A New Method to Detect Variants of SARS-CoV-2 Using Reverse Transcription Loop-Mediated Isothermal Amplification Combined with a Bioluminescent Assay in Real Time (RT-LAMP-BART).
Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), of which there are several variants. The three major variants (Alpha, Delta, and Omicron) carry the N501Y, L452R, and Q493R/Q498R mutations, respectively, in the S gene. Control of COVID-19 requires rapid and reliable detection of not only SARS-CoV-2 but also its variants. We previously developed a reverse transcription loop-mediated isothermal amplification assay combined with a bioluminescent assay in real time (RT-LAMP-BART) to detect the L452R mutation in the SARS-CoV-2 spike protein. In this study, we established LAMP primers and peptide nucleic acid probes to detect N501Y and Q493R/Q498R. The LAMP primer sets and PNA probes were designed for the N501Y and Q493R/Q498R mutations on the S gene of SARS-CoV-2. The specificities of RT-LAMP-BART assays were evaluated using five viral and four bacterial reference strains. The sensitivities of RT-LAMP-BART assays were evaluated using synthetic RNAs that included the target sequences, together with RNA-spiked clinical nasopharyngeal and salivary specimens. The results were compared with those of conventional real-time reverse transcription-polymerase chain reaction (RT-PCR) methods. The method correctly identified N501Y and Q493R/Q498R. Within 30 min, the RT-LAMP-BART assays detected up to 100-200 copies of the target genes; conventional real-time RT-PCR required 130 min and detected up to 500-3000 copies. Surprisingly, the real-time RT-PCR for N501Y did not detect the BA.1 and BA.2 variants (Omicron) that exhibited the N501Y mutation. The novel RT-LAMP-BART assay is highly specific and more sensitive than conventional real-time RT-PCR. The new assay is simple, inexpensive, and rapid; thus, it can be useful in efforts to identify SARS-CoV-2 variants of concern.


Evaluation of Bone Thickness and Density in the Lower Incisors' Region in Adults with Different Types of Skeletal Malocclusion using Cone-beam Computed Tomography.
To evaluate the bone thickness and density in the lower incisors' region in orthodontically untreated adults, and to examine any possible relationship between thickness and density in different skeletal patterns using cone-beam computed tomography (CBCT). The CBCT records of 48 patients were obtained from the archive of orthodontic department comprising three groups of malocclusion (class I, II and III) with 16 patients in each group. Using OnDemand 3D software, sagittal sections were made for each lower incisor. Thicknesses and densities were measured at three levels of the root (cervical, middle and apical regions) from the labial and lingual sides. Accuracy and reliability tests were undertaken to assess the intraobserver reliability and to detect systematic error. Pearson correlation coefficients were calculated and one-way analysis of variance (ANOVA) was employed to detect significant differences among the three groups of skeletal malocclusion. Apical buccal thickness (ABT) in the four incisors was higher in class II and I patients than in class III patients (p < 0.05). There were significant differences between buccal and lingual surfaces at the apical and middle regions only in class II and III patients. Statistical differences were found between class I and II patients for the cervical buccal density (CBD) and between class II and III patients for apical buccal density (ABD). Relationship between bone thickness and density values ranged from strong at the cervical regions to weak at the apical regions. Sagittal skeletal patterns affect apical bone thickness and density at buccal surfaces of the four lower incisors' roots. Alveolar bone thickness and density increased from the cervical to the apical regions.


Multimodal cortical and subcortical exercise compared with treadmill training for spinal cord injury.
Spared fibers after spinal cord injury (SCI) tend to consist predominantly of subcortical circuits that are not under volitional (cortical) control. We aim to improve function after SCI by using targeted physical exercises designed to simultaneously stimulate cortical and spared subcortical neural circuits. Participants with chronic motor-incomplete SCI enrolled in a single-center, prospective interventional crossover study. Participants underwent 48 sessions each of weight-supported robotic-assisted treadmill training and a novel combination of balance and fine hand exercises, in randomized order, with a 6-week washout period. Change post-intervention was measured for lower extremity motor score, soleus H-reflex facilitation; seated balance function; ambulation; spasticity; and pain. Only 9 of 21 enrolled participants completed both interventions. Thirteen participants completed at least one intervention. Although there were no statistically significant differences, multimodal training tended to increase short-interval H-reflex facilitation, whereas treadmill training tended to improve dynamic seated balance. The low number of participants who completed both phases of the crossover intervention limited the power of this study to detect significant effects. Other potential explanations for the lack of significant differences with multimodal training could include insufficient engagement of lower extremity motor cortex using skilled upper extremity exercises; and lack of skill transfer from upright postural stability during multimodal training to seated dynamic balance during testing. To our knowledge, this is the first published study to report seated posturography outcomes after rehabilitation interventions in individuals with SCI. In participants with chronic incomplete SCI, a novel mix of multimodal exercises incorporating balance exercises with skilled upper extremity exercises showed no benefit compared to an active control program of body weight-supported treadmill training. To improve participant retention in long-term rehabilitation studies, subsequent trials would benefit from a parallel group rather than crossover study design.


Intelligent Internet-based information system optimises diabetes mellitus management in communities.
To evaluate the effect of an intelligent Internet-based information system upon optimising the management of patients diagnosed with type 2 diabetes mellitus (T2DM). In 2015, a T2DM information system was introduced to optimise the management of T2DM patients for 1 year in Fangzhuang community of Beijing, China. A total of 602 T2DM patients who were registered in the health service centre of Fangzhuang community were enrolled based on an isometric sampling technique. The data from 587 patients were used in the final analysis. The intervention effect was subsequently assessed by statistically comparing multiple parameters, such as the prevalence of glycaemic control, standard health management and annual outpatient consultation visits per person, before and after the implementation of the T2DM information system. In 2015, a total of 1668 T2DM patients were newly registered in Fangzhuang community. The glycaemic control rate was calculated as 37.65% in 2014 and significantly elevated up to 62.35% in 2015 ( p < 0.001). After application of the Internet-based information system, the rate of standard health management was increased from 48.04% to 85.01% ( p < 0.001). Among all registered T2DM patients, the annual outpatient consultation visits per person in Fangzhuang community was 24.88% in 2014, considerably decreased to 22.84% in 2015 ( p < 0.001) and declined from 14.59% to 13.66% in general hospitals ( p < 0.05). Application of the T2DM information system optimised the management of T2DM patients in Fangzhuang community and decreased the outpatient numbers in both community and general hospitals, which played a positive role in assisting T2DM patients and their healthcare providers to better manage this chronic illness.


Transcription mapping as a tool in phage genomics: the case of the temperate Streptococcus thermophilus phage Sfi21.
For the lytic growth cycle of the temperate cos-site Streptococcus thermophilus phage Sfi21 a transcription map was developed on the basis of systematic Northern blot hybridizations. All deduced 5' ends were confirmed by primer extension analysis. Three time classes of transcripts were observed. Early transcripts were identified in four different genome regions. One prominent early mRNA of 4.8 kb length covered a group of 12 genes located between the origin of replication and the cos-site. Two short early mRNAs represented a single gene from the direct vicinity of the cos-site and the superinfection immunity gene from the lysogeny module, respectively. A fourth early transcript covered a group of four genes located between the lysin and the integrase gene. Middle transcripts of 2.1 and 5.8 kb length covered cro-like and ant-like repressor genes and the DNA replication module, respectively. Four types of late transcripts were identified. The transcripts covered the likely DNA packaging genes, the head morphogenesis module plus the major tail gene, the remainder of the tail genes, and the putative tail fiber plus lysis genes, respectively. Only the transcript from the head morphogenesis genes yielded defined late mRNA species. The transcription map concurred with most of the in silico predictions for the genome organization of phage Sfi21 except for the separation of the DNA replication module from a possible transcription regulation module. Most 5' ends of the transcripts determined in primer-extension experiments were not preceded by a consensus promoter sequence. The involvement of phage-encoded regulators for middle and late transcription was suggested by chloramphenicol-inhibition experiments.


Use of complementary and alternative medicine in Swedish patients with inflammatory bowel disease: a controlled study.
There is an increasing interest in complementary and alternative medicine (CAM) in patients with chronic diseases, including those with inflammatory bowel disease (IBD). Patients may turn to CAM when conventional therapies are inadequate or associated with side effects for symptomatic relief or to regain control over their disease. The objectives were to explore CAM use and perceived effects in IBD patients in comparison with a control group. A cross-sectional, multicenter, controlled study was carried out. IBD patients were invited from 12 IBD clinics in Sweden. Controls were selected randomly from a residence registry. A study-specific questionnaire was used for data collection. Overall, 48.3% of patients with IBD had used some kind of CAM during the past year compared with 53.5% in controls (P=0.025, adjusted for age, sex, geographic residence, and diet). The most frequently used CAM among IBD patients was massage (21.3%), versus controls (31.4%) (adjusted P=0.0003). The second most used CAM was natural products, 18.7% in IBD patients versus 22.3% of the controls (unadjusted P=0.018). In all, 83.1% of the patients experienced positive effects from CAM and 14.4% experienced negative effects. Overall, 48.3% of Swedish IBD patients used some kind of CAM and controls used CAM significantly more. Natural products were used by one-fifth of the patients and even more by controls. This is notable from a patient safety perspective considering the possible risks of interactions with conventional medication. In all, 40% of the patients reported adverse events from conventional medicine. Patients experienced predominantly positive effects from CAM, and so did controls.


[Access to child's health care in primary care services].
It was conducted a qualitative study based on the methodological framework of dialectical hermeneutics, aiming to identify the attribute access from primary care to solve the health problems of children under one year old from the reports of parents and caregivers. Sixteen caregivers of children were involved, all of them seen in the emergency units of Cascavel-PR, in 2010. Four thematic categories were recognized: Family counselling in seeking health care for the child; Absence of reception on the first contact; Presence of risk classification to the child´s health attention; Barriers that block the access to health care. It was conclude that, families showed difficulties to reach the solution for their children´s health, because of the lack of access to primary care services.


