RF9 Acts as a KISS1R Agonist In Vivo and In Vitro.
RF9, a reported antagonist of the mammalian gonadotropin-inhibitory hormone receptor, stimulates gonadotropin secretion in mammals. Recent studies have suggested that the stimulatory effect of RF9 on gonadotropin secretion relies on intact kisspeptin receptor (KISS1R) signaling, but the underlying mechanisms remain to be elucidated. Using Chinese Hamster Ovary cells stably transfected with KISS1R, we show that RF9 binds specifically to KISS1R, with a Kd of 1.6 × 10(-5)M, and stimulates an increase in intracellular calcium and inositol phosphate accumulation in a KISS1R-dependent manner, with EC50 values of 3.0 × 10(-6)M and 1.6 × 10(-7)M, respectively. RF9 also stimulated ERK phosphorylation, with a time course similar to that of kisspeptin-10. RFRP-3, the putative endogenous ligand for NPFFR1, did not stimulate inositol phosphate accumulation or pERK, nor did it alter responses to of kisspeptin-10 or RF9. In agreement with these in vitro data, we found that RF9 stimulated a robust LH increase in Npffr1(-/-) mice, similar to that in wild-type littermates, whereas the stimulatory effect of RF9 was markedly reduced in Kiss1r(-/-) and double Kiss1r(-/-)/Npfrr1(-/-) mice. The stimulatory effect of RF9 on LH secretion was restored by the selective rescue of Kiss1r expression in GnRH neurons, in Kiss1r(-/-T) mice. Taken together, our study demonstrates that RF9 acts primarily as a KISS1R agonist, but not as an allosteric modulator, to stimulate LH secretion. Our findings raise questions regarding the utility of RF9 for assessing NPFF1R function and de-emphasize a predominant role of this signaling system in central regulation of reproduction.


Changes in Circulating Kisspeptin Levels During Each Trimester in Women With Antenatal Complications.
Antenatal complications such as hypertensive disorders of pregnancy (HDP), fetal growth restriction (FGR), gestational diabetes (GDM), and preterm birth (PTB) are associated with placental dysfunction. Kisspeptin has emerged as a putative marker of placental function, but limited data exist describing circulating kisspeptin levels across all 3 trimesters in women with antenatal complications. We aimed to assess whether kisspeptin levels are altered in women with antenatal complications. Women with antenatal complications (n = 105) and those with uncomplicated pregnancies (n = 265) underwent serial ultrasound scans and blood sampling at the Early Pregnancy Assessment Unit at Hammersmith Hospital, UK, at least once during each trimester (March 2014 to March 2017). The women with antenatal complications (HDP [n = 32], FGR [n = 17], GDM [n = 35], PTB [n = 11], and multiple complications [n=10]) provided 373 blood samples and the controls provided 930 samples. Differences in circulating kisspeptin levels were assessed. Third-trimester kisspeptin levels were higher than controls in HDP but lower in FGR. The odds of HDP adjusted for gestational age, maternal age, ethnicity, BMI, smoking, and parity were increased by 30% (95% CI, 16%-47%; P < 0.0001), and of FGR were reduced by 28% (95% CI, 4-46%; P = 0.025), for every 1 nmol/L increase in plasma kisspeptin. Multiple of gestation-specific median values of kisspeptin were higher in pregnancies affected by PTB (P = 0.014) and lower in those with GDM (P = 0.020), but not significantly on multivariable analysis. We delineate changes in circulating kisspeptin levels at different trimesters and evaluate the potential of kisspeptin as a biomarker for antenatal complications.


Centrifugal deposition of microgels for the rapid assembly of nonfouling thin films.
Thin films assembled from microgel building blocks have been constructed using a simple, high-throughput, and reproducible centrifugation (or "active") deposition technique. When compared to a common passive adsorption method (e.g., dip coating), microgels that are actively deposited onto a surface have smaller footprints and are more closely packed. Under both active and passive deposition conditions, the microgel footprint areas decrease during deposition. However, under active deposition, the microgel footprint appears to decrease continually and to a greater degree over the course of the deposition, forming a tightly packed, homogeneous film. Taking advantage of the rapid and uniform assembly of these films, we demonstrate the use of active deposition toward the fabrication of polyelectrolyte multilayers containing anionic microgels and a cationic linear polymer. Microgel multilayers successfully demonstrated effective blocking of the underlying substrate toward macrophage adhesion, which is a highly sought-after property for modulating the inflammatory response to an implanted biomaterial.


Where to Sit? Type of Sitting Matters for the Framingham Cardiovascular Risk Score.
Current evidence on associations of type-specific sedentary behavior with cardiovascular disease (CVD) is limited to mainly screen-time sedentary behavior (SB). We aimed to study the associations of type-specific and total time spent sitting with the Framingham 10-year cardiovascular disease risk score (Framingham score) in Finnish adults. Data comprise the National FINRISK 2007 and 2012 health examination surveys with 10,185 participants aged 25-74 years, apparently free of CVD. Participants reported average daily time spent sitting in different locations: work-related sitting, at home in front of television (TV), at home in front of computer, in a vehicle, and elsewhere. Total SB time was calculated from these context-specific self-reports. Accelerometer-based sedentary time was assessed in 988 FINRISK 2012 participants. Framingham score was calculated using information on blood pressure and its medication, cholesterol levels, age, diabetes status, and smoking. Analyses were adjusted for age, study year, education, employment status, leisure time physical activity, and body mass index. Out of several type-specific sitting behaviors, only TV sitting showed systematic associations with the Framingham score in both genders. The lowest Framingham risk was found for TV sitting from 6 minutes to less than 1 hour daily. Of other types of sitting, computer sitting was inversely associated with the Framingham risk in men only. Total self-reported sitting time did not show significant associations with the Framingham score, but instead higher objectively assessed sedentary time showed higher Framingham risk in men. TV sitting showed most systematic associations with CVD risk score. This suggests that of all types of SB, reducing TV sitting should be targeted for reducing CVD risk.


Differential Effects of Infant Vocalizations on Approach-Avoidance Postural Movements in Mothers.
Infant vocalization plays a pivotal role in communicating infant mood to parents and thereby motivating parenting responses. Although many psychological and neural responses to infant vocalization have been reported, few studies have examined maternal approach-avoidance behavior in response to infant vocalization. Thus, this research sought to determine how infant emotional vocalization affects maternal behavior. Twenty mothers participated in this behavioral study, all of whom had infants of 24 months old or less. In the experiment, they stood on a Balance Board that collected real-time data regarding center of pressure (COP), while listening to a series of infant vocalizations including cry, laugh, and babbling. They then listened to the same vocalizations for a second time and rated their felt emotions in response to each vocalization. The participants demonstrated significant postural movements of approaching in response to cry stimuli or to stimuli regarded as highly urgent. In contrast, they demonstrated postural movement of avoidance in response to laugh vocalization. These findings suggest that parenting behavior in response to infant emotional vocalization is regulated not by the pleasant-unpleasant axis but by the urgency of the stimulus.


[Study of deglutition using various sound signals].
In man quantitative information on deglutition may be obtained with the aid of various sounds recorded by way of microphone and magnetic tapes. The different tapes, microphonic, dynamic and piezoelectric, can be compared through the use of a Doppler signal in high middle position, thus showing the backward movements of the mylohyoïdeus. The sound of the deglutition consists of 1 to 3 peaks of great amplitude: 350 +/- 180 microV or 14 +/- 3.3 mV according to the type of microphone used (the piezo gives the greatest amplitude, specially in low frequency range); duration for the main phoneburst: 48 +/- 24 ms with a prolongation with the smaller noises: so total duration amounts to 400 ms. Each sound impulsion repeated in 10 Hz range includes frequency up to 6 KHz. The direct recording on a polygraph falls into 10-60 range; upper frequencies may be eliminated by filtering. In front, the inspiratory relative time increases of 57 +/- 12% without deglutition whereas it reaches 62 +/- 16% with deglutition. In clinical situation, a magnetic tape recorder can be used. The main components in normal situation of deglutition of saliva, water or yogurt show a frequent variability. Nevertheless, a certain number of recurring impulsions can be defined according to the type of deglutition, thus further defining several basic types of deglutition. Amplitude and duration deglutition type 1 (= one impulsion) was observed in young subjects for saliva and yogurt; deglutition type 2-3 (greater than or equal to 200 ms) more frequently for water and also in oldest subjects, whatever the mode of deglutition. In some pathological situations, a significant increase of amplitude and duration was observed. Technical conditions are discussed for application in clinical situations and their control in laboratory.


[Study of the virustatic action of rimantadine based on a phage-bacterium model].
The action of rimantadin on the lambda phages was studied. The maximal inhibitory effect on the compound was observed on the 1st-6th minutes after the infection. There was no such effect on the T-4 and lambda phage replication. According to the data of incorporation of the radioactive precursors into the phage DNA, RNA, and proteins, and the manifestation of the rimantadin action on phage replication it was supposed that the inhibitory effect of rimantadin was determined by its influence on the RNA-polymerases, preponderantly on the phage RNA-polymerase.


Validation of an automated tractography method for the optic radiations as a biomarker of visual acuity in neurofibromatosis-associated optic pathway glioma.
Fractional anisotropy (FA) of the optic radiations has been associated with vision deficit in multiple intrinsic brain pathologies including NF1 associated optic pathway glioma, but hand-drawn regions of interest used in previous tractography methods limit consistency of this potential biomarker. We created an automated method to identify white matter tracts in the optic radiations and compared this method to previously reported hand-drawn tractography. Automated tractography of the optic radiation using probabilistic streamline fiber tracking between the lateral geniculate nucleus of the thalamus and the occipital cortex was compared to the hand-drawn method between regions of interest posterior to Meyer's loop and anterior to tract branching near the calcarine cortex. Reliability was assessed by two independent raters in a sample of 20 healthy child controls. Among 50 children with NF1-associated optic pathway glioma, the association of FA and visual acuity deficit was compared for both tractography methods. Hand-drawn tractography methods required 2.6±0.9min/participant; automated methods were performed in <1min of operator time for all participants. Cronbach's alpha was 0.83 between two independent raters for FA in hand-drawn tractography, but repeated automated tractography resulted in identical FA values (Cronbach's alpha=1). On univariate and multivariate analyses, FA was similarly associated with visual acuity loss using both methods. Receiver operator characteristic curves of both multivariate models demonstrated that both automated and hand-drawn tractography methods were equally able to distinguish normal from abnormal visual acuity. Automated tractography of the optic radiations offers a fast, reliable and consistent method of tract identification that is not reliant on operator time or expertise. This method of tract identification may be useful as DTI is developed as a potential biomarker for visual acuity.


