-OV-3 and OVCAR-3) on adipose tissue-derived MSCs (ADSCs). Exosome treatment induced ADSCs to exhibit the typical characteristics of tumor-associated myofibroblasts, with increased expression of α-SMA, and also increased expression of tumor-promoting factors (SDF-1 and TGF-β). This phenomenon was correlated with an increased expression of TGF-β receptors I and II. Analysis of TGF-β receptor-mediated downstream signaling pathways revealed that each exosome activated different signaling pathways, showing that exosomes from SK-OV-3 cells increased the phosphorylated form of SMAD2, which is essential in the SMAD-dependent pathway, whereas exosomes from OVCAR-3 cells increased the phosphorylated form of AKT, a representative SMAD-independent pathway. Taken together, exosomes from ovarian cancer cells induced the myofibroblastic phenotype and functionality in ADSCs by activating an intracellular signaling pathway, although the activated pathway could differ from exosome-to-exosome. The current study suggested that ovarian cancer-derived exosomes contribute to the generation of tumor-associated myofibroblasts from MSCs in tumor stroma.


[Adalimumab].
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation of the synovial joints, and eventual destruction of cartilage and bone, as well as various extra-articular signs and symptoms. The TNF-alpha blocker adalimumab (ADA) is a fully human IgG1 monoclonal antibody that neutralizes both soluble and membrane-bound TNF in humans. Several clinical trials have provided compelling evidence of the safety and clinical efficacy of ADA for both the induction and maintenance of remission in RA. Moreover, the beneficial effects of ADA on bone destruction seen in the joint of RA have been demonstrated by recent clinical investigation. This review will discuss the clinical efficacy and utility of ADA in the management of RA.


The nasal vestibulum is the optimal sampling site for MRSA screening in hospitalised horses.
The increased incidence of methicillin-resistant Staphylococcus aureus (MRSA) infection in equine hospitals highlights the need for infection control protocols based on optimal patient screening. In horses, the deep ventral meatus of the nasal cavity is the principal site sampled to detect MRSA. However, in humans, the anterior nares are the preferred sampling site. The objective of this study was to determine the optimal sampling location in the nasal chambers for MRSA in horses by comparing the results obtained from three different locations (the vestibulum, diverticulum and ventral meatus) in 240 hospitalised animals. Antimicrobial susceptibility testing and epidemiological typing were conducted on representative subsets of the isolates obtained. Compared to the more invasive ventral meatus sampling (relative sensitivity 68.9%; isolation rate 37.9%), vestibulum (RS 81.1%; IR 44.6%, P=0.13) and diverticulum (RS 52.3%; IR 28.8%, P=0.03) sampling were more or less sensitive, respectively. In total, 132 horses (55%) were MRSA positive with the vast majority (98.5%) carrying genotyped isolates of the livestock-associated (LA)-MRSA clonal complex (CC) 398, and only a minority (1.5%) CC8. Of the 22 MLST typed isolates, five belonged to a novel ST2197 (t011, CC398). Although 93.9% of the isolates were multi-resistant (to β-lactam, tetracycline, trimethoprim, and gentamicin), <5% were resistant to virtually all antimicrobials commonly used in equine medicine. The study findings indicate that detection of MRSA in horses may be enhanced by replacing the traditional deep sampling of the ventral nasal meatus by the less invasive approach of sampling the nasal vestibulum.


An iron-sulfur cluster in the zinc-binding domain of the SARS-CoV-2 helicase modulates its RNA-binding and -unwinding activities.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, uses an RNA-dependent RNA polymerase along with several accessory factors to replicate its genome and transcribe its genes. Nonstructural protein (nsp) 13 is a helicase required for viral replication. Here, we found that nsp13 ligates iron, in addition to zinc, when purified anoxically. Using inductively coupled plasma mass spectrometry, UV-visible absorption, EPR, and Mössbauer spectroscopies, we characterized nsp13 as an iron-sulfur (Fe-S) protein that ligates an Fe4S4 cluster in the treble-clef metal-binding site of its zinc-binding domain. The Fe-S cluster in nsp13 modulates both its binding to the template RNA and its unwinding activity. Exposure of the protein to the stable nitroxide TEMPOL oxidizes and degrades the cluster and drastically diminishes unwinding activity. Thus, optimal function of nsp13 depends on a labile Fe-S cluster that is potentially targetable for COVID-19 treatment.