Folic acid conjugated magnetic iron oxide nanoparticles for nondestructive separation and detection of ovarian cancer cells from whole blood.
Because of the lack of early screening strategies, ovarian cancer is the most deadly cause of gynecologic malignancies. This paper describes an effective method for the separation and detection of ovarian cancer cells from female whole blood, using folic acid (FA) conjugated magnetic iron oxide nanoparticles (IO-FA nanoparticles). The IO nanoparticles were synthesized by thermal decomposition and then covalently conjugated with FA. The IO-FA nanoparticles were stably attached to the surface of ovarian cancer cells by coupling to the over-expressed folate receptor (FR), thereby making the cells magnetic. These "magnetic cells" were separated from the complex blood matrix without destruction under a magnetic field. The separation efficiency was as high as 61.3% when the abundance of spiked ovarian cancer SKOV3 cells was as low as 5 × 10(-5)%. We also successfully detected five (5) out of ten (10) metastatic ovarian cancer patients' whole blood. This study suggested the feasibility of early detecting of metastatic ovarian cancer cells, which may potentially improve the ovarian cancers patients' overall survival rate for clinical applications.


Nephrology and renal replacement therapy in Romania.
In the context of the transformation of the Health Systems of Central and Eastern European countries, the role of professional associations is increasing, especially as regards data collection, analysis, and implementation of programmes for development of nephrology and renal replacement therapy (RRT). The Romanian Renal Registry sent questionnaires to the heads of Haemodialysis and Nephrology Centres. The need for renal replacement therapy was deduced from the annual incidence (127 patients p.m.p.) of chronic renal failure. Although the rates of increase in the numbers of Nephrology Departments (+82%), HD Centres (+142%), and total number of patients alive on RRT (+196%) from 1991 to 1995 were higher than the European mean, only 27-30% of the incident patients (459 of 1000-1200 patients) could be provided with RRT. Sixty-two percent of the need for RRT in the age group 25-44 years was met, while only 20% of children (age < 15 years) and people over 55 years requiring RRT received this treatment. Primary renal diseases in patients on RRT were glomerulonephritis (49%) or interstitial nephropathies (23%); diabetic nephropathies, nephroangiosclerosis and systemic diseases were rare (4, 2, and 1% respectively). Most of the CRF patients (88%) were treated by HD. Renal transplantation and peritoneal dialysis were seldom performed (8 and 4%). The cost of HD treatment in Romania (87 USD) is low, even though dialyser reuse is not common practice. The increase in renal replacement therapy in Romania was mainly due to the expansion of the number of haemodialysis centres. Although a significant progress was realized, only one-third of the patients needing RRT could be treated in Romania in 1995.


Thinking outside the black box: are the brain endothelial cells the new main target in Alzheimer's disease?
The blood-brain barrier is the interface through which the brain interacts with the milieu and consists mainly of a sophisticated network of brain endothelial cells that forms blood vessels and selectively moves molecules inside and outside the brain through multiple mechanisms of transport. Although brain endothelial cell function is crucial for brain homeostasis, their role in neurodegenerative diseases has historically not been considered with the same importance as other brain cells such as microglia, astroglia, neurons, or even molecules such as amyloid beta, Tau, or alpha-synuclein. Alzheimer's disease is the most common neurodegenerative disease, and brain endothelial cell dysfunction has been reported by several groups. However, its impairment has barely been considered as a potential therapeutic target. Here we review the most recent advances in the relationship between Alzheimer's disease and brain endothelial cells commitment and analyze the possible mechanisms through which their alterations contribute to this neurodegenerative disease, highlighting their inflammatory phenotype and the possibility of an impaired secretory pattern of brain endothelial cells that could contribute to the progression of this ailment. Finally, we discuss why shall brain endothelial cells be appreciated as a therapeutic target instead of solely an obstacle for delivering treatments to the injured brain in Alzheimer's disease.


Neuroimaging features of fatal high-altitude cerebral edema.
Acute high-altitude cerebral edema can occur in an unacclimatised individual on exposure to high altitudes and sometimes it can be fatal. Here we have described the neuroimaging features of a patient who suffered from fatal high altitude cerebral edema. Available literature is reviewed. Probable pathogenesis is discussed. The risk of acute mountain sickness is reported up to 25% in individuals who ascend to an altitude of 3500 meter and in more than 50% subjects at an altitude of 6000 meter. The lack of availability of advanced imaging facilities at such a higher altitude makes imaging of such condition a less described entity.


In vivo analysis of Schwann cell programmed cell death in the embryonic chick: regulation by axons and glial growth factor.
The present study uses the embryonic chick to examine in vivo the mechanisms and regulation of Schwann cell programmed cell death (PCD) in spinal and cranial peripheral nerves. Schwann cells are highly dependent on the presence of axons for survival because the in ovo administration of NMDA, which excitotoxically eliminates motoneurons and their axons by necrosis, results in a significant increase in apoptotic Schwann cell death. Additionally, pharmacological and surgical manipulation of axon numbers also affects the relative amounts of Schwann cell PCD. Schwann cells undergoing both normal and induced PCD display an apoptotic-like cell death, using a caspase-dependent pathway. Furthermore, axon elimination results in upregulation of the p75 and platelet-derived growth factor receptors in mature Schwann cells within the degenerating ventral root. During early development, Schwann cells are also dependent on axon-derived mitogens; the loss of axons results in a decrease in Schwann cell proliferation. Axon removal during late embryonic stages, however, elicits an increase in proliferation, as is expected from these more differentiated Schwann cells. In rodents, Schwann cell survival is regulated by glial growth factor (GGF), a member of the neuregulin family of growth factors. GGF administration to chick embryos selectively rescued Schwann cells during both normal PCD and after the loss of axons, whereas other trophic factors tested had no effect on Schwann cell survival. In conclusion, avian Schwann cells exhibit many similarities to mammalian Schwann cells in terms of their dependence on axon-derived signals during early and later stages of development.


Dietary glutamate supplementation ameliorates mycotoxin-induced abnormalities in the intestinal structure and expression of amino acid transporters in young pigs.
The purpose of this study was to investigate the hypothesis that dietary supplementation with glutamic acid has beneficial effects on growth performance, antioxidant system, intestinal morphology, serum amino acid profile and the gene expression of intestinal amino acid transporters in growing swine fed mold-contaminated feed. Fifteen pigs (Landrace×Large White) with a mean body weight (BW) of 55 kg were randomly divided into control group (basal feed), mycotoxin group (contaminated feed) and glutamate group (2% glutamate+contaminated feed). Compared with control group, mold-contaminated feed decreased average daily gain (ADG) and increased feed conversion rate (FCR). Meanwhile, fed mold-contaminated feed impaired anti-oxidative system and intestinal morphology, as well as modified the serum amino acid profile in growing pigs. However, supplementation with glutamate exhibited potential positive effects on growth performance of pigs fed mold-contaminated feed, ameliorated the imbalance antioxidant system and abnormalities of intestinal structure caused by mycotoxins. In addition, dietary glutamate supplementation to some extent restored changed serum amino acid profile caused by mold-contaminated feed. In conclusion, glutamic acid may be act as a nutritional regulating factor to ameliorate the adverse effects induced by mycotoxins.


Intraspeech spread of masking in normal-hearing and hearing-impaired listeners.
Hearing-impaired and normal-hearing listeners labeled synthetic consonant-vowel stimuli (/ba/, /da/, /ga/, /be/, /de/, /ge/) presented at moderate and high signal levels. First formant (F1) regions were synthesized at normal and at attenuated levels to test whether F1 attenuation might reduce upward spread of masking, making information contained in higher formant regions more available. Performance was tested in quiet and in broadband noise sufficient to mask initial release bursts. Although complete removal of F1 consistently reduced performance, F1 attenuation of up to 18 dB led to increased labeling accuracy, particularly in the /a/ vowel context. Benefit associated with F1 attenuation was more consistently seen for hearing-impaired than for normal-hearing listeners and, in particular, for listeners with steep increases in audiometric thresholds between the first and second formant regions of the test stimuli. The availability of initial bursts as a source of place cues during testing in quiet did not reduce the benefit associated with F1 attenuation.


Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus.
Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that modulate gene expression. Therapeutic agents targeting 2 distinct families of PPARs (alpha and gamma) have been introduced in the United States. The first dual-PPAR agonist, muraglitazar, was reviewed by a US Food and Drug Administration (FDA) advisory committee on September 9, 2005, resulting in a vote of 8:1 recommending approval for its use in controlling blood glucose levels in patients with type 2 diabetes. To evaluate the incidence of death, myocardial infarction (MI), stroke, congestive heart failure (CHF), and transient ischemic attack (TIA) in diabetic patients treated with muraglitazar compared with controls. The source material for this analysis consisted of documents about phase 2 and 3 clinical trials released under public disclosure laws for the FDA advisory committee meeting. All reviewed trials were prospective, randomized, double-blind, multicenter studies enrolling patients with type 2 diabetes and hemoglobin A(1c) levels between 7% and 10%. Patients (N = 3725) were randomized to receive differing doses of muraglitazar, pioglitazone, or placebo as monotherapy or in combination with metformin or glyburide in trials ranging from 24 to 104 weeks. The primary outcome was the incidence of death, nonfatal MI, or nonfatal stroke. A more comprehensive composite outcome included these events plus the incidence of CHF and TIA. In the muraglitazar-treated patients, death, MI, or stroke occurred in 35 of 2374 (1.47%) patients compared with 9 of 1351 (0.67%) patients in the combined placebo and pioglitazone treatment groups (controls) (relative risk [RR], 2.23; 95% confidence interval [CI], 1.07-4.66; P = .03). For the more comprehensive outcome measure that included TIA and CHF, the incidence was 50 of 2374 (2.11%) for muraglitazar compared with 11 of 1351 (0.81%) for controls (RR, 2.62; 95% CI, 1.36-5.05; P = .004). Relative risks for each of the individual components of the composite end point exceeded 2.1 but were not statistically significant. Incidence of adjudicated CHF was 13 of 2374 (0.55%) muraglitazar-treated patients and 1 of 1351 controls (0.07%) (RR, 7.43; 95% CI, 0.97-56.8; P = .053). Compared with placebo or pioglitazone, muraglitazar was associated with an excess incidence of the composite end point of death, major adverse cardiovascular events (MI, stroke, TIA), and CHF. This agent should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial.