Pathophysiology and management of severe asthma.
Severe asthma is characterized by marked airway obstruction caused by mucus plugging, airway edema and inflammation, and contractions of airway smooth muscle. This leads to a complex series of pathophysiologic events that can be reversed with vigorous treatment given for a sufficient period of time. Standard treatment includes not only bronchodilating agents and corticosteroids but in some instances mechanical ventilation.


The Aggregate Demand Index: measuring the balance between pharmacist supply and demand, 1999-2001.
To describe the development and 2-year performance of the Aggregate Demand Index (ADI) survey, a tool for longitudinally tracking the difficulty of filling open pharmacist positions throughout the United States. From August 1999 through July 2001, panelists completed a monthly survey on the difficulty of filling open pharmacist positions by state. Results are reported on the Web (www.pharmacymanpower.com). Panelists estimated difficulty filling pharmacist vacancies in the community, institutional, both community and institutional, and nonpatient care pharmacy settings. A panel of individuals involved in the direct hiring of pharmacists. A monthly survey. Monthly indices reflecting the level of difficulty filling open pharmacy positions at the state, regional, and national levels and by pharmacy position type. Over time, these data formed a longitudinal record of the balance between the supply of and demand for pharmacists. Cumulative data from 50 states and the District of Columbia showed, on average, excess demand over available supply. The five states with the highest unmet demand level (i.e., where it was most difficult to fill open positions) were Minnesota, California, Wisconsin, Iowa, and Kentucky. The only states in which demand was in balance with supply were Hawaii and Rhode Island. Over 2 years, at least 92% of the U.S. population each month resided in areas where demand for pharmacists exceeded supply. The demand level in the Northeast was significantly lower than in other regions. Unmet demand was greatest for organizations with both community and institutional positions and least for organizations with primarily community positions. For the study period, the demand for pharmacists exceeded the available supply in the United States; ADI survey data indicated than open pharmacist positions were "somewhat difficult" to "difficult" to fill. Substantial but unexplained differences were noted by state, by region, and by type of pharmacy position. Other health care professions could use the ADI survey methodology to study workforce issues.


Subspace tracking for phase noise source separation in frequency combs.
It is widely acknowledged that the phase noise of an optical frequency comb primarily stems from the common mode (carrier-envelope) and the repetition rate phase noise. However, owing to technical noise sources or other intricate intra-cavity factors, residual phase noise components, distinct from the common mode and the repetition rate phase noise, may also exist. We introduce a measurement technique that combines subspace tracking and multi-heterodyne coherent detection for the separation of different phase noise sources. This method allows us to break down the overall phase noise sources associated with a specific comb-line into distinct phase noise components associated with the common mode, the repetition rate and the residual phase noise terms. The measurement method allow us, for the first time, to identify and measure residual phase noise sources of a frequency modulated mode-locked laser.


Appendicitis Following Blunt Abdominal Trauma: An Illustrative Case.
Acute appendicitis is the most common abdominal surgical emergency, with an average of 7-9% of individuals developing the condition within their lifetime.1 While cases of acute traumatic appendicitis are rare, medical literature supports their plausibility with the most famous case stretching back to the controversial 1926 death of stunt performer, Harry Houdini. Several mechanisms have been proposed by which blunt abdominal trauma results in acute appendicitis. In this review, we describe a young, otherwise healthy male, who developed epigastric abdominal pain after being struck in the abdomen while wrestling with his cousin of similar age. The patient was found to have peri-appendiceal inflammatory change, appendiceal mural thickening and edema consistent with acute uncomplicated appendicitis.


Optical Control of Polarization Switching in a Single-Component Organic Ferroelectric Crystal.
The optical control of polarization switching is attracting tremendous interest because photoirradiation stands out as a nondestructive, noncontact, and remote-control means beyond an electric or strain field. The current research mainly uses various photoexcited electronic effects to achieve the photocontrol polarization, such as a light-driven flexoelectric effect and a photovoltaic effect. However, since photochromism was discovered in 1867, the structural phase transition caused by photoisomerization has never been associated with ferroelectricity. Here, we successfully synthesized an organic photochromic ferroelectric with polar space group Pna21, 3,4,5-trifluoro-N-(3,5-di-tert-butylsalicylidene)aniline, whose color can change between yellow and orange via laser illumination. Its dielectric permittivity and spontaneous polarization can be switched reversibly with a photoinduced phase transition triggered by structural photoisomerization between the enol form and the trans-keto form. To our knowledge, this is the first photoswitchable ferroelectric crystal to achieve polarization switching through a structural phase transition triggered by photoisomerization. This finding paves the way toward photocontrol of smart materials and biomechanical applications in the future.


Hypersexuality in neurocognitive disorders in elderly people - a comprehensive review of the literature and case study.
Hypersexuality is defined as an increase in libido. It is often confounded with sexual disinhibition and inappropriate sexual behavior directed against oneself or against others. It is described in 2.9 to 8% of patients living at home and in 3.8 to 7% of patients in institutions. The pathophysiology of hypersexuality is complex. Several brain areas are involved. The psychological factors are also important. We found it useful to present a clinical case of a patient who presented with symptoms of hypersexuality and to discuss the diagnosis and the management. Data collection was based on the case of a patient hospitalized in the Department of Psychosomatic medicine in CHU Mont-Godinne - Yvoir - Belgium in February 2013. For the literature review, we used the database PubMed with the following keywords: hypersexuality, dementia. A total of 40 articles were selected for this study. The patient had symptoms of hypersexuality, and hyperorality in the context of delirium induced by benzodiazepine withdrawal. A blood test and brain imaging were normal. She was put under risperidone 2 mg with complete resolution of symptoms within a few days. The diagnosis of Kluver-Bucy syndrome in the context of a minor neurocognitive disorder was retained. Management is mainly non-pharmacological using behavioral techniques. The education of the patient, his partner and caregivers are essential. Pharmacotherapy is sometimes necessary. It is reserved as a last resort because of the serious side effects of the drugs used.


Ventilation in a Residential Building Brings Outdoor NOx Indoors with Limited Implications for VOC Oxidation from NO3 Radicals.
Energy-efficient residential building standards require the use of mechanical ventilation systems that replace indoor air with outdoor air. Transient outdoor pollution events can be transported indoors via the mechanical ventilation system and other outdoor air entry pathways and impact indoor air chemistry. In the spring of 2022, we observed elevated levels of NOx (NO + NO2) that originated outdoors, entering the National Institute of Standards and Technology (NIST) Net-Zero Energy Residential Test Facility through the mechanical ventilation system. Using measurements of NOx, ozone (O3), and volatile organic compounds (VOCs), we modeled the effect of the outdoor-to-indoor ventilation of NOx pollution on the production of nitrate radical (NO3), a potentially important indoor oxidant. We evaluated how VOC oxidation chemistry was affected by NO3 during NOx pollution events compared to background conditions. We found that nitric oxide (NO) pollution introduced indoors titrated O3 and inhibited the modeled production of NO3. NO ventilated indoors also likely ceased most gas-phase VOC oxidation chemistry during plume events. Only through the artificial introduction of O3 to the ventilation duct during a NOx pollution event (i.e., when O3 and NO2 concentrations were high relative to typical conditions) were we able to measure NO3-initiated VOC oxidation products, indicating that NO3 was impacting VOC oxidation chemistry.


Effects and possible mechanism of a picosecond pulsed electric field on angiogenesis in cervical cancer in vitro.
Picosecond pulsed electric field (psPEF) is an athermal, minimally invasive and local ablative biomedical engineering technique used in cancer therapy. However, to the best of our knowledge, the effect of psPEF on angiogenesis in cervical cancer is unknown. Therefore, the aim of the current study was to investigate the effects and possible mechanism of psPEF on angiogenesis in cervical cancer in vitro. HeLa cell and human umbilical vein endothelial cell (HUVEC) suspensions were exposed to psPEF with an increasing gradient of electric field intensity (0, 200, 400 and 600 kV/cm). A Cell Counting kit-8 assay and flow cytometry were used to investigate the effect of psPEF on the proliferation and apoptosis of HUVECs. The invasion, migration and tube formation capabilities of HUVECs following psPEF treatment were investigated by Transwell invasion assay, scratch test and lumen formation assay, respectively. Changes in the protein and mRNA levels of angiogenesis-associated factors in HeLa cells were detected by western blot analysis and reverse transcription-quantitative polymerase chain reaction. psPEF was identified to inhibit proliferation and tube formation, and induce apoptosis and necrosis of HUVECs in a dose-dependent manner. psPEF was revealed to decrease the protein and mRNA expression levels of vascular endothelial growth factor and hypoxia-inducible factor 1α in HeLa cells. In summary, psPEF exhibited anti-angiogenic effects in cervical cancer in vitro by exerting direct effects on HUVECs and indirect effects on angiogenesis-associated factors in HeLa cells.


Treatment of pterygium with conjunctival limbal autograft and mitomycin C--a comparative study.
A total of 60 eyes with primary progressive pterygium were selected. They were randomly divided into two groups ie, group A and group B each consisting of 30 eyes. Group A patients were treated with pteryglum excision with ipsilateral conjunctival-limbal autografting. Group B patients were treated with pterygium excision followed by mitomycin C 0.02% for two minutes. Both groups were followed up for one year postoperatively to document recurrence rates and postoperative complications. In group A recurrence rate was 3.0% with minimal ocular complication after one year follow-up. But in group B recurrence rate was high as 10.0% and ocular complications were significant after the same period of postoperative follow-up. Both conjunctival-limbal autograft and intra-operative mitomycin use are effective method of surgical treatment of pterygium but considering the rate of recurrence and other postoperative ocular morbidity conjunctival-limbal autografting seems to be the best method of pterygium treatment.