A simple comparison of the extrinsic noise in gene expression between native and foreign regulations in Escherichia coli.
Living cells reorganize their gene expression through regulatory machineries in response to external perturbations. The contribution of the regulation to the noise in gene expression is of great interest. In this study, we evaluate the contribution of both native and foreign regulations to the extrinsic noise in gene expression. We analyzed the gene expression data of a mini-library containing 70 genetic constructs of 136 clones into which the gfp gene had been chromosomally incorporated under the control of either native or foreign regulation. We found that the substitution of native by foreign regulation, i.e., the insertion of the Ptet promoter, triggered a decrease in the extrinsic noise, which was independent of the protein abundance. The reanalyses of varied genomic data sets verified that the noisy gene expression mediated by native regulations is a common feature, regardless of the diversity in the genetic approaches used. Disturbing native regulations by a synthetic promoter reduced the extrinsic noise in gene expression in Escherichia coli. It indicated that the extrinsic noise in gene expression caused by the native regulation could be further repressed. These results suggest a tendency of released regulation leading to reduced noise and a linkage between noise and plasticity in the regulation of gene expression.


Brain somatostatin receptors in spontaneously hypertensive rats: an autoradiographic study.
The apparent densities of brain somatostatin (SRIF) receptor sites were compared in adult spontaneously hypertensive rats (SH) and their normotensive genetic counterparts (Wistar-Kyoto; WKY) using quantitative receptor autoradiography. Globally, the distribution of brain [125I][Tyr0, D-Trp8]SRIF14 binding sites was very similar in both strains. However, apparent densities of specific labeling were either higher (subfornical organ, 3.2 x; locus coeruleus, 1.9 x; lateroanterior hypothalamic nucleus, 1.3 x) or lower (basolateral amygdaloid nucleus, 0.8 x; spinal trigeminal sensory nucleus, 0.6 x) in SH than WKY rats in areas especially relevant to CNS cardiovascular integration. This provides further evidence for the possible involvement of brain SRIF neurons in cardiovascular regulation.


Selank, a Peptide Analog of Tuftsin, Attenuates Aversive Signs of Morphine Withdrawal in Rats.
Activity of a peptide tuftsin analogue Selank was studied in outbred rats using the naloxone-precipitated morphine withdrawal model. Single intraperitoneal injection of Selank in an anxiolytic dose of 0.3 mg/kg reduced the total index of morphine withdrawal syndrome by 39.6%, significantly (р<0.0001) attenuated convulsive reactions, ptosis, and posture disorders, and 9-fold increased the tactile sensitivity threshold in morphine-dependent rats in comparison with the group of active control; at the same time, Selank was slightly inferior to diazepam in a dose of 2 mg/kg by pharmacological activity (the decrease in total index of morphine withdrawal syndrome by 49.3% and 13-fold increase in sensitivity threshold). Thus, Selank, like diazepam, weakens the aversive signs of morphine withdrawal in rats with opiate dependence.


Characterization of HU-like protein from Bifidobacterium longum.
A HU-like protein (HBl) of Bifidobacterium longum was purified and characterized. HBl is heat-stable and acid-resistant, and has a molecular weight of about 9.1 kDa as estimated by its mobility on electrophoresis. HBl is intermediate in basicity (pI 9.8) between the HU-1 and HU-2 proteins of Escherichia coli, and is dissociated from a calf thymus DNA-cellulose column at 300-400 mM NaCl. Its amino acid composition shows many similarities with that of E coli HU. The NH2-terminal amino acid sequence of HBl also shows significant similarities to the consensus sequence deduced from the sequences of eleven HU-like proteins from prokaryotic sources. Chemical crosslinking analysis indicated that the HBl protein predominantly forms a homotypic dimer.


