Age- and gender-related dispersion of brain networks across the lifespan.
The effects of age and gender on large-scale resting-state networks (RSNs) reflecting within- and between-network connectivity in the healthy brain remain unclear. This study investigated how age and gender influence the brain network roles and topological properties underlying the ageing process. Ten RSNs were constructed based on 998 participants from the REST-meta-MDD cohort. Multivariate linear regression analysis was used to examine the independent and interactive influences of age and gender on large-scale RSNs and their topological properties. A support vector regression model integrating whole-brain network features was used to predict brain age across the lifespan and cognitive decline in an Alzheimer's disease spectrum (ADS) sample. Differential effects of age and gender on brain network roles were demonstrated across the lifespan. Specifically, cingulo-opercular, auditory, and visual (VIS) networks showed more incohesive features reflected by decreased intra-network connectivity with ageing. Further, females displayed distinctive brain network trajectory patterns in middle-early age, showing enhanced network connectivity within the fronto-parietal network (FPN) and salience network (SAN) and weakened network connectivity between the FPN-somatomotor, FPN-VIS, and SAN-VIS networks. Age - but not gender - induced widespread decrease in topological properties of brain networks. Importantly, these differential network features predicted brain age and cognitive impairment in the ADS sample. By showing that age and gender exert specific dispersion of dynamic network roles and trajectories across the lifespan, this study has expanded our understanding of age- and gender-related brain changes with ageing. Moreover, the findings may be useful for detecting early-stage dementia.


Small molecule RL71 targets SERCA2 at a novel site in the treatment of human colorectal cancer.
While targeted agents are an important part of the treatment arsenal for colorectal cancer, there is still a lack of efficient small-molecule targeted agents based on the understanding of pathogenic molecular mechanisms. In this study, curcumin analog RL71 displayed potent cytotoxicity towards human colon cancer cells with an IC50 of 0.8 µM in SW480 cells and inhibited xenotransplanted tumor growth in a dose-dependent manner. Using affinity chromatography, we identified sarco/endoplasmic reticulum calcium-ATPase (SERCA) 2 as the binding target of RL71. Most notably, RL71 demonstrated special binding to SERCA2 at a novel site with the lowest estimated free energy -8.89 kcal mol(-1), and the SERCA2 residues critical for RL71 binding were identified. RL71 suppressed the Ca(2+)-ATPase activity of SERCA2 both in vitro and in vivo, accompanied by the induction of endoplasmic reticulum stress leading to apoptosis and G2/M cycle arrest in SW480 cells. In addition, RL71 showed synergistic cytotoxicity with the pan-SERCA inhibitor thapsigargin. These results suggest that RL71 could be a selective small-molecule inhibitor of SERCA2, and that it may serve as a lead compound for the study of targeted colorectal cancer therapy.


Improvement of the image quality of T1-weighted anatomical brain scans.
T1-weighted anatomical brain scans are routinely used in neuroimaging studies, for example, as anatomical reference for functional data and in brain morphometry studies. Subject motion can degrade the quality of these images. An additional problem is the occurrence of signal dropouts in the case of long echo times and low receiver bandwidths. These problems are addressed in two different studies. In the first study, it is shown that the high scalp signal, which results from the low T1 value of fat, may cause a typical ringing artefact in the presence of head motion. This problem may be enhanced if phased array coils are used for signal reception due to their increased sensitivity in the peripheral head regions. It is shown that this artefact can be avoided by combining certain fat suppression techniques that reduce the scalp signal. In the second study, it is shown that signal dropout affects mainly the orbitofrontal cortex and the temporal lobes, and that a bandwidth of 100 Hz/pixel should be chosen for the investigation of these areas to avoid signal losses while maintaining an acceptable signal-to-noise ratio. Experimental results are based on the MDEFT sequence but can be applied to other T1-weighted sequences like FLASH and MP-RAGE. Furthermore, the presented methods for improving the image quality can be combined with other artefact reduction techniques.


Expanding the phenotype of COL4A1-related disorders-Four novel variants.
COL4A1 variant causes severe central nervous system (CNS) anomalies, including hydranencephaly. However, the pathogenic mechanism underlying the COL4A1 phenotype remains unclear. Here, we report de novo COL4A1 variants in four Japanese patients with typical or rare CNS involvement and exhibiting diverse phenotypes. We identified and enrolled four patients with white matter abnormalities and cerebral structural defects suggestive of cerebrovascular disease. Genetic analysis was performed using panel sequencing. All the patients were perinatally asymptomatic during the infantile period but exhibited developmental delay and growth retardation later. All the patients exhibited CNS symptoms, including psychomotor disability, spastic paralysis, and epilepsy. Brain magnetic resonance imaging revealed hydranencephaly (n = 1), ventriculomegaly (n = 4) associated with cerebral hemorrhage, and atretic encephalocele (n = 1). Three patients had developed congenital cataract, while two had hematuria. We identified two COL4A1 missense variants [exon32:c.2555G > A p.(Gly852Asp), exon40:c.3407G > A p.(Gly1136Asp)] and two in frame variants [exon32:c.2603_2609delinsATCCTGA p.(Ala868_Gly870delinsAspProGlu), exon36:c.3054delinsTGTAGAT p.(Leu1018delinsPheValAsp)]. The in frame variants were associated with severe CNS anomalies, hydranencephaly, and severe ventriculomegaly. Atretic encephalocele has never been reported in individuals with COL4A1 variants. Our findings suggest that COL4A1 variants cause variable CNS symptoms. Association between clinical phenotypes and each COL4A1 variant would clarify their underlying etiologies.