Sustaining extended Kangaroo mother care in stable low birthweight babies in NICU: a quality improvement collaborative of six centres of Karnataka.
Kangaroo mother care (KMC) is a proven intervention for intact survival in preterms. Despite evidence, its adoption has been low. We used a point of care quality improvement (QI) approach to implement and sustain KMC in stable low birthweight babies from a baseline of 1.5 hours/baby/day to above 4 hours/baby/day through a series of plan-do-study-act (PDSA) cycles over a period of 53 weeks. All babies with birth weight <2000 g not on any respiratory support or phototherapy and or umbilical lines were eligible. The key quantitative outcome was KMC hours/baby/day. A QI collaborative was formed between six centres of Karnataka mentored by a team with a previous QI experience on KMC. The potential barriers for extended KMC were evaluated using fishbone analysis. Baseline data were collected over 3 weeks. A bundled approach consisting of a variety of parent centric measures (such as staff awareness, making KMC an integral part of treatment order, foster KMC, awareness sessions to parents weekly, recognising KMC champions) was employed in multiple PDSA cycles. The data were aggregated biweekly and the teams shared their implementation experiences monthly. A total of 1443 parent-baby dyads were enrolled. The majority barriers were similar across the centres. Bundled approach incorporating foster KMC helped in the quick implementation of KMC even in outborns. Parental involvement and empowering nurses helped in sustaining KMC. Two centres had KMC rates above 10 hours/baby/day, while remaining four centres had KMC rates sustained above 6 hours/baby/day. Cross-learnings from team meetings helped to sustain efforts. Extended KMC could be implemented and sustained by low intensity training and QI collaboration. Formation of a QI collaborative with mentoring helped in scaling implementation of extended KMC. Extended KMC could be implemented by parent centric best practices in all the centres without any additional need of resources.


[Acquired phimosis due to lichen sclerosus et atrophicus].
From January 1986 to December 1991, 6 cases of acquired phimosis secondary to balanitis xerotica obliterans were observed. The authors report their experience in the diagnosis and treatment of this disease. Five patients were treated with plastic of the foreskin, one was circumcised and treated with local instillation of corticoids. The authors conclude that the histological study of the specimen is very important to demonstrate the nature of the lesion.


The association between maternal serum first trimester free βhCG, second trimester intact hCG levels and foetal growth restriction and preeclampsia.
The purpose of this study was to analyse the association between free beta hCG (fβhCG) increased levels and pregnancy complications (PC), foetal growth restriction (FGR) and preeclampsia (PE). This connection was evaluated in two stages (i) investigating the association between those PC with first trimester fβhCG and second trimester intact hCG (ihCG), and (ii) studying the association between these two analytes in the same pregnancy. This was a retrospective study in two settings: medical centre that provided data on fβhCG and ihCG levels in pregnancies with FGR and PE, and central laboratory that provided fβhCG and ihCG levels that were compared in the same pregnancy. No association was found between those PC and the hCG analytes, except for elevated ihCG levels and FGR. Elevated fβhCG (>3.00 MoM) was found in 570/16,849 (3.4%) women. However, only 14% of whom had elevated second trimester ihCG. A positive correlation was found between the magnitude of first trimester fβhCG levels and the percentage of women who had elevated second trimester ihCG. This association was determined by the magnitude of the elevation of fβhCG levels. Impact statement What is already known on this subject: The two analytes, first trimester fβhCG and second trimester ihCG, are independently produced and parameters of the biochemical screening during pregnancy. What the results of this study add: Referring to 3.00 MoM as cut-off levels, most pregnancies with elevated levels of first trimester fβhCG will have normal ihCG second trimester levels. What the implications are of these findings for clinical practice and/or further research: The risk of developing pregnancy complications, FGR and PE should be associated with second trimester ihCG levels. About 3.5% of women had high fβhCG levels during the first trimester. However, only 14% also had increased ihCG levels, defined as >3.00 MoM; additional studies are needed to explore the association between increased first trimester fβhCG levels and the risk of developing pregnancy complications, independent of ihCG levels in the second trimester.


Retinal branch vein occlusion: a study of argon laser photocoagulation in the treatment of macular oedema.
A control trial is reported which demonstrates that treatment with argon laser photocoagulation to certain patients with macular oedema following a branch vein occlusion does not alter significantly their visual prognosis. It confirms that patients with an intact perifoveal capillary arcade have a better prognosis than those with a broken arcade.


The biological index of frailty: A new index for the assessment of frailty in human skeletal remains.
Frailty is the physiological stress that individuals suffer during their life. In past populations, frailty is conventionally assessed through the occurrence of different biomarkers of biological stress. Some efforts have been made to propose indexes that combine all biomarkers. However, these indices have some critical limitations: they cannot be used on incomplete skeletons, do not consider the severity and/or healing of lesions, and assign equal importance to different biomarkers. To address these limitations, we propose a new index to assess frailty in skeletal individuals. By statistically analyzing a large amount of osteological data available from the Museum of London, and using a Logit model, we were able to define a different weight for each reported biomarker of frailty, based on their importance in increasing the risk of premature death for the individuals. The biological index of frailty (BIF) is the weighted mean of all biomarkers scored on the individuals, according to a different degree of importance assigned to each one. It also considers the severity and healing of the biomarkers when this is relevant to diagnose frailty. We applied BIF on a sample of Monastics and Non-Monastics from medieval England and compared it with the skeletal index of frailty (SFI). BIF is the first frailty index that gives a different weight to each skeletal biomarker of stress, considers both severity and healing of the lesions, and can be applied on partial skeletal remains. The comparison with SFI showed that BIF is applicable to a larger number of skeletal individuals, revealing new differences between the Monastic and the Non-Monastic groups.


ESCRT-III Component CHMP4C Attenuates Cardiac Hypertrophy by Targeting the Endo-Lysosomal Degradation of EGFR.
Cardiac hypertrophy and subsequent heart failure impose a considerable burden on public health worldwide. Impaired protein degradation, especially endo-lysosome-mediated degradation of membrane proteins, is associated with cardiac hypertrophy progression. CHMP4C (charged multivesicular body protein 4C), a critical constituent of multivesicular bodies, is involved in cellular trafficking and signaling. However, the specific role of CHMP4C in the progression of cardiac hypertrophy remains largely unknown. Mouse models with CHMP4C knockout or cardiadc-specific overexpression were subjected to transverse aortic constriction surgery for 4 weeks. Cardiac morphology and function were assessed through histological staining and echocardiography. Confocal imaging and coimmunoprecipitation assays were performed to identify the direct target of CHMP4C. An EGFR (epidermal growth factor receptor) inhibitor was administrated to determine whether effects of CHMP4C on cardiac hypertrophy were EGFR dependent. CHMP4C was significantly upregulated in both pressure-overloaded mice and spontaneously hypertensive rats. Compared with wild-type mice, CHMP4C deficiency exacerbated transverse aortic constriction-induced cardiac hypertrophy, whereas CHMP4C overexpression in cardiomyocytes attenuated cardiac dysfunction. Mechanistically, the effect of CHMP4C on cardiac hypertrophy relied on the EGFR signaling pathway. Fluorescent staining and coimmunoprecipitation assays confirmed that CHMP4C interacts directly with EGFR and promotes lysosome-mediated degradation of activated EGFR, thus attenuating cardiac hypertrophy. Notably, an EGFR inhibitor canertinib counteracted the exacerbation of cardiac hypertrophy induced by CHMP4C knockdown in vitro and in vivo. CHMP4C represses cardiac hypertrophy by modulating lysosomal degradation of EGFR and is a potential therapeutic candidate for cardiac hypertrophy.


Foster youth emancipating from care: caseworkers' reports on needs and services.
This article presents findings from a survey mailed to caseworkers, who answered questions about special needs, independent living skills, educational attainment, and services for 416 randomly selected foster youth in Illinois. A third of the adolescents had a mental health disorder, developmental disability, or other special need that their caseworkers believed would interfere with their ability to live independently. Additionally, urban youth were underserved relative to other youth. Youth with more behavior problems and educational and job skill deficits were less likely than other youth to continue to receive child welfare services past age 18, suggesting that services must be provided throughout adolescence to meet the needs of the most vulnerable clients.


High-resolution computed tomography in pediatric patients with postinfectious bronchiolitis obliterans.
The authors performed a prospective cohort study to define the high-resolution computed tomography features of 31 pediatric patients with postinfectious bronchiolitis obliterans. All patients underwent chest radiographs and lung perfusion scans, and 27 of the 31 patients underwent high-resolution computed tomography of the lung. The most common abnormal features shown on computed tomography included bronchial wall thickening, bronchiectasis, and areas of increased and decreased attenuation. High-resolution computed tomography showed a higher sensitivity than both chest radiography and lung perfusion scanning in detecting pulmonary abnormalities in these patients.


Envelope-dependent, cyclophilin-independent effects of glycosaminoglycans on human immunodeficiency virus type 1 attachment and infection.
Cell surface glycosaminoglycans (GAGs), in particular heparan sulfate (HS), have been proposed to mediate the attachment of human immunodeficiency virus type 1 (HIV-1) to target cells prior to virus entry, and both the viral gp120 envelope protein and virion-associated cyclophilin A (CypA) have been shown to directly interact with HS and its analogues. To determine the role of GAGs in HIV attachment and infection, we generated HIV-susceptible derivatives of CHO cell lines that either express high levels of GAGs (CHO-K1) or lack GAGs (pgsA745). Using a panel of HIV-1 envelopes, we found that cell surface GAG-mediated effects on virion attachment and infection vary in an envelope strain-dependent but coreceptor-independent manner. In fact, cell surface GAG-mediated enhancement of infection is confined to isolates that contain a highly positively charged V3-loop sequence, while infection by most strains is apparently inhibited by the presence of GAGs. Moreover, the enhancing and inhibitory effects of polycations and polyanions on HIV-1 infection are largely dependent on the presence of cell surface GAGs. These observations are consistent with a model in which GAGs influence in vitro HIV-1 infection primarily by modifying the charge characteristics of the target cell surface. Finally, the effects of GAGs on HIV-1 infection are observed to an equivalent extent whether CypA is present in or absent from virions. Overall, these data exclude a major role for GAGs in mediating the attachment of many HIV-1 strains to target cells via interactions with virion-associated gp120 or CypA.