Subiculum-entorhinal cortex interactions during in vitro ictogenesis.
Our aim was to establish the contribution of neuronal networks located in the entorhinal cortex (EC) and subiculum to the generation of interictal and ictal onset patterns recorded in vitro. We employed field potential recordings of epileptiform activity in rat brain slices induced with the application of the K(+) channel blocker 4-aminopyridine. Local connections between the EC and subiculum were severed to understand how EC-subicular circuits contribute to patterns of epileptiform synchronization. First, we found that ictal discharges occurred synchronously in these two structures, initiating from either the EC or subiculum, and were characterized by low voltage fast (LVF) or sudden onsets. Second, sudden onset ictal events initiated more frequently in the EC, whereas LVF onset ictal discharges appeared more likely to initiate in the subiculum (P<0.001). In both structures, polyspike interictal discharges occurred in brain slices generating sudden onset ictal events while isolated slow interictal discharges were recorded in experiments characterized by LVF onset ictal activity. Third, severing the connections between subiculum and EC desynchronized both interictal and ictal discharges occurring in these two regions, leading to a significant decrease in ictal duration (regardless of the onset type) along with blockade of polyspike interictal activity in subiculum. These findings highlight the contribution of EC-subicular interactions to epileptiform synchronization and, specifically, to ictogenesis in this in vitro model.


JSUM ultrasound elastography practice guidelines: basics and terminology.
Ten years have passed since the first commercial equipment for elastography was released; since then clinical utility has been demonstrated. Nowadays, most manufacturers offer an elastography option. The most widely available commercial elastography methods are based on strain imaging, which uses external tissue compression and generates images of the resulting tissue strain. However, imaging methods differ slightly among manufacturers, which results in different image characteristics, for example, spatial and temporal resolution, and different recommended measurement conditions. In addition, many manufacturers have recently provided a shear wave-based method, providing stiffness images based on shear wave propagation speed. Each method of elastography is designed on the basis of assumptions of measurement conditions and tissue properties. Thus, we need to know the basic principles of elastography methods and the physics of tissue elastic properties to enable appropriate use of each piece of equipment and to obtain more precise diagnostic information from elastography. From this perspective, the basic section of this guideline aims to support practice of ultrasound elastography.


Cyclic nucleotides in nervous tissue.
A review of the literature emphasizes that cyclic nucleotides play a key role in regulation of cell growth, differentiation and metabolism in diverse tissues and, in addition, are closely involved in neural tissue function. The role of cAMP as a second messenger is discussed.


Catastrophic health expenditure and its determinants among Nigerian households.
Health expenditure can be substantial, especially in countries without national health insurance schemes, and it can negatively affect people's welfare. This study uses recent data to evaluate the extent to which Nigerian households suffer from catastrophic health expenditure (CHE) and evaluates its determinants. We used the Living Standards Survey 2018-2019 to estimate the headcount of Nigerian households that experience CHE-the proportion of health expenditures exceeding a certain ratio of such expenditures to non-food expenditures. To evaluate the determinants of CHE, we used ordinary least square regression with state fixed effects. The total sample was 22,110 nationally representative households. Many households, especially poorer ones, do not have any health care expenses; only 60.6% of the poorest households had some health-related expenditure. Even with the limited health-seeking behaviors in this demographic, the percentage of households that suffered from CHE was very high: with a 15% cutoff for CHE thresholds, 34.9 to 44.2% of households experienced CHE. Lower education, higher non-food consumption, and rural residence were correlated with higher amounts of health expenditure and higher odds of CHE. Health-seeking behaviors such as clinic visits for sickness treatment and prevention are limited, especially among the poorer households. Even so, the headcount of households experiencing CHE is very high in Nigeria. Advancing the implementation of national health insurance scheme is important to reduce the burden of health expenditure, especially among the poor, as well as to remove financial barriers to their seeking adequate health services.