Mild versus conventional antagonist ovarian stimulation protocols in expected normal responders undergoing IVF/ICSI: a case-control study.
Mild controlled ovarian hyperstimulation (COH) protocols combining clomiphene citrate (CC) or letrozole with gonadotropins were introduced as an effective alternative of conventional COH in normal responders undergoing IVF/ICSI. In this case-control study, we compared 41 participants treated with a mild stimulation protocol receiving gonadotropins combined with either CC (n = 24) or letrozole (n = 17) with 71 subfertile participants with matching baseline characteristics, conforming with the same inclusion criteria and treated with a conventional antagonist protocol. Live birth was determined in reduced rates in the study group compared to the control group, reaching marginal statistical significance [4/41 versus 19/71, p = 0.050], as also in the respective number of clinical pregnancies [6/41 versus 22/71, p = 0.054], although the incidence of miscarriage was similar for both groups [2/41 versus 5/71, p = 0.714]. Most of the secondary parameters examined, favored the conventional antagonist protocol. There was no difference in any of the outcomes reported between the three different stimulation groups in post-hoc analysis. Mild stimulation regimens with the aid of either CC or letrozole employing GnRH antagonists do not seem to constitute an equally effective method as compared to the conventional antagonist protocol to be offered in good prognosis subfertile women seeking an induced cycle toward IVF/ICSI.


Strength and aerobic training in overweight females in Gdansk, Poland.
We compared the effects of 16-week-training on rest metabolic rate, aerobic power, and body fat, and the post-exercise effects upon rest oxygen uptake and respiratory exchange ratio in overweight middle-aged females. Twenty nine overweight women (BMI 29.9 ± 1.2 kg*m-2) participated in training (3 days a week). The subjects were divided onto groups of aerobic (AT) and strength (ST) training. The results showed that the total body mass decrease and VO2 max increase did not differ in both groups. Decrease in waist circumference after 16 weeks was higher in the ST group. In the ST group fat-free mass increased during the first 8 weeks. Rest metabolic rate was increased significantly at 16th week compared to initial value in ST group only. Significant increase in post-exercise resting VO2 and respiratory exchange ratio at 12 and 36 h was observed after the strength training session only. Increase in rest metabolic rate and post-exercise rest energy expenditure occurred after strength training but not after aerobic training despite the similar increase in aerobic power. The effect of 8-16 weeks of strength training on body mass decrease was higher in comparison to aerobic training.


[Mould and dampness in houses: health, environmental and social aspects - results of a study by the Bremen local public health office].
Mould and dampness, both long known indoor problems, may cause several health effects. During the last years, this topic has gained increasing importance in the field of environmental hygiene at the Bremen local public health office and has become a major focus of the work. The analysis of the advisory service for private persons has shown: mould and dampness are relevant health and environmental problems in private homes. Data from a questionnaire-based study revealed that mainly people with low social status, especially those with low income, request for information and guidance. This indicates the need for free advice for people with low income.


Revisiting the cumulative effects of drought on global gross primary productivity based on new long-term series data (1982-2018).
Drought has broad and deep impacts on vegetation. Studies on the effects of drought on vegetation have been conducted over years. Recently, the cumulative effect of drought is recognized as another key factor affecting plant growth. However, global-scale studies on this phenomenon are still lacking. Thus, based on new satellite based gross primary productivity (GPP) and multi-temporal scale Standardized Precipitation Evapotranspiration Index data sets, we explored the cumulative effect duration (CED) of drought on global vegetation GPP and analyzed its variability across elevations and climatic zones. The main findings were as follows: (1) The cumulative effect of drought on GPP was widespread, with an average CED of 4.89 months. (2) CED of drought on GPP varied among vegetation types. Specifically, grasslands showed the longest duration, with an average value of 5.28 months, followed by shrublands (5.09 months), wetlands (5.03 months), croplands (4.85 months), savannas (4.58 months), and forestlands (4.57 months). (3) CED of drought on GPP changes with climate conditions. It decreased with the decrease of precipitation in the driest month (Pdry ) and mean annual precipitation in tropical and arid climate zones, respectively. In both temperate and cold climate zones, CED of drought on GPP was shorter in areas with dry winter than that in areas with dry summer. It increased with the decrease of mean annual air temperature in tropical climate zones and decreased with the increase of summer temperature in temperate and cold climatic zones. (4) With increasing elevation, CED of drought on GPP showed a pattern of increasing (0-3000 m), then decreasing (3000-5000 m), and increasing again (>5000 m). Our findings highlight the heterogeneity of CED of drought on GPP, owing to differences in vegetation types, long-term hydrothermal conditions, elevation, etc. The results could deepen our understanding of the effects of drought on global vegetation.


A Comparison Between Two Screening Approaches for ASD Among Toddlers in Israel.
Systematic screening of autism spectrum disorder (ASD) can improve early diagnosis of ASD. We compared the efficacy of two ASD screening methods, the Global Developmental Screening (GDS), and the Modified Checklist for Autism in Toddlers-Revised, with Follow-Up (M-CHAT/F) in 1591 toddlers of ages 18-36 months from 35 government-funded clinics in south Israel. The M-CHAT/F performed better than the GDS in detecting toddlers with ASD (sensitivity: 70.0% vs. 50.0%, and specificity: 98.2% vs. 96.6% respectively). Both methods had an equivalent performance in detecting other forms of developmental delays (sensitivity = 63%; and specificity ~ 98%). In addition, remarkable inter-nurse variation was observed in the GDS referral decisions. Thus, employment of the M-CHAT/F in the Israeli health system may improve early detection of ASD among toddlers.


The impact of intrauterine growth restriction on respiratory outcomes.
Intrauterine growth restriction (IUGR) is caused by fetal growth below what is normal for its genetic potential. Recent studies have shown a distinct association between changes in umbilical artery flow in IUGR subjects and an increased risk of respiratory morbidity and consequently, higher mortality. The aim of this study was to find the impact of IUGR on the respiratory outcomes of premature neonates born with less than 32 weeks gestational age. This retrospective cohort study targeted infants born with less than 32 weeks of gestation, admitted at NCIU, between January 2010 and December 2016. Each selected IUGR case was matched according to gestational age and sex with an appropriate birthweight newborn at a 1:2 ratio, within a 12-month period. The study involved 126 neonates, 42 with IUGR, and 84 control subjects. IUGR was not identified as a predictor of Bronchopulmonary Dysplasia (BDP) (OR 4.80, 95% CI: 1.14-20.21, P=0.033). Abnormal umbilical artery flow (OR 4.80, 95% CI: 1.14-20.21, P=0.033) and late onset sepsis (OR 3.31, 95% CI: 1.04-10.56, P=0.044) were significantly associated with BDP. It is essential to recognize changes in the umbilical artery flow, especially in high-risk pregnancies such as IUGR, since these represent an a priori risk marker for the development of BDP. The individual and combined effect of IUGR, alterations on umbilical artery flow and extreme prematurity has not yet been completely clarified on the impact on lung morbidity, requiring a larger number of studies.


lncRNA C22orf32-1 contributes to the tumorigenesis of nasopharyngeal carcinoma.
The mechanism of nasopharyngeal carcinoma (NPC) remains unclear. The present study investigated the abnormal expression of long non-coding (lnc)RNAs in NPC tissues and one NPC cell line to identify the involvement of lncRNAs in the tumorigenesis of NPC. Using a quantitative reverse transcription polymerase chain reaction (RT-qPCR), the expression of lncRNA C22orf32-1 in NPC tissues and an NPC cell line was verified. The effects of lncRNA C22orf32-1 on NPC cells were investigated with a cell proliferation assay, cell scratch assay, Transwell assay and a cell apoptosis assay. The expression levels of lncRNA C22orf32-1 in NPC tissues and an NPC cell line were upregulated. lncRNA C22orf32-1 promoted the proliferation, migration and invasion of NPC cells, and reduced the apoptosis of NPC cells. The data demonstrated that lncRNA C22orf32-1 may facilitate the tumorigenesis of NPC, and may be used for the early diagnosis and treatment of NPC.


A Social-aware and Mobile Computing-based E-Commerce Product Recommendation System.
E-commerce product recommendation system can help users to find their own products quickly from a large number of products. To address the shortcomings of the current e-commerce product recommendation system, such as low efficiency and large recommendation errors, we designed an intelligent recommendation system based on social awareness and mobile computing. The behavioral characteristics of the current e-commerce product recommendation system are analyzed; the e-commerce product recommendation system is built according to the data processing technology of mobile computing, and the key technologies of the e-commerce product recommendation system are designed. The test results show that the proposed system overcomes the shortcomings of the traditional e-commerce product recommendation system, speeds up the speed of users to find the products they really need from a large number of products, improves the accuracy of e-commerce product recommendations, and the error of e-commerce product recommendations is much lower than that of the traditional, which has higher practical application value.


TomoSim: Simulation of Filamentous Cryo-Electron Tomograms.
As automated filament tracing algorithms in cryo-electron tomography (cryo-ET) continue to improve, the validation of these approaches has become more incumbent. Having a known ground truth on which to base predictions is crucial to reliably test predicted cytoskeletal filaments because the detailed structure of the filaments in experimental tomograms is obscured by a low resolution, as well as by noise and missing Fourier space wedge artifacts. We present a software tool for the realistic simulation of tomographic maps (TomoSim) based on a known filament trace. The parameters of the simulated map are automatically matched to those of a corresponding experimental map. We describe the computational details of the first prototype of our approach, which includes wedge masking in Fourier space, noise color, and signal-to-noise matching. We also discuss current and potential future applications of the approach in the validation of concurrent filament tracing methods in cryo-ET.


A Promising PET Tracer for Imaging of α₇ Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand.
Changes in the expression of α₇ nicotinic acetylcholine receptors (α₇ nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET). We report on a series of new ligands for α₇ nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR) of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT₃ receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a) for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10) has high potential to provide clinically relevant information about the expression and availability of α₇ nAChR in the brain.


Ganglioneuroblastoma of Skull Base.
Neuroblastic tumours are common in childhood and adrenal glands are the most common site. Head and neck ganglioneuroblastomas are extremely rare and nose is a very uncommon site for a ganglioneuroblastoma. The management of this primitive sympathogonic tumour may vary depending on the age of the patient and stage of the tumour. We present a middle-aged man with a ganglioneuroblastoma of skull base, management of this tumour and a review of literature.