Pentachloro(pyrazine)rhenate(IV) complex as precursor of heterobimetallic pyrazine-containing Re(IV)2M(II) (M = Ni, Cu) species: synthesis, crystal structures and magnetic properties.
Three novel Re(IV) mononuclear complexes of formulae NBu4[ReC15(pyz)] (1), NH2Me2[ReCl5(pyz)] (2) and NH4[ReCl5(pyz)].0.75H2O (3), (pyz being pyrazine; NBu4+ = tetra-n-butylammonium cation, NH2Me2+ = dimethylammonium cation and NH4+ = ammonium cation), were synthesized by ligand substitution reaction from [ReCl6]2- anion and pyrazine in N,N-dimethylformamide (DMF). In addition, two new heterobimetallic compounds, the salt namely [ReCl5(pyz)]2[Ni(cyclam)](4) (cyclam = 1,4,8,11-tetraazacyclotetradecane) and the heterotrinuclear [{ReCl5(mu-pyz)}2Cu(DMF)4] (5) complex, were prepared by using as precursor 1 and 3, respectively. Compounds 1-5 were characterized by single-crystal X-ray diffraction. 1-3 are made up of discrete [ReCl5(pyz)]- anions and NBu4 (1), NH2Me2+ (2) and NH4+ (3) cations. [ReCl5(pyz)]- unit interacts toward Ni(II) (4) and Cu(II) (5) metal ions through different modes. In 4 two [ReCl5(pyz)]- anions weakly interact with a [Ni(cyclam)]2+ cation through chloro atoms, while compound 5 is a heterotrinuclear pyrazine-bridged Re(IV)2Cu(II) complex made up of [ReCl5(pyz)]- anions and [Cu(DMF)4]2+ cations. The magnetic properties of 1-5 were investigated in the temperature range 1.9-300 K. The magnetic behaviour of 1 is that of a magnetically diluted Re(IV) complex with a large value of zero-field splitting of the ground state (/2D/ is ca. 18.8(1) cm(-1)), whereas those of 2 and 3 are typical of antiferromagnetically coupled systems exhibiting susceptibility maxima at 10 (2) and 12 K (3). Compound 4 shows antiferromagnetic interactions between Re(IV) metal ions, Ni(II) being diamagnetic (because of its square-planar geometry), while 5 exhibits a ferromagnetic coupling between Re(IV) and Cu(II) metal ions across the pyrazine bridges with a J(ReCu), value of +11.8(1) cm(-1).


A new approach for creating defined geometries by navigated laser ablation based on volumetric 3-D data.
This paper describes a new approach for laser bone treatment according to a preoperative plan. The advantages of using laser systems are the free choice of the cutting geometry and the possibility of bone treatment without any severe thermal damage. On the other hand, the control of bone removal depth is difficult. Due to the lack of haptical feedback, it is only possible to control the bone removal visually. In addition, by selecting wrong laser parameters and incorrect handling,the tissue can sustain thermal damage. To solve this problem, an approach of navigated and model-based calculation of depth ablation has been investigated. The focus of this paper was to verify the feasibility of precise and safe laser bone removal by combining navigation information with mathematical and volumetric modeling. For the mathematical modeling, known approaches are used. On the basis of CT data, cavities in a bovine bone were planned with a navigation system. With an optical measurement system, the position of the laser handpiece was calculated relative to the bone. Using a mathematical model, the theoretical cavity depth was calculated for each laser pulse and displayed on the navigation screen. Thereby, the material removal was determined in a volume model. With this information, five cavities were created by the laser using constant energy settings. A final measurement of the cavities' depths showed an error of less than 1 mm.


Small antisense oligonucleotides against G-quadruplexes: specific mRNA translational switches.
G-quadruplexes (G4) are intricate RNA structures found throughout the transcriptome. Because they are associated with a variety of biological cellular mechanisms, these fascinating structural motifs are seen as potential therapeutic targets against many diseases. While screening of chemical compounds specific to G4 motifs has yielded interesting results, no single compound successfully discriminates between G4 motifs based on nucleotide sequences alone. This level of specificity is best attained using antisense oligonucleotides (ASO). Indeed, oligonucleotide-based strategies are already used to modulate DNA G4 folding in vitro. Here, we report that, in human cells, the use of short ASO to promote and inhibit RNA G4 folding affects the translation of specific mRNAs, including one from the 5'UTR of the H2AFY gene, a histone variant associated with cellular differentiation and cancer. These results suggest that the relatively high specificity of ASO-based strategies holds significant potential for applications aimed at modulating G4-motif folding.


[Correlation between early inflammation indicators and the severity of coronavirus disease 2019].
To explore the correlation between early inflammation indicators and the severity of coronavirus disease 2019 (COVID-19). A retrospective study was conducted. Patients with COVID-19 admitted to Wenzhou Central Hospital from January 17 to February 14, 2020 were enrolled. The general information, chest CT before admission, the first laboratory parameters and chest CT within 24 hours after admission were collected. Patients were followed up for 30 days after the first onset of dyspnea or pulmonary imaging showed that the lesions progressed more than 50% within 24 to 48 hours (according to the criteria for severe cases) as the study endpoint. According to the endpoint, the patients were divided into two groups: mild type/common type group and severe/critical group, and the differences in general information and inflammation index of the two groups were compared. Logistic regression was used to analyze the inflammation index and the severity of COVID-19. Receiver operating characteristic (ROC) curve was draw to evaluate the predictive value of early inflammation indicators for severe/critical in patients with COVID-19. A total of 140 patients with COVID-19 were included, 74 males and 66 females; the average age was (45±14) years old; 6 cases (4.3%) of mild type, 107 cases (76.4%) of common type, and 22 cases (15.7%) of severe type, 5 cases (3.6%) were critical. There were significantly differences in ages (years old: 43±13 vs. 57±13), the proportion of patients with one chronic disease (17.7% vs. 55.6%), C-reactive protein [CRP (mg/L): 7.3 (2.3, 21.0) vs. 40.1 (18.8, 62.6)], lymphocyte count [LYM (×109/L): 1.3 (1.0, 1.8) vs. 0.8 (0.7, 1.1)], the neutrophil/lymphocyte ratio [NLR: 2.1 (1.6, 3.0) vs. 3.1 (2.2, 8.8)] and multilobularinltration, hypo-lymphocytosis, bacterial coinfection, smoking history, hyper-tension and age [MuLBSTA score: 5.0 (3.0, 5.0) vs. 5.0 (5.0, 7.0)] between mild/common group and severe/critical group (all P < 0.05). Univariate Logistic regression analysis showed that CRP, NLR, MuLBSTA score, age, and whether chronic diseases were associated with the severity of COVID-19 [odds ratio (OR) and 95% confidence interval (95%CI) were 1.037 (1.020-1.055), 1.374 (1.123-1.680), 1.574 (1.296-1.911), 1.082 (1.042-1.125), 6.393 (2.551-16.023), respectively, all P < 0.01]. Further multivariate Logistic regression analysis showed that CRP and MuLBSTA score were risk factors for the development of COVID-19 to severe/critical cases [OR and 95%CI were 1.024 (1.002-1.048) and 1.321 (1.027-1.699) respectively, both P < 0.05]. ROC curve analysis showed that the area under the curve for CRP and MuLBSTA score to predict severe/critical cases were both 0.818, and the best cut-off points were 27.4 mg/L and 6.0 points, respectively. CRP and MuLBSTA score are related to the severity of COVID-19, and may have good independent predictive ability for the development of severe/critical illness.


Pathological conditions of the reproductive organs of male stray dogs in the tropics: prevalence, risk factors, morphological findings and testosterone concentrations.
The objective of this study was to estimate the prevalence of and risk factors for pathological conditions of the reproductive organs in stray dogs under tropical conditions. Three hundred and eighteen dogs were examined post-mortem in the period from 1 July 2002 to 30 June 2003. Before killing, a blood sample (from the cephalic vein) for testosterone assay was taken. Pathological conditions of the reproductive organs were found in 135 of the dogs (42.5%) and in 175 of the testes (64.8%). The most frequent pathologies found were testicular degeneration, cryptorchidism, testicular hypoplasia and testicular tumours (in 15.1%, 6.6%, 6.6% and 5.4% of the dogs and 15.1, 4.6, 6.0 and 3.5 of the testes, respectively). Transmissible venereal tumour (TVT) was seen in 5.4% of the dogs. Testicular degeneration was more common in old dogs and underweight dogs (p < 0.05). Testicular tumours were 14.3 times more common in cryptorchid dogs. Age was another important factor for the development of testicular tumours (p < 0.05). Lower levels of testosterone concentration (p < 0.05) were observed in dogs with advanced testicular degeneration (0.7 +/- 0.8 nM), dogs with hypoplastic testicles (0.8 +/- 0.9 nM) and dogs with one degenerated and one retained testis or with bilateral cryptorchidism (1.2 +/- 0.9 nM) compared to dogs with one or two normal testes (7.0 +/- 5.5 nM). Testicular volume and weight were significantly lower in degenerated, hypoplastic and retained testes compared with the contralateral normal testis. Some spermatogenic activity was found in three of the retained testes, producing oligozoospermic smears with a high percentage of sperm abnormalities. No comparable epidemiological data about male pathological conditions of the reproductive organs in the dog is available. The prevalence found in this study, yet, appears high.


The effects of alpha- or beta-adrenergic receptor agonists and antagonists and calcium entry blockers on the spontaneous vasomotion.
The effects of systemic injections of vasoactive substances were studied in the micro-circulation of the hamster skin fold window preparation, which can be observed without anesthesia, exposure, and acute surgical procedures. The effects were characterized by the continuous measurement of the diameter of the arterial microvessels ranging from 100 to 8 micron. Power spectrum analysis was utilized to determine the frequency and the amplitude of the fundamental component of spontaneous diameter changes. Epinephrine and norepinephrine increased the frequency of vasomotion and reduced mean diameter at low dosages. Phentolamine reduced the frequency of vasomotion and increased mean diameter. Propranolol increased the frequency of vasomotion and did not significantly change mean diameter. Adenosine and verapamil suppressed vasomotion and increased mean diameter. These results are explained by postulating that low-dosage alpha-adrenergic receptor stimulation facilitates the spontaneous discharge of smooth muscle cells; beta-adrenergic receptor stimulation has the opposite effect, whereas beta-adrenergic receptor inhibition also enhances the vasomotor effect. Calcium entry blockers abolish the rhythmic discharge. This explanation of the activity of the various substances supports the hypothesis that the spontaneous vasomotion of the arterial microvessels is related to the intrinsic property of smooth muscle cells.


Family histories of children with SLI who show extended optional infinitives.
Previous family history studies have demonstrated that there are elevated rates of language and language-related impairments in families identified through probands with language impairments. This study examines family histories of children with specific language impairment (SLI) known to have particular grammatical limitations in a core feature of grammatical acquisition, a stage known as Extended Optional Infinitives (EOI). Family affectedness rates are reported for 31 families identified through preschool probands with this clearly defined language impairment and 67 control families, identified through nonaffected preschool children developmentally similar to the probands. It was found that significantly more speech and language difficulties, as well as language-related difficulties, such as reading, were reported for proband families than control families. The elevated rates were obtained for nuclear family members and extended family members as well. Fathers of probands were more often reported as having difficulties (29% for speech/language impairments) than were mothers of probands (7%), but there was no difference between brothers (26%) and sisters (29%). No differences were evident between proband families based on proband gender. The findings are relevant for theoretical models of sources of unexplained variations in grammatical competence in young children. In addition, the findings contribute new information about expected rates of affectedness, means of identification of affected family members, and comorbidity of symptomatology.