Replication of biosynthetic reactions enables efficient synthesis of A-factor, a γ-butyrolactone autoinducer from Streptomyces griseus.
We report a concise synthesis of A-factor, the prototypical γ-butyrolactone signalling compound of Streptomyces bacteria. In analogy to enzymatic reactions in A-factor biosynthesis, our synthesis features a tandem esterification-Knoevenagel condensation yielding a 2-acyl butenolide and a surprising, chemoselective conjugate reduction of this α,β-unsaturated carbonyl compound using sodium cyanoborohydride.


Characterization of the planarian surface electroencephalogram.
Despite large morphological differences between the nervous systems of lower animals and humans, striking functional similarities have been reported. However, little is known about how these functional similarities translate to cognitive similarities. As a first step towards studying the cognitive abilities of simple nervous systems, we here characterize the ongoing electrophysiological activity of the planarian Schmidtea mediterranea. One previous report using invasive microelectrodes describes that the ongoing neural activity is characterized by a 1/fx power spectrum with the exponent 'x' of the power spectrum close to 1. To extend these findings, we aimed to establish a recording protocol to measure ongoing neural activity safely and securely from alive and healthy planarians under different lighting conditions using non-invasive surface electrodes. As a replication and extension of the previous results, we show that the ongoing neural activity is characterized by a 1/fx power spectrum, that the exponent 'x' in living planarians is close to 1, and that changes in lighting induce changes in neural activity likely due to the planarian photophobia. We confirm the existence of continuous EEG activity in planarians and show that it is possible to noninvasively record this activity with surface wire electrodes. This opens up broad possibilities for continuous recordings across longer intervals, and repeated recordings from the same animals to study cognitive processes.


Burden of opioid toxicity death in the fentanyl-dominant era for people who experience incarceration in Ontario, Canada, 2015-2020: a whole population retrospective cohort study.
To describe mortality due to opioid toxicity among people who experienced incarceration in Ontario between 2015 and 2020, during the fentanyl-dominant era. In this retrospective cohort study, we linked Ontario coronial data on opioid toxicity deaths between 2015 and 2020 with correctional data for adults incarcerated in Ontario provincial correctional facilities. Ontario, Canada. Whole population data. The primary outcome was opioid toxicity death and the exposure was any incarceration in a provincial correctional facility between 2015 and 2020. We calculated crude death rates and age-standardised mortality ratios (SMR). Between 2015 and 2020, 8460 people died from opioid toxicity in Ontario. Of those, 2207 (26.1%) were exposed to incarceration during the study period. Among those exposed to incarceration during the study period (n=1 29 152), 1.7% died from opioid toxicity during this period. Crude opioid toxicity death rates per 10 000 persons years were 43.6 (95% CI=41.8 to 45.5) for those exposed to incarceration and 0.95 (95% CI=0.93 to 0.97) for those not exposed. Compared with those not exposed, the SMR for people exposed to incarceration was 31.2 (95% CI=29.8 to 32.6), and differed by sex, at 28.1 (95% CI=26.7 to 29.5) for males and 77.7 (95% CI=69.6 to 85.9) for females. For those exposed to incarceration who died from opioid toxicity, 10.6% died within 14 days of release and the risk was highest between days 4 and 7 postrelease, at 288.1 per 10 000 person years (95% CI=227.8 to 348.1). The risk of opioid toxicity death is many times higher for people who experience incarceration compared with others in Ontario. Risk is markedly elevated in the week after release, and women who experience incarceration have a substantially higher SMR than men who experience incarceration. Initiatives to prevent deaths should consider programmes and policies in correctional facilities to address high risk on release.


Effect of photoperiod manipulation on the daily rhythms of melatonin and reproductive hormones in caged European sea bass (Dicentrarchus labrax).
Reproduction in fish is cyclical and timed to guarantee the survival of the offspring. Seasonal variations in reproductive hormones of fish have been deeply investigated in fish over the last years. However, there are few studies regarding the daily changes in reproductive hormone profiles in teleosts. The aim of the present research was to investigate the effects of photoperiod manipulation on melatonin and reproductive hormones (pituitary sbGnRH, pituitary LH and plasma LH, testosterone [T], and 11-ketotestosterone [11KT]) daily rhythms in male sea bass, kept in net cages under farming conditions in winter (9L:15D). Fish were distributed in two groups, one under constant long photoperiod (18L:6D) and the other under natural photoperiod. The photoperiod strongly influenced the daily melatonin profile, so that the duration of the nocturnal melatonin rise was longer in the control group than in the group exposed to the artificial photoperiod (18L:6D). A daily rhythm was observed in the pituitary sbGnRH profile in both groups, showing the lowest levels during the dark period. A daily rhythm of pituitary LH was detected in the control group, which was suppressed in the group under long photoperiod. Daily variations in plasma LH were observed, the highest levels being found in the dark phase in both groups, although this profile was significantly altered by artificial light, maintaining a fixed relationship between the first nocturnal rise of melatonin and the nocturnal peaks of plasma LH in both groups. Plasma T levels showed significant fluctuations in their daily cycle following a sinusoidal pattern with an acrophase around sunrise in both groups, without any influence of light regime. No significant daily variations in plasma levels of 11-KT were observed in none of the groups. Our results provide the first evidence of the presence of daily variations in pituitary sbGnRH content, pituitary and plasma LH, and plasma T in sea bass. Artificial lights suppressed the circulating melatonin and significantly affected the daily rhythm of LH storage and release.