Are hearing sensitivities of freshwater fish adapted to the ambient noise in their habitats?
Several groups of fishes, among them two thirds of all freshwater fishes, have developed hearing specializations that enhance auditory sensitivity and broaden frequency ranges compared with hearing non-specialists (generalists), which lack such adaptations. It has been speculated that the enhanced sensitivities of these so-called hearing specialists have evolved in quiet habitats such as lakes, backwaters of rivers, slowly flowing streams or the deep sea. To test this hypothesis, noise levels and frequency spectra of four different freshwater habitats near Vienna, Austria (Danube River, Triesting stream, Lake Neusiedl, backwaters of the Danube River), were recorded and played back to native fish species while simultaneously measuring their auditory thresholds using the auditory evoked potential (AEP) recording technique. As a representative of hearing specialists, we chose the common carp (Cyprinus carpio, Cyprinidae) and for the hearing generalists the European perch (Perca fluviatilis, Percidae). Data show that the carp's hearing is only moderately masked by the quiet habitat noise level of standing waters (mean threshold shift 9 dB) but is heavily affected by stream and river noise by up to 49 dB in its best hearing range (0.5-1.0 kHz). In contrast, the perch's hearing thresholds were only slightly affected (mean up to 12 dB, at 0.1 kHz) by the highest noise levels presented. Our results indicate that hearing abilities of specialists such as carp are well adapted to the lowest noise levels encountered in freshwater habitats and that their hearing is considerably masked in some parts of their distribution range. Hearing in non-specialists such as perch, on the other hand, is only slightly or not at all impaired in all habitats.


The relationship between lesion and normal appearing brain tissue abnormalities in early relapsing remitting multiple sclerosis.
In multiple sclerosis (MS), pathological changes have been found both in macroscopic lesions and normal appearing tissue. Magnetisation transfer ratio (MTR) and T1 relaxation time are abnormal in normal appearing tissues in established MS. This study used these MR techniques in early MS to study normal appearing tissues and lesions. The purpose was to determine whether abnormalities are already detectable in normal appearing tissues in early MS, and if so how they correlate with lesion characteristics. Twenty two patients with early relapsing remitting (RR) MS (median disease duration 2 years, range 7 months-3 years) and 11 age-matched controls were studied. MTR and T1 relaxation times were measured in 9 regions of normal appearing white matter (NAWM) and 7 of normal appearing grey matter (NAGM). Gadolinium enhancing, T1-hypointense and T2 lesion loads were measured in all patients. When all regions were combined, there was a significant difference between patient and control NAWM for both T1 and MTR; T1 was abnormal in 6/9 and MTR in 3/9 NAWM regions. Global assessment of NAGM revealed a significant difference between patients and controls for Ti but not for MTR; T1 was significantly abnormal only in frontal NAGM. There was no significant correlation between NAWM T1 or MTR and any of the lesion load measurements. This study reveals quantitative MR abnormalities in both NAWM and NAGM in early RR MS, with more extensive changes in the former. The lack of correlation between NAWM and lesion abnormalities suggests that they have developed by at least partly independent mechanisms. T1 may be more sensitive than MTR in detecting subtle pathological changes in NAWM and NAGM.


Genetic compensation: A phenomenon in search of mechanisms.
Several recent studies in a number of model systems including zebrafish, Arabidopsis, and mouse have revealed phenotypic differences between knockouts (i.e., mutants) and knockdowns (e.g., antisense-treated animals). These differences have been attributed to a number of reasons including off-target effects of the antisense reagents. An alternative explanation was recently proposed based on a zebrafish study reporting that genetic compensation was observed in egfl7 mutant but not knockdown animals. Dosage compensation was first reported in Drosophila in 1932, and genetic compensation in response to a gene knockout was first reported in yeast in 1969. Since then, genetic compensation has been documented many times in a number of model organisms; however, our understanding of the underlying molecular mechanisms remains limited. In this review, we revisit studies reporting genetic compensation in higher eukaryotes and outline possible molecular mechanisms, which may include both transcriptional and posttranscriptional processes.


The evolution of colony-level development in the Siphonophora (Cnidaria:Hydrozoa).
Evolutionary developmental biology has focused almost exclusively on multicellular organisms, but there are other relevant levels of biological organization that have remained largely neglected. Animal colonies are made up of multiple physiologically integrated and genetically identical units called zooids that are each homologous to solitary, free-living animals. Siphonophores, a group of pelagic hydrozoans (Cnidaria), have the most complex colony-level organization of all animals. Here the colony-level development of five siphonophore species, strategically sampled across the siphonophore phylogeny, is described from specimens collected using deep-sea submersibles and by self-contained underwater breathing apparatus diving. These species include three cystonects, Bathyphysa sibogae, Rhizophysa filiformis, and Rhizophysa eysenhardti, and two "physonects", Agalma elegans and Nanomia bijuga. These data, together with previous findings, are analyzed in a phylogenetic framework to reconstruct key features of the history of colony-level organization and development in the Siphonophora. It is shown that gonodendra and gastrozooids of the examined cystonects arise as independent buds directly on the stem, whereas probud subdivision (the origin of feeding, reproductive, and other zooids from a single bud) is a synapomorphy of the Codonophora. The origin of probud subdivision is associated with the origin of cormidia as integrated units of colony organization, and may have allowed for greater morphological and ecological diversification in the Codonophora relative to the Cystonectae. It is also found that symmetry is labile in siphonophores, with multiple gains and/or losses of directional asymmetry in the group. This descriptive work will enable future mechanistic and molecular studies of colony-level development in the siphonophores.


Tailor-Made Luminescent Polymers through Unusual Metallophilic Interaction Arrays Au···Au···Ag···Ag.
A novel and efficient strategy for the synthesis of luminescent polymers bearing metallophilic interactions with unprecedented charge sequences has been designed. For this end suitable basic gold units such as [AuR2]-, bearing perhalophenyl derivatives, and dinuclear acid silver terpyridine species, [Ag2(terpy)2](CF3SO3)2, have been chosen. Their combination originates the polymeric derivatives [{AuR2}2Ag2(terpy)2]n (R = C6F5, C6Cl2F3) or [{Au(C6Cl5)2}Ag(terpy)]n. The change of the perhalophenyl group in the gold complex modulates the strength in the metallophilic contacts and, consequently, the polymer arrays and luminescent properties. The X-ray diffraction studies of these derivatives revealed that there are polymers with unusual + + - - + + - - charge sequences for the R = C6F5 and C6Cl2F3 species, whereas the more classical + - + - disposition was found for the bulkiest C6Cl5 derivative. Their luminescent properties also vary depending on the formation of these polymer arrays, and time-dependent density functional theory calculations were performed to determine the origin of the luminescence.


An insight into the anti-ulcerogenic potentials of medicinal herbs and their bioactive metabolites.
Peptic ulcer disease (PUD) ranks top among the most prominent gastrointestinal problems prevalent around the world. Long-term use of non-steroidal anti-inflammatory drugs, pathogenic infection by Helicobacter pylori, imbalances between gastrointestinal regulatory factors and pathological hyperacidity are major contributors towards the development of peptic ulcers. Although synthetic drugs of multiple pharmacological classes are abundantly available, inadequacy of such agents in ensuring complete recovery in not uncommon. Therefore, pharmacological explorations of herbal products including plant extracts and their respective isolated phytoconstituents, for potential gastroprotective and antiulcer properties, are regular practice among the scientific community. Moreover, the historical preferences of a significant share of world population towards herbal-based medication over modern synthetic drugs also contribute significantly to such endeavors. This review has endeavored to present ethnomedicinal and pharmacological prospects of a significant number of authenticated plant species in terms of their capacity to exert gastroprotection and antiulcer activities both in vitro and in vivo. The information delineated along the way was further subjected to critical analysis to ascertain the possible future prospects of such findings into designing plant-derived products in future for the treatment of peptic ulcer. Electronic version of prominent bibliographic databases, including Google Scholar, PubMed, Scopus, ScienceDirect, Wiley Online Library, SpringerLink, Web of Science, and MEDLINE were explored extensively for the identification and compilation of relevant information. The plant names and respective family names were verified through the Plant List (version 1.1) and World Flora Online 2021. All relevant chemical structures were verified through PubChem and SciFinder databases and illustrated with ChemDraw Ultra 12.0. A colossal number of 97 plant species categorized under 58 diverse plant families have been discussed in the review for their gastroprotective and antiulcer properties. In vivo illustrations of the pharmacological properties were achieved for almost all the species under consideration. 29 individual phytoconstituents from these sources were also characterized with similar pharmacological potentials. Majority of the plant extracts as well as their constituents were found to exert their gastroprotective effects through antioxidative pathway featuring both enzymatic and nonenzymatic mechanism. Moreover, active inhibition of acid secretion, upregulation of gastroprotective mediators and downregulation of pro-inflammatory cytokines, were also associated with a prominent number of plants or products thereof. Comparative evaluations of the plant sources for their antiulcer activities, both as individual and as combination formulations, are necessary to be conducted in human subjects under properly regulated clinical conditions. Moreover, the efficacy and safety of such products should also be evaluated against those of the currently available treatment options. This will further facilitate in ascertaining their suitability and superiority, if any, in the treatment of peptic ulcer diseases. Implementation of these endeavors may eventually lead to development of more efficient treatment options in the future.


Complete mitochondrial genome and draft chloroplastic genome of Haslea ostrearia (Simonsen 1974).
The first completed, circular mitochondrial genome and the first draft, linear chloroplastic genome of the blue diatom Haslea ostrearia (Simonsen 1974, Naviculaceae, Bacillariophyceae) were assembled from Illumina and PacBio sequencing. The mitochondrial genome was composed of 38,696 bases and contained 64 genes, including 31 protein-coding genes (CDS), 2 ribosomal RNA (rRNA) genes and 23 transfer RNA (tRNA) genes. For the chloroplast, the genome was composed of 130,200 bases with 169 genes (131 CDS, 6 rRNA genes, 31 tRNA genes, and 1 transfer messenger RNA gene). Phylogenetic trees, using the maximum-likehood method and partial genes currently available for Haslea ostrearia and other diatom species, suggested the proximity of all the Haslea ostrearia strains/isolates and the possibility of using these genomes as future references.