Delineating the role of multiple intraarticular corticosteroid injections in the management of juvenile idiopathic arthritis in the biologic era.
To investigate the outcome and predicting factors of multiple intraarticular corticosteroid (IAC) injections in children with juvenile idiopathic arthritis (JIA). The clinical charts of patients who received their first IAC injection in ≥3 joints between January 2002 and December 2011 were reviewed. The corticosteroid used was triamcinolone hexacetonide for large joints and methylprednisolone acetate for small or difficult to access joints. In each patient, the followup period after IAC injection was censored in case of synovitis flare or at the last visit with continued remission. Predictors included sex, age at disease onset, JIA category, antinuclear antibody (ANA) status, age and disease duration, disease course, general anesthesia, number and type of injected joints, acute-phase reactants, and concomitant systemic medications. A total of 220 patients who had 1,096 joints injected were included. Following IAC therapy, 66.4% of patients had synovitis flare after a median of 0.5 years, whereas 33.6% of patients had sustained remission after a median of 0.9 years. The cumulative probability of survival without synovitis flare was 50.0%, 31.5%, and 19.5% at 1, 2, and 3 years, respectively. On Cox regression analysis, positive C-reactive protein value, negative ANA, lack of concomitant methotrexate administration, and a polyarticular (versus an oligoarticular) disease course were the strongest predictors for synovitis flare. Multiple IAC injection therapy induced sustained remission of joint synovitis in a substantial proportion of patients. A controlled trial comparing multiple IAC injection therapy and methotrexate versus methotrexate and a tumor necrosis factor antagonist is worthy of consideration.


Restructuring of pancreatic islets and insulin secretion in a postnatal critical window.
Function and structure of adult pancreatic islets are determined by early postnatal development, which in rats corresponds to the first month of life. We analyzed changes in blood glucose and hormones during this stage and their association with morphological and functional changes of alpha and beta cell populations during this period. At day 20 (d20), insulin and glucose plasma levels were two- and six-fold higher, respectively, as compared to d6. Interestingly, this period is characterized by physiological hyperglycemia and hyperinsulinemia, where peripheral insulin resistance and a high plasmatic concentration of glucagon are also observed. These functional changes were paralleled by reorganization of islet structure, cell mass and aggregate size of alpha and beta cells. Cultured beta cells from d20 secreted the same amount of insulin in 15.6 mM than in 5.6 mM glucose (basal conditions), and were characterized by a high basal insulin secretion. However, beta cells from d28 were already glucose sensitive. Understanding and establishing morphophysiological relationships in the developing endocrine pancreas may explain how events in early life are important in determining adult islet physiology and metabolism.


Clinical predictors of readmission after surgery for Hirschsprung disease.
The reasons for readmission of children with Hirschsprung disease (HD) are multiple. The study aims to predict the relevant factors for the readmission of children with HD by collecting and analyzing the relevant data of the child's admission to the hospital at the time of surgery.A retrospective review was performed including all patients with surgical treatment of HD at our institution between the years of 2011 to 2020. Univariate and multivariate Logistic regression analysis were performed to obtain the independent risk factor for this study. The receiver operating characteristic curve (ROC) were used to assess the performance of derived models.A total of 162 patients were identified. The average presurgery weights were 6.93 ± 1.78 kg in the readmission group and 8.38 ± 3.17 kg in the non-readmission group. Six children were classified as a low-weight in the readmission group, and 11 children classified as low-weight in the non-readmission group. The length of the intestinal tube after resection was 25.25 ± 15.21 cm in the readmission group, and 16.23 ± 4.10 cm in the non-readmission group. The ROC for the prediction model of readmission after HD surgery (AUC = 0.811).In children undergoing the HD surgery, we showed preoperative low body weight and long intra-operative bowel resection significantly increase the probability of readmission due to complications.


Myocardial Expression Analysis of Osteopontin and Its Splice Variants in Patients Affected by End-Stage Idiopathic or Ischemic Dilated Cardiomyopathy.
Osteopontin (OPN) is a phosphoglycoprotein of cardiac extracellular matrix and it is still poorly defined whether its expression changes in failing heart of different origin. The full-length OPN-a and its isoforms (OPN-b, OPN-c) transcriptomic profile were evaluated in myocardium of patients with dilated or ischemic cardiomyopathy (DCM n = 8; LVEF% = 17.5±3; ICM n = 8; LVEF% = 19.5±5.2) and in auricle of valvular patients (VLP n = 5; LVEF%≥50), by Real-time PCR analysis. OPN-a and thrombin mRNA levels resulted significantly higher in DCM compared to ICM patients (DCM:31.3±7.4, ICM:2.7±1.1, p = 0.0002; DCM:19.1±4.9, ICM:5.4±2.2, p = 0.007, respectively). Although both genes' mRNA levels increased in patients with LVEF<50% (DCM+ICM) with respect to VLP with LVEF>50%, a significant increase in OPN (p = 0.0004) and thrombin (p = 0.001) expression was observed only in DCM. In addition, a correlation between OPN-a and thrombin was found in patients with LVEF<50% (r = 0.6; p = 0.003). The mRNA pattern was confirmed by OPN-a cardiac protein concentration (VLP:1.127±0.26; DCM:1.29±0.22; ICM:1.00±0.077 ng/ml). The OPN splice variants expression were detectable only in ICM (OPN-b: 0.357±0.273; OPN-c: 0.091±0.033) and not in DCM patients. A significant correlation was observed between collagen type I, evaluated by immunohistochemistry analysis, and both OPN-a mRNA expression (r = 0.87, p = 0.002) and OPN protein concentrations (r = 0.77, p = 0.016). Concluding, OPN-a and thrombin mRNA resulted dependent on the origin of heart failure while OPN-b and OPN-c highlighted a different expression for DCM and ICM patients, suggesting their correlation with different clinical-pathophysiological setting.


Concentrations of metronidazole and tinidazole in abdominal tissues after a single intravenous infusion and repetitive oral administration.
Concentrations of metronidazole and tinidazole in serum and abdominal tissues were determined after a single 500-mg intravenous infusion or after a 5-day oral dosage of 500 mg three times daily in groups of 10 patients each. In the patients who got the single infusions, the concentrations in tissues (except fat) reached almost the serum levels 10 min after the infusion. At 24 h, the tinidazole concentrations in serum averaged 3.2 micrograms/ml and those of metronidazole 1.3 micrograms/ml. In the patients who got the 5-day oral dosages, the steady-state levels of tinidazole in both serum and tissues were twice as high as those of metronidazole.


Clinical and biological phenotypes of frontotemporal dementia: Perspectives for disease modifying therapies.
Frontotemporal Dementia (FTD) is a progressive neurodegenerative condition which encompasses a group of clinically, neuropathologically and genetically heterogeneous disorders characterized by selective involvement of the frontal and temporal lobes. FTD is characterized by changes in behaviour and personality, frontal executive deficits and language dysfunction. Different phenotypes have been defined on the basis of presenting clinical symptoms, behavioural variants of FTD (bvFTD) and primary progressive aphasia (PPA), which includes nonfluent/agrammatic variant PPA (avPPA) and semantic variant PPA (svPPA). These presentations can overlap with atypical parkinsonian disorders (i.e., corticobasal syndrome, progressive supranuclear palsy) and amyotrophic lateral sclerosis. Each syndrome can be associated with one or more neuropathological hallmark, and in some cases it may be due to autosomal inherited disorder caused by mutations in a number of genes. Currently, there is no specific treatment available to prevent disease progression. FTD treatment is based on symptomatic management, and most therapies lack quality evidence from randomized, placebo-controlled clinical trials. Recent advances in the understanding of FTD pathophysiology and genetics have led to the development of potentially disease-modifying therapies. In this review, we discussed current knowledge and recommendations with regards to symptomatic and disease-modifying therapies.


Analysis of an Autographa californica multicapsid nucleopolyhedrovirus lef-6-null virus: LEF-6 is not essential for viral replication but appears to accelerate late gene transcription.
The Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV) lef-6 gene was previously shown to be necessary for optimal transcription from an AcMNPV late promoter in transient late expression assays. In the present study, we examined the expression and cellular localization of lef-6 during the AcMNPV infection cycle and generated a lef-6-null virus for studies of the role of lef-6 in the infection cycle. Transcription of lef-6 was detected from 4 to 48 h postinfection, and the LEF-6 protein was identified in dense regions of infected cell nuclei, a finding consistent with its potential role as a late transcription factor. To examine lef-6 in the context of the AcMNPV infection cycle, we deleted the lef-6 gene from an AcMNPV genome propagated as an infectious BACmid in Escherichia coli. Unexpectedly, the resulting AcMNPV lef-6-null BACmid (vAc(lef6KO)) was able to propagate in cell culture, although virus yields were substantially reduced. Thus, the lef-6 gene is not essential for viral replication in Sf9 cells. Two "repair" AcMNPV BACmids (vAc(lef6KO-REP-P) and vAc(lef6KO-REP-ie1P)) were generated by transposition of the lef-6 gene into the polyhedrin locus of the vAc(lef6KO) BACmid. Virus yields from the two repair viruses were similar to those from wild-type AcMNPV or a control (BACmid-derived) virus. The lef-6-null BACmid (vAc(lef6KO)) was further examined to determine whether the deletion of lef-6 affected DNA replication or late gene transcription in the context of an infection. The lef-6 deletion did not appear to affect viral DNA replication. Using Northern blot analysis, we found that although early transcription was apparently unaffected, both late and very late transcription were delayed in cells infected with the lef-6-null BACmid. This phenotype was rescued in viruses containing the lef-6 gene reinserted into the polyhedrin locus. Thus, the lef-6 gene was not essential for either viral DNA replication or late gene transcription, but the absence of lef-6 resulted in a substantial delay in the onset of late transcription. Therefore, lef-6 appears to accelerate the infection cycle of AcMNPV.