Relationship of cerebral intraventricular hemorrhage and early childhood neurologic handicaps.
The outcome in 198 surviving very-low-birth-weight (less than 1501 gm) infants with and without cerebral intraventricular hemorrhage was compared to determine whether CVH is associated with early childhood developmental or neuromotor handicaps. Major handicaps were noted in 10% of the infants without and 28% of the infants with CVH. Among the infants with CVH, a major handicap was present in 9% with grade 1, 11% with grade 2, 36% with grade 3, and 76% with grade 4 CVH. Infants with posthemorrhagic hydrocephalus had the same incidence of major handicaps (59%) as did comparable infants with no hydrocephalus (57%). Our data indicate that grades 1 and 2 CVH do not increase an infant's risk for major handicaps, and there is a direct relationship of grades 3 and 4 CVH and major handicaps.


Animal movements occurring during COVID-19 lockdown were predicted by connectivity models.
Recent events related to the measures taken to control the spread of the Coronavirus (SARS-CoV-2) reduced human mobility (i.e. anthropause), potentially opening connectivity opportunities for wildlife populations. In the Italian Alps, brown bears have recovered after reintroduction within a complex anthropogenic matrix, but failed to establish a metapopulation due to reduced connectivity and human disturbance (i.e. infrastructure, land use, and human mobility). Previous work from Peters et al. (2015, Biol. Cons. 186, 123-133) predicted the main corridors and suitable hot spots for road network crossing for this population across all major roads and settlement zones, to link most suitable habitats. Bears used the identified hot spots for road network crossing over the years, but major barriers such as main motor roads were not overcome, possibly due to functional anthropogenic disturbance, specifically human mobility. By analyzing 404 bear occurrences reported to local authorities (as bear-related complaints) collected between 2016 and 2020 (March 9th - May 18th), hence including the COVID-19 related lockdown, we tested the effect of human presence on brown bears' use of space and hot spots for road network crossing. Animals occupied human-dominated spaces and approached hot spots for crossing at a higher rate during the lockdown than in previous years, suggesting that connectivity temporarily increased with reduced human mobility for this population. As a result of their increased use of hot spots, bears expanded their use of suitable areas beyond the population core area. Movement of animals across structural barriers such as roads and human settlements may therefore occur in absence of active disturbance. We also showed the value of predictive models to identify hot spots for animal barrier crossing, the knowledge of which is critical when implementing management solutions to enhance connectivity. Understanding the factors that influence immigration and emigration across metapopulations of large mammals, particularly carnivores that may compete indirectly with humans for space or directly as super-predators, is critical to ensure the long-term viability of conservation efforts for their persistence. We argue that dynamic factors such as human mobility may play a larger role than previously recognized.


Infliximab for psoriasis.
This review summarizes the use of inflximab in psoriasis and other immune-mediated inflammatory disorders (IMIDs). The magnitude and speed of the response to infliximab monotherapy of moderate to severe psoriasis vulgaris is substantial, being similar to those achieved with cyclosporin. In contrast with cyclosporin, clinical improvement after the initial 3 intravenous influsions of infliximab is maintained for as long as 6 months in approximately half the patients with the absence of any additional treatment. Additionally, infliximab monotherapy normalizes keratinocyte proliferation and differentiation and markedly decreases epidermal inflammation. These results provide a convincing argument for the role of TNF-alpha in the pathogenesis of psoriasis and for the clinical development of infliximab for the treatment of psoriasis.


Mechanics of rat myocardium revisited: investigations of ultra-thin cardiac muscles under high energy demand.
Disregarding the influence of thickness on elevated strength of isolated preparations inevitably leads to erroneous tension-frequency relations, especially in the range of high frequencies. Thus, much of the confusion in interpreting the atypical negative staircase phenomenon of the rat heart is due to this. In view of the fact that the rat has become the preferred laboratory animal in cardiological research, it was imperative to reinvestigate force-frequency relations using ultra-thin preparations of the rat right ventricle (d less than 0.1 mm). Contrary to popular opinion, it could be demonstrated that the rat myocardium shows a positive staircase in the range of physiological heart rates. An increase in tension is still attainable even at frequencies up to 600 min-1. The interval-strength relations exhibit a minimum at frequencies of 60-120 min-1, being shifted to higher frequencies with increasing diameter, vanishing completely for thick preparations (d greater than 1.0 mm). At high extracellular Ca++ concentration the positive staircase even of ultra-thin muscles is flattened. However, it can be reinforced when the strength, and thus the energy expenditure, is reduced by lowering the extension. The same is true for contractions under hypoxia. From these findings it seems probable that many investigations on isolated heart muscles of the rat, as well as other species, are objectionable when done under high energy demand, as diffusion problems will certainly limit any rise in contractility.