Hepatitis A and B in the family unit. Nonparenteral transmission by asymptomatic children.
Investigation of an outbreak of hepatitis A among members of an adoption organization implicated recently arrived Vietnamese orphans as the source of infection. A serologic study disclosed a 27% prevalence of hepatitis B surface antigen among Vietnamese orphans and a 23.1% (6 of 26) prevalence of hepatitis B antibody among American children of adopting families. Five of the six antibody-positive American children were in families with HBsAg-positive orphans. Thus,healthy orphans from high hepatitis incidence areas may transmit hepatitis B, as well as hepatitis A, in the family unit.


Activating FOXO3a, NF-kappaB and p53 by targeting IKKs: an effective multi-faceted targeting of the tumor-cell phenotype?
Tumor cells frequently recruit the PI3K/Akt pathway in order to evade cell death, terminal differentiation and replicative inhibition. A wealth of targets for the PI3K/Akt pathway involved in these processes has been described. Among others, targets for the Akt-kinase include certain members of the Forkhead Box Class O (FOXO) transcription factors, involved in DNA damage repair, apoptosis, cell cycle progression and arrest. Akt regulates the sub-cellular localization of FOXO3a by phosphorylation thereby preventing the protein to translocate to the nucleus and regulate transcription. Constitutive Akt-activation is frequently correlated with cytoplasmatic FOXO3a in breast tumors and this is associated with decreased patient survival. In a recent paper (Hu MC, et al. Cell 2004; 117:225-237) FOXO3a was found in the cytoplasm in the absence of activated Akt. Instead, IKKbeta was shown to interact with and phosphorylate FOXO3a. The recent findings suggest that the IKKs might serve as a potential drug target in anti-cancer therapy since multiple signal transduction pathways inhibiting proliferation and facilitating cell death could be activated.


Research publication credit assignment: nurses' views.
A national survey of 1,693 persons (primarily nurses) from eight target groups was done to assess views on publication credit assignment. Data were collected using scenarios in a questionnaire based on the instrument developed by Spiegel and Keith-Spiegel (1970). Scenario items and the percentages of 897 respondents selecting each response alternative are presented in an appendix. Response rates indicated that authorship credit assignment is an important issue for nurses functioning primarily in academic settings. Among items selected by 85% or more of 620 nurses in four subsample groups (American Academy of Nursing, Council of Nurse Researchers, authors, and nursing doctoral students) with response rates greater than 50%, 10 points of agreement were found. These points are summarized as possible guidelines for publication credit assignment. Few differences were found among scenario item responses of: (a) subjects classified as high and low publishers, (b) those with research as their major role responsibility and others, and (c) doctoral students and others.


Environmental determinants of total IgE among school children living in the rural Tropics: importance of geohelminth infections and effect of anthelmintic treatment.
The environmental factors that determine the elevated levels of polyclonal IgE observed in populations living in the Tropics are poorly understood but may include geohelminth infections. We investigated the association between geohelminth infections and total IgE levels in school children in rural tropical Ecuador, and assessed the effect on IgE of repeated anthelmintic treatments over a period of 12 months. The study was nested within a cluster-randomized study that randomized 68 schools to receive either 400 mg of albendazole every 2 months over a year or no treatment. We studied random samples of children completing follow-up and representing four groups stratified by the presence of geohelminth infection at baseline and treatment allocation. We measured levels of total IgE and anti-A. lumbricoides IgG (used as a measure of past and current geohelminth infectious exposure) in blood samples collected at the start of the study and after 12 months. We observed elevated levels of total IgE (compared to standard reference values) at the start of the study in this population of school children (geometric mean, 1,004 IU/mL, range 12 to 22,608 IU/mL)) and baseline IgE levels were strongly associated with parameters of geohelminth infection but not with age, nutritional and socioeconomic status. After 12 months, levels of IgE fell significantly in the treatment (by 35.1%) and no treatment (by 10.4%) groups, respectively, but the fall was significantly greater in the treatment group. Falls in IgE were independently associated with albendazole treatment, having a baseline geohelminth infection and with high baseline levels of anti-A. lumbricoides IgG. Increases in IgE at 12 months were associated with the presence of geohelminth infections and increasing levels of anti-A. lumbricoides IgG at 12 months independent of treatment allocation. The data provide evidence that geohelminth infections are an important determinant of total IgE in school children in the rural Tropics and that periodic anthelmintic treatments over 12 months are associated with reductions in IgE. The failure of anthelmintic treatment to reduce IgE levels to that considered normal in industrialized countries may be attributed to continued exposure of children to geohelminths or to the effects of infections in early life in programming a long-lasting Th2-biassed immunity.


Surface located procollagen N-propeptides on dermatosparactic collagen fibrils are not cleaved by procollagen N-proteinase and do not inhibit binding of decorin to the fibril surface.
Dermatosparaxis is a recessive disorder of animals (including man) which is caused by mutations in the gene for the enzyme procollagen N-proteinase and is characterised by extreme skin fragility. Partial loss of enzyme activity results in accumulation of pNcollagen (collagen with N-propeptides) and abnormal collagen fibrils in the fragile skin. How the N-propeptides persist in the tissue and how abnormal fibril morphology results in fragile skin is poorly understood. Using biochemical and quantitative mass mapping electron microscopy we showed that the collagen fibrils in the skin of a dermatosparactic calf contained 57% type I pNcollagen and 43% type I collagen and the fibrils were irregularly arranged in bundles and hieroglyphic in cross-section. Image analysis of the fibril cross-sections suggested that the deviation from circularity of dermatosparactic fibrils was caused by N-propeptides of pNcollagen being located at the fibril surface. Comparison of experimental and theoretical axial mass distributions of the fibrils showed that the N-propeptides were located to the overlap zone of the fibril D-period (where D=67 nm, the characteristic axial periodicity of collagen fibrils). Treatment of the dermatosparactic fibrils with N-proteinase did not remove the N-propeptides from the fibrils, although the N-propeptides were efficiently removed by trypsin and chymotrypsin. However, the N-propeptides were efficiently cleaved by the N-proteinase when the pNcollagen molecules were extracted from the fibrils. These results are consistent with close packing of N-propeptides at the fibril surface which prevented cleavage by the N-proteinase. Long-range axial mass determination along the fibril length showed gross non-uniformity with multiple mass bulges. Of note is the skin fragility in dermatosparaxis, and also the appearance of mass bulges along the fibril long axis symptomatic of the fragile skin of mice which lack decorin. Western blot analysis showed that the dermatosparactic fibrils bound elevated levels of the proteoglycan, compared with normal skin fibrils. The results showed that N-propeptides can distort the morphology of fibrils, that they do not inhibit binding of gap-associated macromolecules (such as decorin) and that the normal mechanical properties of skin are strongly dependent on the close association of near-cylindrical fibrils, thereby enabling maximal fibril-fibril interactions.


Pharmacogenetic approach for cancer treatment-tailored medicine in practice.
This article focuses on pharmacogenetic associations between genetic polymorphism of uridine diphosphate glucuronosyltransferase (UGT) 1A1 gene and irinotecan toxicity. Accumulating evidence provides support to the idea that determination of UGT1A1 polymorphisms before irinotecan treatment is clinically useful and important for predicting and avoiding related toxicities. On the basis of these backgrounds, the irinotecan label was updated in 2005 in the United States to provide pharmacogenetic information, and a dose reduction of irinotecan should be considered for patients known to be homozygous for the UGT1A1*28 allele when administered in combination with other agents or a single agent. The irinotecan/UGT1A1 issue and the development of molecular diagnostic testing are now to be translated into clinical practice.


Patterns of secretion of GnRH, LH and FSH during the postovulatory period in mares: mechanisms prolonging the LH surge.
To study the mechanisms responsible for the unusually slow decline of the ovulatory LH surge in mares, secretion patterns of GnRH, LH and FSH were monitored in pituitary venous blood collected every 2 or 5 min for 10.5-18.0 h from five mares on the third (n = 4) or fifth day after ovulation (first sampling period). To determine the effectiveness of progesterone negative feedback, mares were then given a luteolytic dose of a prostaglandin analogue (PGF2 alpha) and pituitary venous sampling (every 2 or 5 min for 16 h) recommenced 20-22 h later (second sampling period). During the declining arm of the LH surge, large peaks (detected by the Cluster algorithm) of concurrent LH and FSH secretion occurred infrequently, with four peaks being detected in a combined sampling period of 75 h. Outside the peaks, LH or FSH secretion continued (as assessed by a pituitary to jugular-venous concentration ratio > or = 1.25) during 46% +/- 13 or 40% +/- 10, respectively, of the sampling period. GnRH immunoactivity was detected during each spontaneous gonadotrophin peak, but at other times was generally at assay sensitivity. After PGF2 alpha, plasma progesterone fell (ng ml-1, mean +/- SEM; first sampling period: 8.6 +/- 0.8; second; 2.0 +/- 0.3; P = 0.001) and the frequency of LH (P < 0.05) and FSH (P < 0.02) peaks rose, with 28 peaks detected for each hormone in a total of 80 h sampling. Peaks in LH were smaller during the second period, with decreases observed in maximum (P = 0.027) and mean (P = 0.025) secretion rates. Maximum GnRH secretion rate during peaks also declined (P = 0.010); however, the decrement (-30 +/- 6%) was less than that in maximum LH secretion rate (-82 +/- 5%; P = 0.040), suggesting that other factors contribute to the reduced LH peak amplitude. In summary, gonadotrophin peak frequency during the downswing of the surge in mares is slow, as in the midluteal phase, and the slow rate of decline in peripheral gonadotrophin concentrations is due, at least in part, to continued secretion between pulses. Moreover, progesterone negative feedback is highly effective in early dioestrus, in that lessening it without complete removal markedly accelerates gonadotrophin pulse frequency.