Plaque hemorrhage is a marker of thromboembolic activity in patients with symptomatic carotid disease.
To assess whether carotid plaque hemorrhage depicted with magnetic resonance (MR) imaging was associated with thromboembolic activity as assessed with transcranial Doppler imaging. The local research ethics committee approved the study, and all patients gave informed written consent. Between April 2005 and December 2006, patients with high-grade symptomatic carotid stenosis were prospectively recruited. All underwent MR imaging of the carotid arteries for plaque hemorrhage and diffusion-weighted imaging of the brain. Transcranial Doppler imaging of the symptomatic carotid artery was performed over 1 hour to assess the presence of microembolic signal. To determine the relationship between the presence of plaque hemorrhage and diffusion-weighted imaging-positive signal and presence of microembolic signal, a logistic regression analysis was performed. Fifty-one patients (23 women and 28 men; mean age ± standard deviation, 72 years ± 11) underwent complete MR imaging; 46 (86%) of these patients underwent complete transcranial Doppler imaging. In 32 (63%) patients, there was plaque hemorrhage in the index carotid artery. The presence of plaque hemorrhage increased the risk for ipsilateral abnormalities at diffusion-weighted imaging (odds ratio, 6.2 [95% confidence interval: 1.7, 21.8]; P < .05). Multiple diffusion-weighted imaging-depicted abnormalities of multiple ages were present exclusively in patients with plaque hemorrhage shown at MR imaging (12 of 32 [38%] patients with plaque hemorrhage versus none of 19 patients without plaque hemorrhage; P < .05). The presence of plaque hemorrhage also increased the presence of microembolic signal (odds ratio, 6.0 [95% confidence interval: 1.8, 19.9]; P = .003). In patients with carotid plaque hemorrhage demonstrated at MR imaging, there was increased spontaneous microembolic activity at transcranial Doppler imaging and cerebral ischemic lesion patterns suggestive of recurrent embolic events; these findings suggest that plaque hemorrhage shown at MR imaging might be a marker of thromboembolic activity and further validate the usefulness of carotid imaging in identifying patients with active carotid arterial disease.


The Changes of Energy Interactions between Nucleus Function and Mitochondria Functions Causing Transmutation of Chronic Inflammation into Cancer Metabolism.
Interactions between nucleus and mitochondria functions induce the mechanism of maintenance stability of cellular internal energy according to the first law of thermodynamics in able-bodied cells and changes the mechanisms of maintenance stability of cellular internal energy creating a transition stationary state of ablebodied cells into quasi-stationary pathologic states of acute inflammation transiting then into chronic inflammation and then transmuting into cancer metabolism. The mechanisms' influences of intruding etiologic pathologic agents (microbe, virus, etc.) lead to these changes of energy interactions between nucleus and mitochondria functions causing general acute inflammation, then passing into local chronic inflammation, and reversing into cancer metabolism transmutation. Interactions between biochemical processes and biophysical processes of cellular capacitors' operations create a supplementary mechanism of maintenance stability of cellular internal energy in the norm and in pathology. Discussion of some scientific works eliminates doubts of the authors of these works.


A qualitative assessment of an abstinence-oriented therapeutic community for prisoners with substance use disorders in Kyrgyzstan.
Kyrgyzstan, where HIV is concentrated in prisons and driven by injection drug use, provides a prison-based methadone maintenance therapy program as well as abstinence-oriented therapeutic community based on the 12-step model called the "Clean Zone." We aimed to qualitatively assess how prisoners navigate between these treatment options to understand the persistence of the Clean Zone despite a lack of evidence to support its effectiveness in treating opioid use disorders. We conducted an analysis of policy documents and over 60 h of participant observation in February 2016, which included focus groups with a convenience sample of 20 therapeutic community staff members, 110 prisoners across three male and one female prisons, and qualitative interviews with two former Clean Zone participants. Field notes containing verbatim quotes from participants were analyzed through iterative reading and discussion to understand how participants generally perceive the program, barriers to entry and retention, and implications for future treatment within prisons. Our analyses discerned three themes: pride in the mission of the Clean Zone, idealism regarding addiction treatment outcomes against all odds, and the demonization of methadone. Despite low enrollment and lack of an evidence base, the therapeutic community is buttressed by the strong support of the prison administration and its clients as an "ordered" alternative to what is seen as chaotic life outside of the Clean Zone. The lack of services for Clean Zone patients after release likely contributes to high rates of relapse to drug use. The Clean Zone would benefit from integration of stabilized methadone patients combined with a post-release program.


[Cytomegalovirus hyperimmunoglobulin prophylaxis following kidney transplantation. Results of a prospective randomized study].
The effectiveness of preventing cytomegalovirus (CMV) infections by administering CMV hyperimmunoglobulin was evaluated in a prospective randomized trial. The patients in the treatment group (n = 50) had intravenous infusions of 2 ml/kg bodyweight of CMV-Polyglobin at three-week intervals, up to day 105 after kidney transplantation. The 50 patients in the control group received no infusions. There was no significant difference between the treatment and control groups in transplant survival or patients survival rates. But the number of symptomatic CMV infections was higher in the control (n = 11) than the treatment group (n = 5). There were also significantly fewer symptomatic herpes-simplex infections in the treatment (n = 6) than in the control group (n = 25). It is concluded from these results that prophylaxis with CMV hyperimmunoglobulin should be undertaken either selectively or for shorter periods than those chosen for the reported trial.


The mycorrhiza-dependent defensin MtDefMd1 of Medicago truncatula acts during the late restructuring stages of arbuscule-containing cells.
Different symbiotic and pathogenic plant-microbe interactions involve the production of cysteine-rich antimicrobial defensins. In Medicago truncatula, the expression of four MtDefMd genes, encoding arbuscular mycorrhiza-dependent defensins containing an N-terminal signal peptide and exhibiting some differences to non-symbiotic defensins, raised over the time of fungal colonization. Whereas the MtDefMd1 and MtDefMd2 promoters were inactive in cells containing young arbuscules, cells with fully developed arbuscules displayed different levels of promoter activities, indicating an up-regulation towards later stages of arbuscule formation. MtDefMd1 and MtDefMd2 expression was absent or strongly down-regulated in mycorrhized ram1-1 and pt4-2 mutants, known for defects in arbuscule branching or premature arbuscule degeneration, respectively. A ~97% knock-down of MtDefMd1/MtDefMd2 expression did not significantly affect arbuscule size. Although overexpression of MtDefMd1 in arbuscule-containing cells led to an up-regulation of MtRam1, encoding a key transcriptional regulator of arbuscule formation, no morphological changes were evident. Co-localization of an MtDefMd1-mGFP6 fusion with additional, subcellular markers revealed that this defensin is associated with arbuscules in later stages of their life-cycle. MtDefMd1-mGFP6 was detected in cells with older arbuscules about to collapse, and ultimately in vacuolar compartments. Comparisons with mycorrhized roots expressing a tonoplast marker indicated that MtDefMd1 acts during late restructuring processes of arbuscule-containing cells, upon their transition into a post-symbiotic state.


Yersinia enterocolitica YopQ: strain-dependent cytosolic accumulation and post-translational secretion.
YopQ in Yersinia enterocolitica (YopK in Yersinia pseudotuberculosis) is a type III secreted protein required for virulence of yersiniae. In this study YopQ expression, secretion and nucleotide sequences of the corresponding yopQ gene from different yersinia strains were analysed. The cytosolic accumulation differed significantly among serotypes of Y. enterocolitica. These differences might be attributable to variations in the nucleotide sequence and their consequences on mRNA secondary structure. An mRNA signal hypothesis has been proposed for YopQ, predicting the coupling of translation and secretion via an mRNA signal. This hypothesis claims a strictly co-translational secretion of YopQ without its intracellular accumulation. The presence of YopQ in the cytosol, even with a closed secretion apparatus, is demonstrated. Moreover, post-translational secretion of YopQ could be demonstrated. These findings do not support the mRNA signal hypothesis for co-translational secretion.


Review of Cryptosporidium and Giardia in the eastern part of Europe, 2016.
IntroductionThis paper reviews the current knowledge and understanding of Cryptosporidium spp. and Giardia spp. in humans, animals and the environment in 10 countries in the eastern part of Europe: Bosnia and Herzegovina, Croatia, Czech Republic, Estonia, Hungary, Latvia, Poland, Romania, Serbia and Slovenia. Methods: Published scientific papers and conference proceedings from the international and local literature, official national health service reports, national databases and doctoral theses in local languages were reviewed to provide an extensive overview on the epidemiology, diagnostics and research on these pathogens, as well as analyse knowledge gaps and areas for further research. Results:Cryptosporidium spp. and Giardia spp. were found to be common in eastern Europe, but the results from different countries are difficult to compare because of variations in reporting practices and detection methodologies used. Conclusion: Upgrading and making the diagnosis/detection procedures more uniform is recommended throughout the region. Public health authorities should actively work towards increasing reporting and standardising reporting practices as these prerequisites for the reported data to be valid and therefore necessary for appropriate control plans.


Four-Dimensional Probing of Phase-Reaction Dynamics in Au/GaAs Nanowires.
Nanoeutectic phase reaction covers the fundamental study of a chemical and physical reaction of multiple phases at the nanoscale. Here, we report the direct visualization of phase-reaction dynamics in Au/GaAs nanowires (NWs) using four-dimensional (4D) electron microscopy. The NW phase reactions were initiated with a pump laser pulse, while the following dynamics in the Au/GaAs NW was probed by a precisely time-delayed electron pulse. Single-pulse imaging reveals that the cubic zinc-blende NW presents a transient length increase within the time duration of ∼150 ns, giving the appearance of intermediate phase reactions at an early stage. A final length reduction of the NW is observed after the phase reactions have fully ended. In contrast, only length reduction is seen throughout the entire process in GaAs/AlGaAs core-shell and hexagonal wurtzite GaAs NWs. The reasons for the above intriguing phenomena are discussed. The eutectic-related phenomena in both zinc-blende and wurtzite materials offer a comprehensive understanding of phase-reaction dynamics in polytypic structures commonly available in compound semiconductors.


In vitro damage of basal lamina-associated anionic sites by hydroxyl radical.
We examined the effect of chemically generated hydroxyl radical on basal lamina-associated anionic sites. Cytochemical studies showed that hydroxyl radical produced a loss of cationic tracer-positive, anionic particles, and this effect was inhibited by a specific scavenger, thiourea. These data might suggest that anionic sites were degraded by hydroxyl radical which was derived, for example, from the activated leukocytes in close contact with the dermal-epidermal junction during acute inflammation resulting in the disturbance of the charge-selective permeability barrier.