Characterization of Solid Dispersion of Itraconazole Prepared by Solubilization in Concentrated Aqueous Solutions of Weak Organic Acids and Drying.
The purpose of this study was to develop an amorphous solid dispersion (SD) of an extremely water-insoluble and very weakly basic drug, itraconazole (ITZ), by interaction with weak organic acids and then drying that would enhance dissolution rate of drug and physical stability of formulation. Aqueous solubility of ITZ in concentrated solutions of weak organic acids, such as glutaric, tartaric, malic and citric acid, was determined. Solutions with high drug solubility were dried using vacuum oven and the resulting SDs having 2 to 20% drug load were characterized by differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD) and attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy. The dissolution of SDs was initially studied in 250 mL of 0.1 N HCl (pH 1.1), and any undissolved solids were collected and analyzed by PXRD. The pH of the dissolution medium was then changed from 1.1 to 5.5, particle size of precipitates were measured, and drug concentrations in solution were determined by filtration through membrane filters of varying pore sizes. The aqueous solubility of ITZ was greatly enhanced in presence of weak acids. While the solubility of ITZ in water was ~4 ng/ mL, it increased to 25-40 mg per g of solution at 25°C and 200 mg per g of solution at 65°C at a high acid concentration leading to extremely high solubilization. PXRD of SDs indicated that ITZ was present in the amorphous form, wherein the acid formed a partially crystalline matrix. ATR-FTIR results showed possible weak interactions, such as hydrogen bonding, between drug and acid but there was no salt formation. SDs formed highly supersaturated solutions at pH 1.1 and had superior dissolution rate as compared to amorphous drug and physical mixtures of drug and acids. Following the change in pH from 1.1 to 5.5, ITZ precipitated as mostly nanoparticles, providing high surface area for relatively rapid redissolution. A method of highly solubilizing an extremely water-insoluble drug, ITZ, in aqueous media and converting it into an amorphous form in a physically stable SD was successfully investigated. The dissolution rate and the extent of supersaturation of the drug in dissolution media improved greatly, and any precipitate formed at high pH had very small particle size.


Systemic treatment in patients with Child-Pugh B liver dysfunction and advanced hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) is a major cause of death among patients with liver cirrhosis. The rise of immuno-oncology has revolutionized treatment for advanced HCC. However, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child-Pugh-Turcotte B), despite the high incidence of liver disease in patients with HCC at the time of diagnosis. Overall survival in patients with HCC and moderate liver dysfunction treated with sorafenib has been found to be only approximately 3-5 months, underlining the need for improved treatment algorithms for this increasingly important subgroup of patients. In this review, we summarize available data on the treatment of patients with HCC and moderate liver dysfunction. Opportunities, as well as clinical challenges, are discussed in detail, highlighting potential changes to the therapeutic landscape.


[Influence of frequent instillations of anti-infective solutions on eye tissues (an experimental study)].
To investigate the toxic effects of frequent instillations of anti-infective solutions (antibiotic eye drops - 0.3 and 1.4% tobramycin, 0.5% levofloxacin and 0.5% moxifloxacin; antiseptic eye drops - 0.05% pyloxidine and 0.025% chlorhexidine; antifungal drug - 2 mg/ml fluconazole solution) on ocular tissues. The study was conducted on 21 Wistar rats (42 eyes) using method of semi-fine sections. The majority of antibiotics and antifungal agents do not cause toxic reactions in rats` eyes when instilled with frequent regimen with the exception of 'fortified' 1.4% tobramycin and pyloxidine solutions, which caused a decrease in corneal endothelial cells density and formation of fibrovascular tissue in the anterior chamber. Frequent instillations of antimicrobial drug solutions is a safe method for the treatment of purulent corneal ulcers and purulent keratitis. The exceptions were solutions of 'fortified' 1.4% tobramycin and piloxidine (vitabact).


Estimation of start and stop numbers for cluster resolution feature selection algorithm: an empirical approach using null distribution analysis of Fisher ratios.
Cluster resolution feature selection (CR-FS) is a hybrid feature selection algorithm which involves the evaluation of ranked variables via sequential backward elimination (SBE) and sequential forward selection (SFS). The implementation of CR-FS requires two main inputs, namely, start and stop number. The start number is the number of the highly ranked variables for the SBE while the stop number is the point at which the search for additional features during the SFS stage is halted. The setting of these critical parameters has always relied on trial and error which introduced subjectivity in the results obtained. The start and stop numbers are known to vary with each dataset. Drawing inspiration from overlapping coefficients, a method for comparing two probability density functions, empirical equations toward the estimation of start and stop number for a dataset were developed. All of the parameters in the empirical equations are obtained from the comparisons of the two probability density functions except the constant termed d. The equations were optimized using three real-world datasets. The optimum range of d was determined to be 0.48 to 0.57. An implementation of CR-FS using two new datasets demonstrated the validity of this approach. Partial least squares discriminant analysis (PLS-DA) model prediction accuracies increased from 90 and 96 to 100% for both datasets using start and stop numbers calculated with this approach. Additionally, there was a twofold increase in the explained variance captured in the first two principal components. Graphical abstract Here, we describe how to determine the start and stop numbers for an automated feature selection routine, ensuring that you get the best model you can for your data with minimal effort.


Homoiterons and expansion in ribosomal RNAs.
Ribosomal RNAs in both prokaryotes and eukaryotes feature numerous repeats of three or more nucleotides with the same nucleobase (homoiterons). In prokaryotes these repeats are much more frequent in thermophile compared to mesophile or psychrophile species, and have similar frequency in both large RNAs. These features point to use of prokaryotic homoiterons in stabilization of both ribosomal subunits. The two large RNAs of eukaryotic cytoplasmic ribosomes have expanded to a different degree across the evolutionary ladder. The big RNA of the larger subunit (60S LSU) evolved expansion segments of up to 2400 nucleotides, and the smaller subunit (40S SSU) RNA acquired expansion segments of not more than 700 nucleotides. In the examined eukaryotes abundance of rRNA homoiterons generally follows size and nucleotide bias of the expansion segments, and increases with GC content and especially with phylogenetic rank. Both the nucleotide bias and frequency of homoiterons are much larger in metazoan and angiosperm LSU compared to the respective SSU RNAs. This is especially pronounced in the tetrapod vertebrates and seems to culminate in the hominid mammals. The stability of secondary structure in polyribonucleotides would significantly connect to GC content, and should also relate to G and C homoiteron content. RNA modeling points to considerable presence of homoiteron-rich double-stranded segments especially in vertebrate LSU RNAs, and homoiterons with four or more nucleotides in the vertebrate and angiosperm LSU RNAs are largely confined to the expansion segments. These features could mainly relate to protein export function and attachment of LSU to endoplasmic reticulum and other subcellular networks.