The Benefits of a Real-Time Web-Based Response System for Enhancing Engaged Learning in Classrooms and Public Science Events.
Large introduction to neuroscience classes and small science cafés have the same goal: bridging the gap between the presenter and the audience to convey the information while being engaging. Early classroom response systems became the cornerstone of flipped and engaged learning. These "clickers" helped turn lectures into dialogues, allowing the presenter to become a facilitator rather than a "sage on the stage." Rapid technological developments, especially the increase of computing power opened up new opportunities, moving these systems from a clicker device onto cellphones and laptops. This allowed students to use their own devices, and instructors to use new question types, such as clicking on a picture or ranking concepts. A variety of question types makes the learning environment more engaging, allows better examples for creative and critical thinking, and facilitates assessment. Online access makes these response systems scalable, bringing the strength of formative assessments and surveys to public science communication events, neuroscience journal clubs and distance learning. In addition to the new opportunities, online polling systems also create new challenges for the presenters. For example, allowing mobile devices in the classroom can be distracting. Here, a web-based, real-time response system called Poll Everywhere was compared to iClickers, highlighting the benefits and the pitfalls of both systems. In conclusion, the authors observe that the benefits of web-based response systems outweigh the challenges, and this form of digital pedagogy can help create a rich dialogue with the audience in large classrooms as well as in public science events.


APRI test and hyaluronic acid as non-invasive diagnostic tools for post HCV liver fibrosis: Systematic review and meta-analysis.
Hepatitis C virus (HCV) accounts for a sizable proportion of chronic liver disease cases and represents the most common indication for liver transplantation. Precise diagnosis of hepatic fibrosis stage is considered a funnel-neck in proper management and follow-up of HCV-infected patients. Given the possible complications of liver biopsy, a non-invasive method for assessing hepatic fibrosis is needed. This study aimed to evaluate the diagnostic accuracy of APRI and hyaluronic acid as non-invasive diagnostic assessment tools for post HCV liver fibrosis. Systematic literature searching identified studies performed on Egyptian territory to evaluate APRI and hyaluronic acid as non-invasive tests of fibrosis and using liver biopsy as the reference standard. Meta-analysis was performed for areas with an adequate number of publications. Validation of meta- analysis on APRI was done on a subset of 150 treatment-naïve post-hepatitis C patients. Both APRI and hyaluronic acid have superior predictive power for hepatic cirrhosis (F4) than for significant fibrosis (F2-F3). The pooled estimate for sensitivities and specificities of APRI and hyaluronic acid to diagnose F4 were (84% and 82%) and (83% and 89%) respectively. In the subgroup of treatment naïve post-hepatitis C patients, APRI had higher diagnostic performance to diagnose liver cirrhosis with 93.8% sensitivity and 72.4% specificity (AUC; 0.908, 95%CI; 0.851-0.965, p-value; <0.001) compared to its accuracy to diagnose significant hepatic fibrosis with 65.1% sensitivity and 77.8% (AUC; 0.685, 95% CI; 0.59-0.78, p-value; 0.001). APRI score and hyaluronic acid levels are simple and reliable non-invasive markers to detect advanced fibrosis among post-hepatitis C patients.


A spatial model to estimate habitat fragmentation and its consequences on long-term persistence of animal populations.
The increasing use of the landscape by humans has led to important diminutions of natural surfaces. The remaining patches of wild habitat are small and isolated from each other among a matrix of inhospitable land-uses. This habitat fragmentation, by disabling population movements and stopping their spread to new habitats, is a major threat to the survival of numerous plant and animal species. We developed a general model, adaptable for specific species, capable of identifying suitable habitat patches within fragmented landscapes and investigating the capacity of populations to move between these patches. This approach combines GIS analysis of a landscape, with spatial dynamic modeling. Suitable habitat is identified using a threshold area to perimeter ratio. Potential movement pathways of species between habitat patches are modeled using a cellular automaton. Habitat connectivity is estimated by overlaying habitat patches with movement pathways. The maximum potential population is calculated within and between connected habitat patches and potential risk of inbreeding within meta-populations is considered. The model was tested on a sample map and applied to scenario maps of predicted land-use change in the Peoria Tri-county region (IL). It (1) showed area of natural area alone was insufficient to estimate the consequences on animal populations; (2) underscored the necessity to use approaches investigating the effect of land-use change spatially through the landscape and the importance of considering species-specific life history characteristics; and (3) highlighted the model's potential utility as an indicator of species likelihood to be affected negatively by land-use scenarios and therefore requiring detailed investigation.


Impact of heat shock step on bacterial transformation efficiency.
CaCl2 treatment followed by heat shock is the most common method for artificial transformation. Here, the cells were transformed using CaCl2 treatment either with heat shock (standard protocol) or without heat shock (lab protocol) to comprehend the difference in transformation efficiency. The BL21 strain of Escherichia coli (E. coli) was being susceptible using CaCl2 treatment. Some Cells were kept at -80 oC while the others were kept at 4 ˚C. Afterwards the susceptible cells were transformed using either standard or lab protocol. The transformation efficiency between cells experienced heat shock and those were not influenced by heat shock was almost the same. Moreover, regardless of transformation protocol, the cells kept at 4 ˚C were transformed more efficiently in compared to those were kept at -80 oC.


Regulatory T cells prevent CD8 T cell maturation by inhibiting CD4 Th cells at tumor sites.
Natural regulatory T cells (Tregs) are present in high frequencies among tumor-infiltrating lymphocytes and in draining lymph nodes, supposedly facilitating tumor development. To investigate their role in controlling local immune responses, we analyzed intratumoral T cell accumulation and function in the presence or absence of Tregs. Tumors that grew in normal BALB/c mice injected with the 4T1 tumor cell line were highly infiltrated by Tregs, CD4 and CD8 cells, all having unique characteristics. Most infiltrating Tregs expressed low levels of CD25Rs and Foxp3. They did not proliferate even in the presence of IL-2 but maintained a strong suppressor activity. CD4 T cells were profoundly anergic and CD8 T cell proliferation and cytotoxicity were severely impaired. Depletion of Tregs modified the characteristics of tumor infiltrates. Tumors were initially invaded by activated CD4(+)CD25(-) T cells, which produced IL-2 and IFN-gamma. This was followed by the recruitment of highly cytotoxic CD8(+) T cells at tumor sites leading to tumor rejection. The beneficial effect of Treg depletion in tumor regression was abrogated when CD4 helper cells were also depleted. These findings indicate that the massive infiltration of tumors by Tregs prevents the development of a successful helper response. The Tregs in our model prevent Th cell activation and subsequent development of efficient CD8 T cell activity required for the control of tumor growth.


Temporal coherence for pure tones in budgerigars (Melopsittacus undulatus) and humans (Homo sapiens).
Auditory scene analysis has been suggested as a universal process that exists across all animals. Relative to humans, however, little work has been devoted to how animals perceptually isolate different sound sources. Frequency separation of sounds is arguably the most common parameter studied in auditory streaming, but it is not the only factor contributing to how the auditory scene is perceived. Researchers have found that in humans, even at large frequency separations, synchronous tones are heard as a single auditory stream, whereas asynchronous tones with the same frequency separations are perceived as 2 distinct sounds. These findings demonstrate how both the timing and frequency separation of sounds are important for auditory scene analysis. It is unclear how animals, such as budgerigars (Melopsittacus undulatus), perceive synchronous and asynchronous sounds. In this study, budgerigars and humans (Homo sapiens) were tested on their perception of synchronous, asynchronous, and partially overlapping pure tones using the same psychophysical procedures. Species differences were found between budgerigars and humans in how partially overlapping sounds were perceived, with budgerigars more likely to segregate overlapping sounds and humans more apt to fuse the 2 sounds together. The results also illustrated that temporal cues are particularly important for stream segregation of overlapping sounds. Lastly, budgerigars were found to segregate partially overlapping sounds in a manner predicted by computational models of streaming, whereas humans were not.


The split-heel technique in the management of chronic calcaneal osteomyelitis in children.
The split-heel technique has distinct advantages over the conventional medial or lateral approach in the operative debridement of extensive and predominantly plantar chronic calcaneal osteomyelitis in children above 5 years of age. We report three cases (age 5.5-11 years old) of chronic calcaneal osteomyelitis in children treated using the split-heel approach with 3-10 years follow-up showing excellent functional and cosmetic results.


Strangers bearing gifts: a retrospective look at the early years of community mental health center consultation.
Many early community mental health center (CMHC) consultations floundered when consultants attempted to apply Gerald Caplan 's community consultation theory, which the author describes as based on a private consultation paradigm, to the very different realities of government-mandated public paradigm consultation by CMHCs to public agencies. CMHC consultants were often perceived by consultees as "strangers bearing gifts" due to the lack of clarity concerning the rationale, contracts, roles, responsibilities, evaluation, and consultant- consultee exchanges of their public paradigm consultations. The otherwise disastrous recent losses of financial support for CMHCs are beneficially forcing them to shift their community consultation practices toward the private paradigm.


[Clinico-pathological analysis of interstitial pneumonia associated with collagen vascular disease in patients with lung cancer].
We investigated interstitial pneumonia associated with collagen vascular disease (IP-CVD) in association with lung cancer. Seventy-three cases of IP-CVD were included in this study. Nine (12%) of the 73 cases were associated with lung cancer, one of which had double lung cancers. The histological types of the cancers were adenocarcinoma (5 cases), epidermoid carcinoma (2 cases), small cell carcinoma, large cell carcinoma and large cell neuroendocrine carcinoma (one case each). The lesions were located in the central or peripheral lung in 3 and 7 of the ten cancers, respectively. Of the seven cases diagnosed as having IP-CVD followed by lung cancer, five had stage I disease, and one each of the remaining two cases was in stage IIIA and stage IV. Six of the seven peripheral cancer lesions which were resected or autopsied could be analyzed with regard to the topographical relationship between the primary site and fibrotic lesions. Only three cancers were encased by or in close proximity to, honeycomb lung, although most of the lung cancers arose in relation to fibrotic lesions. Moreover, the acute exacerbation of IP-CVD after operation or chemotherapy without thoracic irradiation should be monitored carefully.