Herpes simplex virus isolation in chronic stromal keratitis: human and laboratory studies.
The corneal discs of 41 patients with scarring reminiscent of herpetic infection were organ cultured for HSV isolation. Of the 41 patients, 34 had a definite history of herpetic keratitis, from 10 of whom (29.4%) HSV was isolated. There were no clinical features which distinguished between these groups; there was however an indication that those from whom HSV was not isolated had been previously treated with substantial amounts of topical acycloguanosine. In three patients of 12 patients when the disc was separated into 7 parts using a punch technique, virus was isolated exclusively from those portions demonstrating clinical scarring. Electron microscopy (EM) demonstrated HSV particles in stromal cells in the cultured corneas of seven patients. In two of the patients no virus was detected prior to culture with EM. In one patient HSV antigen was not found using peroxidase-antiperoxidase (PAP) staining prior to subsequently positive organ culture. Studies were made to determine how HSV accedes to the corneal stroma using a murine model in which keratitis occurs by zosteriform spread of HSV following inoculation of the snout. Preliminary evidence using PAP staining indicates that the virus reaches the stroma at the same time as the epithelium, via the sensory nerves. Evidence of HSV persistence in anterior segments was obtained in the same model, in contrast to which no virus could be isolated following direct inoculation into the cornea. It is speculated that for virus to set up a longterm association with the stromal keratocyte, it must be introduced via the sensory nerve.(ABSTRACT TRUNCATED AT 250 WORDS)


Demands and stress before and during the COVID-19 pandemic of parents to children with autism spectrum disorder.
Parents to children with Autism Spectrum Disorder (ASD) face diverse daily demands that can lead to stress. The aim of this study was to examine to which extent stress in parents to children with ASD can be explained by daily demands before and during the COVID-19 pandemic (after lockdowns; first half of 2022), and whether there are differences between the two time periods in this regard. Data from parents to children with ASD living in Germany from two independent questionnaire studies (before the pandemic: N = 168, during the pandemic: N = 105) were matched for comparability. Simple and multiple linear regression analyses were used to answer the research question. Parental stress as well as all demands examined showed higher levels during the COVID-19 pandemic than before. Significant predictors of parental stress before and during the COVID-19 pandemic were (1) the daily demands to deal with the child's problem behavior, (2) the restriction of one's personal way of life, and (3) the challenge to cooperate with the partner. During the COVID-19 pandemic, the child's problem behavior was particularly relevant. It was also found that the demand to deal with stigmatizing reactions did not explain parental stress during the COVID-19 pandemic whereas before the pandemic it had been a significant predictor. Although parental stress and the demands of daily life increased during the pandemic, most of the stress can be explained by the same demands. It is suggested that the increased levels may be due to an increase in the child's ASD symptomatology, which is why it is advisable to install therapeutic and care structures that prepare children with ASD for future crises.


Nursing protects honeybee larvae from secondary metabolites of pollen.
The pollen of many plants contains toxic secondary compounds, sometimes in concentrations higher than those found in the flowers or leaves. The ecological significance of these compounds remains unclear, and their impact on bees is largely unexplored. Here, we studied the impact of pyrrolizidine alkaloids (PAs) found in the pollen of Echium vulgare on honeybee adults and larvae. Echimidine, a PA present in E. vulgare pollen, was isolated and added to the honeybee diets in order to perform toxicity bioassays. While adult bees showed relatively high tolerance to PAs, larvae were much more sensitive. In contrast to other bees, the honeybee larval diet typically contains only traces of pollen and consists predominantly of hypopharyngeal and mandibular secretions produced by nurse bees, which feed on large quantities of pollen-containing bee bread. We quantified the transfer of PAs to nursing secretions produced by bees that had previously consumed bee bread supplemented with PAs. The PA concentration in these secretions was reduced by three orders of magnitude as compared to the PA content in the nurse diet and was well below the toxicity threshold for larvae. Our results suggest that larval nursing protects honeybee larvae from the toxic effect of secondary metabolites of pollen.


Use of covered Cheatham-Platinum stents in aortic coarctation and recoarctation.
We inserted covered Cheatham-Platinum stents in 4 patients, ranging in age from 12 to 19 years, who weighed between 45 and 94 kg. All the patients had aortic coarctation, with surgical repair having been attempted previously in one, and with balloon dilation having been performed as the primary treatment in two, resulting in formation of aneurysms. The fourth patient had not received any treatment. The gradients were reduced from 10 to 40 mmHg before insertion of the stent to 0 to 5 mmHg after stenting. No complications were encountered. All the patients are well at an interval of 3 to 14 months after stenting.


Trypanosome trans-sialidase targets TrkA tyrosine kinase receptor and induces receptor internalization and activation.
Trypanosome trans-sialidase (TS) is a sialic acid-transferring enzyme that hydrolyzes alpha2,3-linked sialic acids and transfers them to acceptor molecules. Here we show that a highly purified recombinant TS derived from T. cruzi parasites targets TrkA receptors on TrkA-expressing PC12 cells and colocalizes with TrkA internalization and phosphorylation (pTrkA). Maackia amurensis lectin II (MAL-II) and Sambucus nigra lectin (SNA) block TS binding to TrkA-PC12 cells in a dose-dependent manner with subsequent inhibition of TS colocalization with pTrkA. Cells treated with lectins alone do not express pTrkA. The catalytically inactive mutant TSDeltaAsp98-Glu also binds to TrkA-expressing cells, but is unable to induce pTrkA. TrkA-PC12 cells treated with a purified recombinant alpha2,3-neuraminidase (Streptococcus pneumoniae) express pTrkA. Wild-type TS but not the mutant TSDeltaAsp98-Glu promotes neurite outgrowth in TrkA-expressing PC12 cells. In contrast, these effects are not observed in TrkA deficient PC12nnr5 cells but are reestablished in PC12nnr5 cells stably transfected with TrkA and are significantly blocked by inhibitors of tyrosine kinase (K-252a) and MAP/MEK protein kinase (PD98059). Together these observations suggest for the first time that hydrolysis of sialyl alpha2,3-linked beta-galactosyl residues of TrkA receptors plays an important role in TrkA receptor activation, sufficient to promote cell differentiation (neurite outgrowth) independent of nerve growth factor.


Capnography-An Essential Monitor, Everywhere: A Narrative Review.
Capnography is now recognized as an indispensable patient safety monitor. Evidence suggests that its use improves outcomes in operating rooms, intensive care units, and emergency departments, as well as in sedation suites, in postanesthesia recovery units, and on general postsurgical wards. Capnography can accurately and rapidly detect respiratory, circulatory, and metabolic derangements. In addition to being useful for diagnosing and managing esophageal intubation, capnography provides crucial information when used for monitoring airway patency and hypoventilation in patients without instrumented airways. Despite its ubiquitous use in high-income-country operating rooms, deaths from esophageal intubations continue to occur in these contexts due to incorrect use or interpretation of capnography. National and international society guidelines on airway management mandate capnography's use during intubations across all hospital areas, and recommend it when ventilation may be impaired, such as during procedural sedation. Nevertheless, capnography's use across high-income-country intensive care units, emergency departments, and postanesthesia recovery units remains inconsistent. While capnography is universally used in high-income-country operating rooms, it remains largely unavailable to anesthesia providers in low- and middle-income countries. This lack of access to capnography likely contributes to more frequent and serious airway events and higher rates of perioperative mortality in low- and middle-income countries. New capnography equipment, which overcomes cost and context barriers, has recently been developed. Increasing access to capnography in low- and middle-income countries must occur to improve patient outcomes and expand universal health care. It is time to extend capnography's safety benefits to all patients, everywhere.


Reversible Ortner's Syndrome as a Presenting Feature of Thyrotoxicosis in an Adolescent: A Rare Case Report.
Ortner's or cardiovocal syndrome is hoarseness attributable to left recurrent laryngeal nerve (RLN) palsy associated with mechanical compression of the nerve by pathologically enlarged cardiovascular structures. Ortner's syndrome is a rare condition, and to our knowledge, only a few cases have been reported in Korea. Furthermore, this condition is extremely uncommon in pediatric patients with thyrotoxicosis-related RLN paralysis. We report a case of reversible Ortner's syndrome in an adolescent who presented with secondary pulmonary hypertension related to thyrotoxicosis.


Sociocultural and individual psychological predictors of body image in young girls: a prospective study.
This study investigated the prospective predictors of body image in 9- to 12-year-old girls. Participants were 150 girls in Grades 4-6 with a mean age of 10.3 years. Girls completed questionnaire measures of media and peer influences (television/magazine exposure, peer appearance conversations), individual psychological variables (appearance schemas, internalization of appearance ideals, autonomy), and body image (figure discrepancy and body esteem) at Time 1 and 1 year later at Time 2. Linear panel analyses showed that after controlling for Time 1 levels of body image, none of the Time 1 sociocultural variables predicted body image variables at Time 2. Body mass index (BMI; a biological variable) and psychological variables, however, did offer significant prospective prediction. Specifically, higher BMI, higher appearance schemas, higher internalization of appearance ideals, and lower autonomy predicted worsening body image 1 year later. Thus, higher weight and certain psychological characteristics were temporally antecedent to body image concerns. It was concluded that both biological and individual psychological variables play a role in the development of body image in children. Individual psychological variables, in particular, may provide useful targets in prevention and intervention programs addressing body image in 9- to 12-year-old girls.


How do you put the client's needs first? Aspects of AIDS counselling in nursing.
While it is generally accepted that counselling should be client centred, that offered to people with Aids or who are HIV positive tends to be more prescriptive in approach. A study was therefore devised to determine Aids counsellors' concepts of their role and its requirements.


ECG-edit function in multidetector-row computed tomography coronary arteriography for patients with arrhythmias.
ECG-gating is necessary for cardiac computed tomography, but is not suitable for arrhythmias, so the aim of this study was to evaluate the usefulness of the ECG-edit function for this purpose. Of 1,221 patients undergoing 64-row multidetector-row computed tomography coronary angiography (coronary MDCT), 123 patients (28 atrial fibrillation (Af), 39 premature atrial contractions (PAC), 42 premature ventricular contractions (PVC), 3 PAC + PVC, 10 sinus arrhythmias (SA), and a second-degree atrioventricular block (2 degrees AVB)) had arrhythmias necessitating the ECG-edit function. Short R-R interval was deleted and mid-diastolic phases were selected from the long R-R intervals using the "R+absolute time" method. In the present study, the reconstructed images were evaluated using a triple-grade scale A-C, representing excellent, acceptable, and unacceptable image quality. Image quality, categorized as A, B and C, respectively, was 50%, 36% and 14% for the 28 patients with Af; 56%, 36% and 8% for the 39 PAC patients, and 65%, 33% and 2% in the 42 PVC patients. None of the scans of the PAC + PVC, SA, and 2 degrees AVB patients was ranked as C. The ECG-edit function is useful for reconstructing coronary MDCT images in many arrhythmias, and provides clinically acceptable images in most cases.