Lack of rivaroxaban influence on a prothrombinase-based assay for the detection of activated C protein resistance: an Italian ex vivo and in vitro study in normal subjects and factor V Leiden carriers.
Activated protein C resistance (APCr) leads to hypercoagulability and is due, often but not exclusively, to Factor V Leiden (FVL). The aim of this study was to assess the ex vivo and in vitro interference of the direct factor Xa inhibitor rivaroxaban (RIV) on a prothrombinase-based assay for APCr detection. An ex vivo study was performed on fresh plasma samples obtained from 44 subjects with FV wild-type and seven with FVL heterozygous, all treated with RIV. An in vitro study was performed on 15 plasma samples (six from normal subjects, six from heterozygous, and three from homozygous FVL carriers, all frozen specimens) spiked with RIV. RIV concentration was evaluated using a chromogenic assay, and APCr was evaluated by a prothrombinase-based assay. No significant interference of RIV on APCr results obtained by a prothrombinase-based assay was observed for drug concentrations up to 400 ng/mL in FV wild-type and FVL carriers (homozygous and heterozygous). These results were confirmed both ex vivo and in vitro. RIV did not significantly interfere with the prothrombinase-based assay used for the assessment of APCr, and this was observed to occur independently of FV status. However, only concentrations up to 400 ng/mL were tested and, therefore, what occurs in the presence of higher doses remains to be investigated.


The Epidemiology of COVID-19 in Malaysia.
COVID-19 has rapidly spread across the globe. Critical to the control of COVID-19 is the characterisation of its epidemiology. Despite this, there has been a paucity of evidence from many parts of the world, including Malaysia. We aim to describe the epidemiology of COVID-19 in Malaysia to inform prevention and control policies better. Malaysian COVID-19 data was extracted from 16 March 2020 up to 31 May 2021. We estimated the following epidemiological indicators: 7-day incidence rates, 7-day mortality rates, case fatality rates, test positive ratios, testing rates and the time-varying reproduction number (Rt). Between 16 March 2020 and 31 May 2021, Malaysia has reported 571,901 cases and 2,796 deaths. Malaysia's average 7-day incidence rate was 26•6 reported infections per 100,000 population (95% CI: 17•8, 38•1). The average test positive ratio and testing rate were 4•3% (95% CI: 1•6, 10•2) and 0•8 tests per 1,000 population (95% CI: <0•1, 3•7), respectively. The case fatality rates (CFR) was 0•6% (95% CI: <0•1, 3•7). Among the 2,796 cases who died, 87•3% were ≥ 50 years. The public health response was successful in the suppression of COVID-19 transmission or the first half of 2020. However, a state election and outbreaks in institutionalised populations have been the catalyst for more significant community propagation. This rising community transmission has continued in 2021, leading to increased incidence and strained healthcare systems. Calibrating NPI based on epidemiological indicators remain critical for us to live with the virus. (243 words). This study is part of the COVID-19 Epidemiological Analysis and Strategies (CEASe) Project with funding from the Ministry of Science, Technology and Innovation (UM.0000245/HGA.GV).


The efficacy and safety of catheter balloon dilatation in the treatment of dysphagia after stroke: A protocol for systematic review and meta-analysis.
Dysphagia is a serious complication after stroke, which has a significant influence on the health as well as life quality of global people. Patients with dysphagia tend to be a higher risk rate of an aspiration than general person. Catheter balloon dilatation is an additional therapy for treating dysphagia in recent years, which can improve the symptom of achalasia of cricopharyngeal muscle. This research will be used for confirming the efficacy and safety of the catheter balloon dilatation for resolving dysphagia. We intend to search literature related to the research in different databases, for instance, China National Knowledge Infrastructure, Wanfang Data, PubMed, Cochrane Library, and Embase up to January 2022. Literature selection, data collection, as well as assessment of bias risk, will be carried out by 2 independent researchers. Data analysis will be conducted by using Stata and review manager 5.4. The results will be submitted to a peer-reviewed journal. The research will verify whether or not catheter balloon dilatation can improve dysphagia by submitting high-quality data syntheses. CRD42022358433.