Plasma beta 2 microglobulin as a means of predicting gentamicin serum concentrations.
A novel and accurate method for predicting gentamicin peak serum concentration is described. The method considers body weight and renal function as determined by the concentration of beta 2 microglobulin in plasma. In 32 subjects whose renal function ranged from normal to severely impaired, the peak serum concentration of gentamicin was more closely correlated with beta 2 microglobulin (r = 0.69) and with creatinine clearance (r = 0.69) than with serum creatinine (r = 0.53). A nomogram was constructed which related plasma beta 2 microglobulin concentrations and body weight to predicted gentamicin peak serum concentrations. When the nomogram was clinically applied, the predicted peak gentamicin concentrations corresponded closely to the actual measurements obtained (t = 0.64; P is not significant). We suggest that plasma beta 2 microglobulin concentrations compare favorably with serum creatinine values in the prediction of gentamicin peak concentrations in patients with renal impairment.


Large spontaneous coronary artery-to-right ventricular fistula.
We report a case of the spontaneous formation of a left anterior descending artery to right ventricular fistula. The unprovoked appearance of this fistulous connection was clearly documented by serial angiography and confirmed during surgery.


Investigating the Functional Role of Hypothetical Proteins From an Antarctic Bacterium Pseudomonas sp. Lz4W: Emphasis on Identifying Proteins Involved in Cold Adaptation.
Exploring the molecular mechanisms behind bacterial adaptation to extreme temperatures has potential biotechnological applications. In the present study, Pseudomonas sp. Lz4W, a Gram-negative psychrophilic bacterium adapted to survive in Antarctica, was selected to decipher the molecular mechanism underlying the cold adaptation. Proteome analysis of the isolates grown at 4°C was performed to identify the proteins and pathways that are responsible for the adaptation. However, many proteins from the expressed proteome were found to be hypothetical proteins (HPs), whose function is unknown. Investigating the functional roles of these proteins may provide additional information in the biological understanding of the bacterial cold adaptation. Thus, our study aimed to assign functions to these HPs and understand their role at the molecular level. We used a structured insilico workflow combining different bioinformatics tools and databases for functional annotation. Pseudomonas sp. Lz4W genome (CP017432, version 1) contains 4493 genes and 4412 coding sequences (CDS), of which 743 CDS were annotated as HPs. Of these, from the proteome analysis, 61 HPs were found to be expressed consistently at the protein level. The amino acid sequences of these 61 HPs were submitted to our workflow and we could successfully assign a function to 18 HPs. Most of these proteins were predicted to be involved in biological mechanisms of cold adaptations such as peptidoglycan metabolism, cell wall organization, ATP hydrolysis, outer membrane fluidity, catalysis, and others. This study provided a better understanding of the functional significance of HPs in cold adaptation of Pseudomonas sp. Lz4W. Our approach emphasizes the importance of addressing the "hypothetical protein problem" for a thorough understanding of mechanisms at the cellular level, as well as, provided the assessment of integrating proteomics methods with various annotation and curation approaches to characterize hypothetical or uncharacterized protein data. The MS proteomics data generated from this study has been deposited to the ProteomeXchange through PRIDE with the dataset identifier-PXD029741.


Study of the plasma pharmacokinetics and faecal excretion of the prodrug olsalazine and its metabolites after oral administration to horses.
Olsalazine sodium (Dipentum*) has been used therapeutically against inflammatory bowel disease in human medicine as an alternative to sulphasalazine over the past 20 years. Bacteria in the colon split this prodrug into two molecules of the locally effective 5-aminosalicylic acid (5-ASA). Considering the potential therapeutic use in equine colitis, the pharmacokinetics of olsalazine (OLZ) after single oral administration to six horses at a dosage of 30 mg/kg was investigated. Plasma concentrations of OLZ, 5-ASA, and its main metabolite N-acetyl-5-aminosalicylic acid (Ac-5-ASA) were analysed by high-performance liquid chromatography methods. Evaluation of the plasma pharmacokinetics revealed a rapid, but low extent of absorption of OLZ (peak concentrations around 1 microg/mL at 0.5-1.5 h), and a delayed minimal absorption of 5-ASA (concentrations < 0.2 microg/mL, at 11-35 h), which is immediately metabolized to Ac-5-ASA. As indicators of the local availability in the colon, high faecal water concentrations of 5-ASA and Ac-5-ASA (mean C(max) about 300 and 130 microg/mL, respectively), but only traces of OLZ were found in faeces excreted 18-50 h after dosing. Of the administered OLZ dose 26% could be recovered from faeces, almost completely as 5-ASA and Ac-5-ASA. Routine clinical examination of the horses and assay of standard haematological and serum chemistry parameters before and after OLZ administration confirmed that a single dosage of 30 mg/kg was well tolerated. To estimate the systemic availability of 5-ASA liberated from OLZ, 5-ASA was administered i.v. at a dosage of 1.5 mg/kg to four horses and plasma concentrations of 5-ASA and Ac-5-ASA were determined. The pharmacokinetic evaluation showed a very low bioavailability of 2.4% for 5-ASA, released from orally administered OLZ. Furthermore, in an in vitro experiment, the metabolic transformation of 5-ASA to Ac-5-ASA mediated by bacteria in the caecal content of horses was determined at 38 degrees C for 31 h and compared with the metabolism data of the in vivo study. The markedly lower degree of acetylation in vitro supports the assumption that biotransformation of 5-ASA in vivo occurs not only by colonic bacteria, but also at other sites.


Poor and Unsatisfactory Disposal of Expired and Unused Pharmaceuticals: A Global Issue.
Pharmaceuticals are beneficial to humankind and emerged as crucial arms to treat/manage multiple disease pathogenesis in the present era. In analogous, these medicines/ medical devices should be used cautiously as they possess a potential threat to induce multiple undesired effects that may be related to human health or the environment. Daunting effects may arise due to the improper disposal of unused/expired medicines. Hence, to minimize such harm, there should be adequate knowledge and practice among the population regarding the safe disposal of unused/expired medicines or related pharmaceutical devices. The lack of approved information regarding safe disposal of such substances may invite serious concerns like environmental pollution, which may induce immediate health hazards to the present population and upcoming future generations. There are numerous ways to dispose of, or manage the unused and expired pharmaceutical substances. Sharing the medicines among siblings, friends, and family members are never free from serious health risks. Storing the unused and expired medicines in the home increases the risk of intentional or accidental ingestion of such substances and may create a health emergency. Disposing medicines like household and municipal waste may lead to environmental pollution and harm to humans and animals. The present review finds the multiple unsafe ways of disposal of unutilized medications/tools. Furthermore, it also summarizes the disposal pattern of unutilized medications among the few developed and undeveloped nations.


Activation of human platelets by antibodies to thymocytes and beta 2-microglobulin. II. Effect of purified beta 2m on the platelet aggregating and lymphocytotoxic activities of HATG and SA beta 2mG.
Platelet aggregating (PAA) and lymphocytotoxic activities (LTA) of antibody preparations known to have immunosuppressive properties were studied in this work. In comparison to sheep anti-human beta-2-microglobulin globulin (SA beta 2mG), horse anti-human thymocyte globulin (HATG) was about twice as potent by weight in LTA than in PAA, suggesting that a considerable portion of antibodies in HATG had been generated against lymphocyte specific antigens. Evidence is presented that not only the LTA but also the PAA is a direct effect of both HATG and SA beta 2mG on lymphocytes and platelets. The specificity of the antibodies was investigated by means of purified human urinary beta-2-microglobulin (beta 2m). Beta-2-microglobulin had no detectable inhibitory effect on the LTA and, in most cases, on the PAA of HATG. Even in a highly sensitive assay system, no more than 5 to 7% of the total PAA of HATG was inhibitable by beta 2m. In contrast, both the PAA and LTA of SA beta 2mG could be inhibited by beta 2m in a time- and dose-dependent fashion. The results prove that HATG and SA beta 2mG exert their actions through different membrane components on both platelets and lymphocytes. This is consistent with our earlier observation that the PAA of HATG and SA beta 2mG may widely dissociate among various human platelet-rich plasmas. Relatively low response to anti-beta 2m in the presence of high reactivity to ALG/ATG can also be explained by varying plasma levels of beta 2m. Finally, inhibition of the PAA of SA beta 2mG by purified beta 2m provides the first model where the platelet aggregating effect on an inducer (anti-beta 2m) can quantitatively be blocked by its specific "solubilized" receptor (beta 2m) whose structure is fully understood.


[Indications for a bridging plate osteosynthesis of compound femoral shaft fractures].
We performed the clinical and radiological follow-up of 29 comminuted fractures of the femoral shaft treated by bridging plate osteosynthesis. Complete bone healing in 6 open fractures took place within 33 weeks, in 15 closed fractures within 22 weeks. We had to meet 5 postoperative complications: 2 cases of osteomyelitis following open fractures, 1 early wound infection and 2 haematomas. Primary cancellous bone grafting we found unnecessary in all of the 29 fractures. We recommend the technique of bridging plate osteosynthesis for the stabilization of comminuted fractures of the femur especially under the clinical circumstances as follows: 1. Polytrauma, 2. Metaphyseal or condylar fracture, 3. Open fracture, 4. Redisplacement, 5. Fracture in children.


Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes.
We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment.


Long-term expression of an HLA-DQ molecule in the EBV-transformed bare lymphocyte cell line, BLS-1, using a plasmid vector.
The HLA class II molecule, DQ6, confers strong natural protection against the development of type 1 diabetes. The mechanism of disease protection is unknown, but is likely to be related to the function of the molecule in antigen presentation. In order to investigate this function, we have created an in vitro model which expresses DQ6 in isolation by introducing the relevant DQ alleles into an Epstein-Barr virus (EBV)-transformed, human leucocyte antigen (HLA) class II-deficient B cell line, bare lymphocyte syndrome (BLS)-1. A recent report suggested that the expression of transferred genes in human EBV-transformed B cells might be limited in duration. We present a plasmid-based transfection method that allows long-term stable expression of the DQ molecule. The DQA1*0102 and DQB1*0602 alleles were cloned into the pCIneo expression vector and the constructs were introduced into BLS-1 by electroporation. Stable transfectants were selected using magnetic sorting and cloned by limiting dilution. Two clones were shown to express functionally active DQ6 molecules even after 14 months of continuous culture. These clones will be used in functional studies to investigate the antigen binding and T-cell activation properties of the DQ6 molecule.