Antibacterial activity of composite resin with glass-ionomer filler particles.
The purpose of this study was to examine the antibacterial activity of composite resin with glass-ionomer filler particles versus that of contemporary commercial composite resins. Three composite resins were used: Beautifil II (containing S-PRG filler), Clearfil AP-X, and Filtek Z250. Resin blocks were bonded to maxillary first molars, and plaque accumulation on the resin block surface was examined after 8 hours. For the antibacterial test, the number of Streptococcus mutans in contact with the composite resin blocks after incubation for 12 hours was determined, and adherence of radiolabeled bacteria was evaluated. Less dental plaque was formed on Beautifil II resin block as compared to the other two materials. Antibacterial test revealed that there were no significant differences in the number of Streptococcus mutans among the three composite resins. However, the adherence of radiolabeled bacteria to the saliva-treated resin surface was significantly (p<0.01) lower in Beautifil II than in the other two materials. These results suggested that Beautifil II could reduce dental plaque formation and bacterial adherence, leading to prevention of secondary caries.


Inhibition of HIV-1 replication by small interfering RNAs directed against glioma pathogenesis related protein (GliPR) expression.
Previously, we showed that glioma pathogenesis related protein (GliPR) is induced in CEM T cells upon HIV-1 infection in vitro. To examine whether GliPR plays a role as HIV dependency factor (HDF), we tested the effect of GliPR suppression by siRNA on HIV-1 replication. Induction of GliPR expression by HIV-1 was confirmed in P4-CCR5 cells. When GliPR was suppressed by siRNA, HIV-1 replication was significantly reduced as measured by HIV-1 transcript levels, HIV-1 p24 protein levels, and HIV-1 LTR-driven reporter gene expression, suggesting that GliPR is a cellular co-factor of HIV-1. Microarray analysis of uninfected HeLa cells following knockdown of GliPR revealed, among a multitude of gene expression alterations, a down-regulation of syndecan-1, syndecan-2, protein kinase C alpha (PRKCA), the catalytic subunit beta of cAMP-dependent protein kinase (PRKACB), nuclear receptor co-activator 3 (NCOA3), and cell surface protein CD59 (protectin), all genes having relevance for HIV-1 pathology. The up-regulation of GliPR by HIV-1 and the early significant inhibition of HIV-1 replication mediated by knockdown of GliPR reveal GliPR as an important HIV-1 dependency factor (HDF), which may be exploited for HIV-1 inhibition.


Toward the Classical Description of Halogen Bonds: A Quantum Based Generalized Empirical Potential for Fluorine, Chlorine, and Bromine.
The electronic effects in supramolecular systems are a great challenge for computational chemistry, and the understanding of ligand-protein interactions driven by halogen bonds can be limited by molecular mechanics point of view. In fact, the variations of the halogen bond acceptors, such as an aromatic ring and electrons lone pairs, restrict the classical approximations even more. Our work enhances the statement that halogen bonds are led mainly by orbital interactions via σ*C-X. Nonetheless, we have pointed a straight relationship between the maximum ESP value on the σ-hole and the LUMO energy levels of the halogen bond donor. In line with this scenario, the current work introduces a new promising empirical potential based on quantum parametrizations able to describe general halogen bonded systems. The new parameters allow force fields to detect variations on the molecular electronic structure of halogenated organic compounds to improve the description of fluorine, chlorine, and bromine in halogen bonds.


Formoterol as dry powder oral inhalation compared with salbutamol metered-dose inhaler in acute exacerbations of chronic obstructive pulmonary disease.
Acute exacerbations of chronic obstructive pulmonary disease (COPD) are managed with increased doses or frequency of the patient's existing bronchodilator therapy. The use of formoterol in the treatment of mild acute exacerbations of COPD has been suggested; however, a comparison of cumulative doses of formoterol with salbutamol, the gold standard bronchodilator agent for this pathologic condition, is still lacking. The aim of the study was to compare the inhaled beta2-agonists salbutamol (rapid onset, short duration of action) and formoterol (rapid onset, long duration of action), both used as needed in patients attending outpatient clinics because of mild acute exacerbations of COPD (Anthonisen exacerbation type I or II). A dose-response curve to formoterol via Turbuhaler or salbutamol via pressurized metered-dose inhaler (pMDI) was constructed. On 2 consecutive days, the patients received, in randomized order, both of the following active dose regimens: A = 12 + 12 + 24 microg formoterol via Turbuhaler (48-microg cumulative metered dose); B = 200 + 200 + 400 microg salbutamol via pMDI (800-microg cumulative metered dose). Dose increments were given at 30-minute intervals, with measurements made 25 minutes after each dose. The maximum forced expiratory volume in 1 second (FEV1) value during the dose-response curve to formoterol or salbutamol was chosen as the primary outcome variable to compare the 2 treatments. Oxygen saturation by pulse oximetry (SpO2) and pulse rate were also measured at each assessment period. Every adverse event, either reported spontaneously by the patients or observed by the investigators, was recorded. Sixteen patients (2 women, 14 men) aged 51 to 77 years (most older than 65 years) participated in the study. Both formoterol and salbutamol induced a large, significant, dose-dependent increase in FEV1, inspiratory capacity (IC), and forced vital ca- pacity (FVC). There was no significant difference between FEV1, IC, and FVC values after 48 microg formoterol and 800 microg salbutamol. There was no significant difference in FEV1 after 24 microg formoterol and 800 microg salbutamol; however, the difference in FEV1 after 24 and 48 microg formoterol was significant. Neither heart rate (mean differences from baseline after 48 microg formoterol, 1.9 beats/min [95% CI, -3.4, 7.2] and 800 microg salbutamol, 3.7 beats/min [95% CI, -1.1, 8.5]) nor SpO2 (mean percentage differences from baseline after 48 microg formoterol, -0.37% [95% CI, -1.22, 0.47] and 800 microg salbutamol, -0.75% [95% CI, -1.73, 0.23]) changed significantly. However, SpO2 decreased below 90% in 2 patients after the highest dose of formoterol and in 1 patient after the highest dose of salbutamol. In this small, selected group of patients with mild acute exacerbations of COPD, formoterol via Turbuhaler induced a fast bronchodilation that was dose dependent and not significantly different from that caused by salbutamol. Furthermore, formoterol appeared to be as well tolerated as salbutamol.


Historical perspective of sexually transmitted infections and their control in Peru.
In designing an effective national response to sexually transmitted infections (STIs), one must incorporate a historical perspective of previous efforts that have addressed different aspects of STIs. One must understand who have been the key players, what aspects of STIs were the focus of efforts (prevention, treatment or control), and which, if any, societal subgroups were targeted (i.e. sex workers, military, men who have sex with men [MSM], etc.). In addition, one must consider historical and modern attitudes towards sex, sexuality and STIs, especially in terms of taboos and stigmas that may be attached to each. Most importantly, one must recognize which efforts have succeeded, which have failed, and why. This paper presents a historical overview of the perceptions of and responses to STIs at different points in Peru's history, and discusses current efforts to build upon past successes and avoid repeating previous failures that could be helpful for other countries in the Latin American region.


Neuroprotective mechanisms of miR-124 activating PI3K/Akt signaling pathway in ischemic stroke.
The neuroprotective mechanisms of miR-124 activating phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in ischemic stroke were investigated. The oxygen-glucose deprivation model of nerve cells induced by PC12 cells was established in vitro, then miR-124 mimics or inhibitor was transfected and synthesized by liposome. Cells were divided into the blank control, model, mimics and inhibitor groups, and the apoptotic rate was determined using flow cytometry. Additionally, the expression levels of PI3K, Akt, Bax, Bcl-2, caspase-3 mRNA and protein were tested by quantitative PCR and western blot analysis at 0, 3, 6, 12 and 24 h, respectively. The apoptotic rate at each time-point in the blank control group was not significantly different. The apoptotic rate of the model and inhibitor groups increased over time, whereas the mimics group decreased (P<0.05). The apoptotic rate at each time-point in the mimics group was significantly lower than that of the model and inhibitor groups, and the rate of the inhibitor group was higher than that of the model group (P<0.05). PI3K, Akt and Bcl-2 mRNA and protein expression levels at the different time-points in the mimics group were significantly higher than those of the remaining groups (P<0.05). The expression levels of Bax and caspase-3 mRNA and protein in the inhibitor group were the highest, followed by the model and mimics groups, while that of the blank control group was the lowest (P<0.05). The results suggest that miR-124 participates in the neural protection of ischemic stroke by activating the PI3K/Akt signaling pathway.


Serum zinc in athletes in training.
Serum zinc was determined using atomic absorption spectrophotometry in 160 training athletes (57 females) in the morning at rest. In 23.3% of the male and 43% of the female athletes, serum Zn was lower than the limit accepted for the normal range (75 microgram/dl or 11.5 mumol/l). The average serum Zn (96.7 +/- 12.6 microgram/dl) and the range of the values found in a control group of 15 young adult males did not differ from the accepted values in the literature. In 22 randomly selected male athletes, serum Zn fractions were determined using polyethylene glycol precipitation at pH 7.1; 22.2% of total Zn was bóund to alpha2-macroglobulin, the ratio being very close to 1 atom of metal per molecule of globulin. The possible reasons that may influence the serum Zn level in athletes are discussed with regard to the present knowledge in both exercise physiology and metabolism of zinc in man.


Autohydrolysis of Diglycine-Activated Succinic Esters Boosts Cellular Uptake.
Rapid cellular uptake of synthetic molecules remains a challenge, and the motif frequently employed to generate prodrugs, succinic ester, unfortunately lowers the efficacy of the desired drugs due to their slow ester hydrolysis and low cell entry. Here we show that succinic ester-containing diglycine drastically boosts the cellular uptake of supramolecular assemblies or prodrugs. Specifically, autohydrolysis of the diglycine-activated succinic esters turns the nanofibers of the conjugates of succinic ester and self-assembling motif into nanoparticles for fast cellular uptake. The autohydrolysis of diglycine-activated succinic esters and drug conjugates also restores the efficacy of the drugs. 2D nuclear magnetic resonance (NMR) suggests that a "U-turn" of diglycine favors intramolecular hydrolysis of diglycine-activated succinic esters to promote autohydrolysis. As an example of rapid autohydrolysis of diglycine-activated succinic esters for instant cellular uptake, this work illustrates a nonenzymatic bond cleavage approach to develop effective therapeutics for intracellular targeting.