Cardiometabolic diseases, polygenic risk score, APOE genotype, and risk of incident dementia: A population-based prospective cohort study.
Objective We aimed to prospective investigate the association between cardiometabolic diseases (CMDs) with dementia, and to examine whether genetic factors and CMDs jointly contribute to the incidence of dementia. Methods We used data from the UK biobank of 204,646 adults aged 37-73 free of dementia at baseline. Genetic risk for dementia including APOE ε4 status and polygenic risk score (PRS) categorized as low, intermediate, and high. CMDs including ischemic heart disease (IHD), stroke, and type 2 diabetes (T2D) were confirmed by touchscreen questionnaires, medical examinations, and hospital inpatient records. Results Over the follow-up (median: 12.5 years), 5,750 participants developed dementia. The HRs (95% CI) of those with APOE ε4 carriers and high PRS were 3.16 (3.00-3.33) and 1.50 (1.41-1.60), respectively. The risk of dementia was 70% higher among those with CMDs (HR: 1.70; 95% CI: 1.60-1.82). In joint effect analyses, compared to no CMDs and APOE ε4 non-carriers, the HRs (95% CIs) of dementia were 3.53 (3.31-3.76)/2.06 (1.89-2.23) in participants with only APOE ε4 carriers and CMDs, and 5.06 (4.64-5.53) for those with APOE ε4 carriers plus CMDs. Compared to no CMDs and low PRS, the HRs (95% CIs) of dementia were 1.29 (1.19-1.40)/1.60 (1.48-1.73) in participants with only intermediate and high PRS, and 2.00 (1.79-2.23)/2.63 (2.38-2.92) for those with intermediate, and high PRS plus CMDs. Moreover, there were significant additive and multiplication interactions between CMDs and APOE ε4 carriers of dementia, but only multiplication interaction was observed for PRS. Conclusions CMDs were associated with higher risk of dementia regardless of genetic risk for dementia.


Quality of life after Girdlestone resection arthroplasty.
To know the result of the Girdlestone resection arthroplasty in the treatment of the infected hip arthroplasty. To analyze the effectiveness in the control of pain and infection, the functional outcome and to contrast factors correlated with the final result. Case series with a total of 17 patients. The control of the infection was assessed according to the presence or absence of sinus, and the clinical status using EuroQol 5D scale, residual pain and limb length discrepancy. The most common infecting germ at the time of removal of the arthroplasty was Staphylococcus CN and one patient presented infection by Candida albicans. In 2 patients the draining sinus persisted. The residual dysmetria was 5.24cm. In the EQ-5D scale, the most affected dimensions were mobility, need for help for self-care and ability to carry out activities of daily life. 8 patients maintained, pain levels worse than 4 in the VAS. The variables of dysmetria were correlated inversely with health index (-0,54) and self-perceived general health status (-0,45). The Girdlestone resection arthroplasty is an alternative in the treatment of the infected hip arthroplasty. Patient perception is inversely corelated to residual dysmetria. The dysmetria is greater in women and in ages over 65 years.


Infective endocarditis resulting from CardioSEAL closure of a patent foramen ovale.
Patent foramen ovale and atrial septal aneurysm are associated with an increased risk of cryptogenic stroke and recurrent thromboembolic events. Percutaneous closure is a therapeutic option to medical therapy and surgical closure. We present the first case of endocarditis associated with a CardioSEAL device closing a patent foramen ovale.


Dietary Lipids Modulate Notch Signaling and Influence Adult Intestinal Development and Metabolism in Drosophila.
Tissue homeostasis involves a complex balance of developmental signals and environmental cues that dictate stem cell function. We found that dietary lipids control enteroendocrine cell production from Drosophila posterior midgut stem cells. Dietary cholesterol influences new intestinal cell differentiation in an Hr96-dependent manner by altering the level and duration of Notch signaling. Exogenous lipids modulate Delta ligand and Notch extracellular domain stability and alter their trafficking in endosomal vesicles. Lipid-modulated Notch signaling occurs in other nutrient-dependent tissues, suggesting that Delta trafficking in many cells is sensitive to cellular sterol levels. These diet-mediated alterations in young animals contribute to a metabolic program that persists after the diet changes. A low-sterol diet also slows the proliferation of enteroendocrine tumors initiated by Notch pathway disruption. Thus, a specific dietary nutrient can modify a key intercellular signaling pathway to shift stem cell differentiation and cause lasting changes in tissue structure and physiology.


Rice noodle quality is structurally driven by the synergistic effect between amylose chain length and amylopectin unit-chain ratio.
Chewiness, slipperiness, and rapid rehydration are satisfactory qualities for rice noodles. These qualities are dependent on rice starch structure. However, the synergistic effect of fine structure of amylose (AM) and amylopectin (AP) on rice noodle quality remains unclear. In this work, six rice varieties, three from early indica and three from late indica, with similar amylose content for each pair were analyzed to assess the synergistic effects between AM and AP fine structures. The results showed that the combination of amylose long-chains and a low amylopectin unit-chain (APC) ratio favored the maintenance of relatively intact starch granules, resulting in a higher die expansion ratio and improvement of the mechanical properties of rice noodles (Hardness varied from 403 g to 1627 g). Meanwhile, higher die expansion was associated with a larger rehydration ratio. These results suggest that the synergistic effect between AM and AP fine structures significantly affects rice noodles' quality.


Role of the endoscope in cochlear implantation: A systematic review.
To review the role of the endoscope in cochlear implantation (CI). MEDLINE, ScienceDirect, Google Scholar and the Cochrane Library databases, as well as other sources, were searched by two independent reviewers. Studies including patients undergoing either exclusively endoscopic or endoscopically assisted CI were eligible for inclusion. Endoscopic CI approaches and postoperative complications were the primary outcomes. Secondary endpoints included the degree of round window (RW) microscopic visualisation according to St Thomas' Hospital classification and type of cochleostomy for electrode insertion in the scala tympani (ST). Fourteen studies met the inclusion criteria comprising 191 endoscopic or endoscopically assisted CI cases. The endoscope was used for better visualisation of the RW across all included studies, facilitated the insertion of the electrode in the ST and spared a mastoidectomy in a number of cases. No facial nerve palsy was reported in any of the studies. The most common complication was external auditory canal/tympanic membrane tear followed by chorda tympani injury. The microscopic CI approach is still the gold standard. The endoscope facilitates the recognition of the RW area and leads to successful and safe implantation, particularly in difficult anatomical scenarios, ear malformations and advanced otosclerosis. Endoscopically assisted CI procedures offer the opportunity to avoid a posterior tympanotomy and reduce the risk of facial nerve injury. To date, the lack of long-term data does not permit the widespread adoption of completely endoscopic CI procedures without a mastoidectomy.