Time-resolved x-ray stroboscopic phase tomography using Talbot interferometer for dynamic deformation measurements.
Time-resolved x-ray phase tomography using a Talbot interferometer and white synchrotron radiation can provide a three-dimensional movie for visualizing the structural change of materials consisting of light elements. In this study, time-resolved x-ray stroboscopic phase tomography using a Talbot interferometer is demonstrated for a vibrating object under 24 Hz compression-stretch fatigue loading. Moiré patterns are recorded by synchronizing drivers for a shutter, grating displacement, and sample rotation with an x-ray camera with a 200 µs exposure, and phase tomograms are reconstructed at specific motion phases of the vibration. The measurement lasts for a few minutes and the δ value changes before breaking, which is considered due to plastic deformation of soft materials under external vibration are depicted three-dimensionally.


Using a local early warning scoring system as a model for the introduction of a national system.
Chelsea and Westminster Hospital introduced the Chelsea Early Warning Score (CEWS) in 2007 to aid the recognition of acutely unwell patients. The Royal College of Physicians subsequently recommended a National Early Warning Score (NEWS) for implementation across the NHS. The aim of this study was to evaluate local adherence to CEWS to identify potential obstacles to the consistent implementation of NEWS. Emergency Department (ED) and Acute Assessment Unit (AAU) notes were retrospectively reviewed for a convenience sample of 102 patients admitted to the AAU. Outcome measures were completeness of documentation of CEWS parameters, documentation and accuracy of aggregate CEWS scores. Aggregate NEWS scores were calculated from the documented observations and the calculated CEWS and NEWS scores were compared. Physiological observations were documented for all patients attending the ED and AAU. Heart rate, blood pressure, respiratory rate, oxygen saturation and conscious level were documented in over 95% of ED and AAU patients. Urine output was recorded for only 48% of ED and 69% of AAU patients. Aggregate CEWS scores were documented for 66% of ED and 84% of AAU patients. These were calculated accurately in 73% of ED and 79% of AAU patients. Calculation errors were eleven times more likely to result in under-scoring than over-scoring. NEWS scores were significantly higher than CEWS for the same observations and would have resulted in a 71% increase in patients requiring escalation of care in the ED and a 116% increase in AAU. Concerns highlighted with CEWS were the incomplete and inaccurate recording of aggregate scores, with underscoring resulting in the potential failure to recognise deteriorating patients. It is anticipated that NEWS will be accompanied by standardised documentation and training across the NHS which will support more complete and accurate recording of physiological data. Furthermore, NEWS appears from this study to be more sensitive than CEWS, thereby minimising the chance of missed deterioration.


The Y99C mutation in guanylyl cyclase-activating protein 1 increases intracellular Ca2+ and causes photoreceptor degeneration in transgenic mice.
Guanylyl cyclase-activating proteins (GCAPs) are Ca2+-binding proteins that activate guanylyl cyclase when free Ca2+ concentrations in retinal rods and cones fall after illumination and inhibit the cyclase when free Ca2+ reaches its resting level in the dark. Several forms of retinal dystrophy are caused by mutations in GUCA1A, the gene coding for GCAP1. To investigate the cellular mechanisms affected by the diseased state, we created transgenic mice that express GCAP1 with a Tyr99Cys substitution (Y99C GCAP1) found in human patients with a late-onset retinal dystrophy (Payne et al., 1998). Y99C GCAP1 shifted the Ca2+ sensitivity of the guanylyl cyclase in photoreceptors, keeping it partially active at 250 nM free Ca2+, the normal resting Ca2+ concentration in darkness. The enhanced activity of the cyclase in the dark increased cyclic nucleotide-gated channel activity and elevated the rod outer segment Ca2+ concentration in darkness, measured by using fluo-5F and laser spot microscopy. In different lines of transgenic mice the magnitude of this effect rose with the Y99C GCAP1 expression. Surprisingly, there was little change in the rod photoresponse, indicating that dynamic Ca2+-dependent regulation of cGMP synthesis was preserved. However, the photoreceptors in these mice degenerated, and the rate of the cell loss increased with the level of the transgene expression, unlike in transgenic mice that overexpressed normal GCAP1. These results provide the first direct evidence that a mutation linked to congenital blindness increases Ca2+ in the outer segment, which may trigger the apoptotic process.


Cytoplasmic Localization of WT1 and Decrease of miRNA-16-1 in Nephrotic Syndrome.
Nephrotic syndrome (NS) is a glomerular disease that is defined by the leakage of protein into the urine and is associated with hypoalbuminemia, hyperlipidemia, and edema. Steroid-resistant NS (SRNS) patients do not respond to treatment with corticosteroids and show decreased Wilms tumor 1 (WT1) expression in podocytes. Downregulation of WT1 has been shown to be affected by certain microRNAs (miRNAs). Twenty-one patients with idiopathic NS (68.75% were SSNS and 31.25% SRNS) and 10 healthy controls were enrolled in the study. Podocyte number and WT1 location were determined by immunofluorescence, and the serum levels of miR-15a, miR-16-1, and miR-193a were quantified by RT-qPCR. Low expression and delocalization of WT1 protein from the nucleus to the cytoplasm were found in kidney biopsies of patients with SRNS and both nuclear and cytoplasmic localization were found in steroid-sensitive NS (SSNS) patients. In sera from NS patients, low expression levels of miR-15a and miR-16-1 were found compared with healthy controls, but only the miR-16-1 expression levels showed statistically significant decrease (p = 0.019). The miR-193a expression levels only slightly increased in NS patients. We concluded that low expression and delocalization from the WT1 protein in NS patients contribute to loss of podocytes while modulation from WT1 protein is not associated with the miRNAs analyzed in sera from the patients.


Pharmacogenomics in admixed populations.
Personalized drug therapy proffered by pharmacogenomics must be based on the recognition of inherent genetic individuality, rather than relying on inter-ethnic differences in the frequency of polymorphisms that affect the pharmacokinetics and targets of drugs. This is particularly significant in admixed populations, in which the substructure created by inter-ethnic crosses further increases the fluidity of racial and/or ethnic labels. Inter-ethnic admixture is either common or increasing quickly in many, if not most, populations, and so extrapolation on a global scale of pharmacogenomic data from well-defined ethnic groups is plagued with uncertainty. To impact positively on global health, pharmacogenomics must broaden its scope of investigation with respect to both target and population diversity, and avoid the risk of contributing to the creation of a genomics divide between regions and nations. In this review, I examine the challenges and advantages of studying pharmacogenomics in admixed populations, drawing examples mainly from the trihybrid populations of the Americas.


CRF-CRF1 system activation mediates withdrawal-induced increases in nicotine self-administration in nicotine-dependent rats.
Nicotine, the main psychoactive ingredient of tobacco, induces negative emotional symptoms during abstinence that contribute to a profound craving for nicotine. However, the neurobiological mechanisms underlying how nicotine produces dependence remains poorly understood. We demonstrate one mechanism for both the anxiety-like symptoms of withdrawal and excessive nicotine intake observed after abstinence, through recruitment of the extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system and activation of CRF(1) receptors. Overactivation of the CRF-CRF(1) system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction.


Effect of concanavalin A on 5'-nucleotidase activity of rabbit blood platelets.
Ecto-5'-nucleotidase (ecto-5'-NU) of platelets was enhanced by concanavalin A (Con A). This effect of Con A was antagonized by alpha-methyl-D-mannose, a specific antagonist of Con A binding to glycoprotein. Coformycin, an adenosine deaminase inhibitor, did not change the effect of Con A on the ecto-5'-NU. Uptake of adenosine by platelets was not affected by Con A. It was suggested that the ecto-5'-NU of platelet might be a direct and primary site of action of Con A.


Using positron emission tomography and florbetapir F18 to image cortical amyloid in patients with mild cognitive impairment or dementia due to Alzheimer disease.
To characterize quantitative florbetapir F 18 (hereafter referred to as simply florbetapir) positron emission tomographic (PET) measurements of fibrillar β-amyloid (Aβ) burden in a large clinical cohort of participants with probable Alzheimer disease (AD) or mild cognitive impairment (MCI) and older healthy controls (OHCs). Cerebral-to-whole-cerebellar florbetapir standard uptake value ratios (SUVRs) were computed. Mean cortical SUVRs were compared. A threshold of SUVRs greater than or equal to 1.17 was used to reflect pathological levels of amyloid associated with AD based on separate antemortem PET and postmortem neuropathology data from 19 end-of-life patients. Similarly, a threshold of SUVRs greater than 1.08 was used to signify the presence of any identifiable Aβ because this was the upper limit from a separate set of 46 individuals 18 to 40 years of age who did not carry apolipoprotein E (APOE) ε4. Multiple research imaging centers. A total of 68 participants with probable AD, 60 participants with MCI, and 82 OHCs who were 55 years of age or older. Main Outcome Measure Florbetapir-PET activity. All of the participants (ie, those with probable AD or MCI and those who were OHCs) differed significantly in mean (SD) cortical florbetapir SUVRs (1.39 [0.24], 1.17 [0.27], and 1.05 [0.16], respectively; P < 1.0 × 10⁻⁷), in percentage meeting levels of amyloid associated with AD by SUVR criteria (80.9%, 40.0%, and 20.7%, respectively; P < 1.0 × 10⁻⁷), and in percentage meeting SUVR criteria for the presence of any identifiable Aβ (85.3%, 46.6%, and 28.1%, respectively; P < 1.0 × 10⁻⁷). Among OHCs, the percentage of florbetapir positivity increased linearly by age decile (P = .05). For the 54 OHCs with available APOE genotypes, APOE ε4 carriers had a higher mean (SD) cortical SUVR than did noncarriers (1.14 [0.2] vs 1.03 [0.16]; P = .048). The findings of our analysis confirm the ability of florbetapir-PET SUVRs to characterize amyloid levels in clinically probable AD, MCI, and OHC groups using continuous and binary measures of fibrillar Aβ burden. It introduces criteria to determine whether an image is associated with an intermediate-to-high likelihood of pathologic AD or with having any identifiable cortical amyloid level above that seen in low-risk young controls.