Effect of polyethyleneglycol (PEG) on spontaneous and polymyxin B-induced histamine release from rat peritoneal mast cells.
Mast cells were isolated from the peritoneal cavity of rat and purified by centrifugation in a gradient of Percoll. The spontaneous and polymyxin B-induced release of histamine was studied after preincubation of the cells with polyethyleneglycols (PEGs) of different molecular weight (200-20,000 dalton) and with fatty acid derivatives of PEG 6000. It was found that very low concentrations (less than 0.1%) of PEG 6000 reduced the spontaneous and polymyxin B-induced release of histamine to a greater extent than the same concentration of bovine serum albumin. The inhibition increased with the size of the PEGs, but was little affected by the presence of fatty acid ligand bound to PEG.


Effect of gonadal status on bone mineral density and radiological spinal deformities in adult patients with growth hormone deficiency.
Growth hormone deficiency (GHD) in adult patients is associated with marked decrease in bone turnover, low bone mass and high risk of clinical and subclinical fractures. We investigated whether the prevalence of spinal deformities in adults with GHD was related to the gonadal status of patients. A total of 89 adult hypopituitary patients with severe GHD were evaluated for bone mineral density (BMD) and vertebral deformities (quantitative morphometric analysis). At the study entry, 54 patients were eugonadic whereas 35 patients were hypogonadic without replacement treatment. Radiological spinal deformities were found in 55 patients (61.8%) with higher prevalence in untreated (56 cases) versus treated (33 cases) GHD patients. Eugonadic and hypogonadic patients showed no significant difference in spinal deformities although T-score was significantly lower in hypogonadic as compared with eugonadic patients. Gonadal function was not correlated with the occurrence of spinal deformities which was instead inversely correlated with rhGH treatment. In conclusion, gonadal status may influence BMD in adult patients with GHD without affecting the risk to develop vertebral deformities. Conversely, rhGH replacement treatment seems to be the only factor influencing the risk to develop vertebral deformities in adult GHD patients.


Surgical correction of descending thoracic aortic aneurysms under simple aortic cross-clamping.
Between June 1983 and December 1987, 52 patients underwent resection of a descending thoracic aortic aneurysm under simple aortic cross-clamping without the use of shunting or bypass techniques. The 30-day mortality rate was 11.5%; 4.8% for elective cases and 36.5% for patients operated on in emergency. Two patients (4%) had spinal cord injury. One patient had paraplegia, and the other had mild paraparesis but completely recovered. Both patients were operated on for ruptured aneurysms. Four patients (7.5%) had severe postoperative renal dysfunction that was strongly related to intraoperative hypotension. The cumulative proportional survival rate was 81% at 1 year and 66% at 2 years for the total group. 85% at 1 year and 72% at 2 years for the patients first seen with nonruptured aneurysms. Aneurysms of the descending thoracic aorta can be safely resected without the use of shunting or bypass techniques. Surgery definitely improves the outcome for these patients who have a poor prognosis if left untreated.


Surgical Outcomes of Biologic Fixation for Subtrochanteric Fracture Using Locking Compression Plates.
This study aimed to evaluate the surgical outcomes of biologic plating using locking compression plate-distal femur (LCP-DF) in patients with subtrochanteric fracture of the femur. Between January 2010 and December 2013, 28 consecutive patients with subtrochanteric fractures of the femur, treated with biologic fixation using LCP-DF, were enrolled. Preoperative values, including patient age, sex, body mass index, fracture type, type of lung injury, and surgical timing from injury to surgery, were retrospectively evaluated. Radiologic assessments included time to union, coronal alignment, rotational alignment, and complications such as implant breakage and screw breakage. Adverse events, including postoperative fat embolism and adult respiratory distress syndrome, infection during the follow-up period, and walking ability at the last follow-up visit, were assessed. Union was achieved in 27 patients (96.4%) after a mean duration of 5.4 months (range, 3-14 months). No patients developed fat embolism or adult respiratory distress syndrome during the hospitalization period of this study. Biologic fixation using locking compression plates may represent a safe surgical option which can be utilized in patients with subtrochanteric fracture regardless of injury severity, surgical timing, fracture type, and presence of lung injury.


The effects of adding group-based lifestyle counselling to individual counselling on changes in plasma glucose levels in a randomized controlled trial: the Inter99 study.
This study aimed to assess whether group-based lifestyle counselling offered to a high-risk population subgroup had any effect beyond individual multifactorial interventions on fasting plasma glucose (FPG) and 2-h plasma glucose (2hPG) changes. In a population-based study of 6784 participants, 4053 were determined to be at high risk based on a risk estimate of ischaemic heart disease or the presence of risk factors (smoking, hypertension, hypercholesterolaemia, obesity, impaired glucose tolerance). Of these subjects, 90% were randomized to high-intensity intervention (group A) and 10% to low-intensity intervention (group B). All participants went through health examinations, risk assessments and individual lifestyle counselling. Participants in group A were further offered group-based lifestyle counselling. The intervention was repeated after 1 and 3 years. A total of 2738 participants free of diabetes at baseline (1999-2001) and with at least one FPG and/or 2hPG measurement during 5 years of follow-up were included in the analyses. Differences in changes of plasma glucose between groups A and B were analyzed using multilevel linear regression. For FPG, crude 5-year changes were significantly different between the two groups (group A: -0.003 mmol/L vs group B: -0.079 mmol/L; P=0.0427). After adjusting for relevant confounders, no differences in FPG changes were observed (P=0.116). Also, no significant differences in the 5-year changes in 2hPG between the two groups were observed (group A: - 0.127 mmol/L vs group B: -0.201 mmol/L; P=0.546). Offering additional group-based intervention to a high-risk population subgroup had no clinical effects on changes in plasma glucose beyond those of individualized multifactorial interventions.


Influence of duodenal secretions and its components on release and activities of human brush-border enzymes.
The in vitro effects of human duodenal secretions and various combinations of its components on activity and release of enzymes from the human brush border were examined. Sucrase retained activity for 90 min in duodenal secretions, and maltase was almost as stable; lactase lost activity rapidly and alkaline phosphatase was of intermediate stability. Inactivation of lactase could only be partly (50%) attributed to luminal proteases, bile salts and phospholipids played no role. Rate of release of an enzyme from the brush border bore no relationship to its rate of inactivation. When individual proteases were studied, elastase was the most potent for releasing disaccharidases from the brush border; trypsin was ineffective alone but augmented the effect of elastase. Sucrase and maltase were activated by proteolytic release, but activation was abolished by simultaneous exposure of brush borders to bile salts. Lactase was released and rapidly inactivated by proteinases, while alkaline phosphatase appeared to be inactivated without significant release. These results show that there are significant interactions between luminal factors which have been inapparent when studying them in isolation. Loss of functionally useful enzyme does not follow release of sucrase or maltase from the brush border into the lumen but does follow release of lactase. Study of the susceptibility of lactase to inactivation by luminal factors in the various forms of lactose intolerance is warranted.


Prognosis of the bradycardia pacemaker recipient assessed at first implantation: a nationwide cohort study.
Pacing technology and care have improved notably over the past decade, justifying an update on the long-term prognosis and pre-implantation determinants of prognosis of bradycardia pacemaker (PM) recipients. Prospective cohort study. 23 Dutch pacemaker centres Pre-implantation characteristics of 1517 patients receiving a first bradycardia PM between 2003-2007 were studied in relation to survival. None; patients were followed up during routine clinical practice. Cause and time to death. At the end of a mean follow-up of 5.8 (SD 1.1) years, 512 patients (33%) died, mostly of non-cardiac cause (67%). There were two PM related deaths. Survival rates were 93%, 81%, 69%, and 61% after 1, 3, 5 and 7 years, respectively. PM recipients without concomitant cardiovascular disease at implantation showed survival rates comparable to age and sex matched controls. Predictors at time of implantation associated with cardiac mortality were: age, coronary artery disease (CAD), diabetes, heart failure, valve disease, and the indication for PM implantation. Predictors for all cause mortality were: male gender, age, body mass index, CAD, cardiac surgery, diabetes, heart failure, and maintained atrioventricular synchrony. A pre-implantation history of heart failure, CAD, and diabetes are the most important predictors for worse prognosis in PM recipients. Without baseline heart disease, survival rates equal that of the general population, suggesting that the prognosis of contemporary PM recipients is mainly determined by comorbid diseases and a bradycardia pacing indication as such does not influence survival. ClinicalTrials.gov Identifier: NCT00135174.


Identification and classification of conopeptides using profile Hidden Markov Models.
Conopeptides are small toxins produced by predatory marine snails of the genus Conus. They are studied with increasing intensity due to their potential in neurosciences and pharmacology. The number of existing conopeptides is estimated to be 1 million, but only about 1000 have been described to date. Thanks to new high-throughput sequencing technologies the number of known conopeptides is likely to increase exponentially in the near future. There is therefore a need for a fast and accurate computational method for identification and classification of the novel conopeptides in large data sets. 62 profile Hidden Markov Models (pHMMs) were built for prediction and classification of all described conopeptide superfamilies and families, based on the different parts of the corresponding protein sequences. These models showed very high specificity in detection of new peptides. 56 out of 62 models do not give a single false positive in a test with the entire UniProtKB/Swiss-Prot protein sequence database. Our study demonstrates the usefulness of mature peptide models for automatic classification with accuracy of 96% for the mature peptide models and 100% for the pro- and signal peptide models. Our conopeptide profile HMMs can be used for finding and annotation of new conopeptides from large datasets generated by transcriptome or genome sequencing. To our knowledge this is the first time this kind of computational method has been applied to predict all known conopeptide superfamilies and some conopeptide families.


Mitochondrial Ca2+ Signaling Is an Electrometabolic Switch to Fuel Phagosome Killing.
Phagocytes reallocate metabolic resources to kill engulfed pathogens, but the intracellular signals that rapidly switch the immunometabolic program necessary to fuel microbial killing are not understood. We report that macrophages use a fast two-step Ca2+ relay to meet the bioenergetic demands of phagosomal killing. Upon detection of a fungal pathogen, macrophages rapidly elevate cytosolic Ca2+ (phase 1), and by concurrently activating the mitochondrial Ca2+ (mCa2+) uniporter (MCU), they trigger a rapid influx of Ca2+ into the mitochondria (phase 2). mCa2+ signaling reprograms mitochondrial metabolism, at least in part, through the activation of pyruvate dehydrogenase (PDH). Deprived of mCa2+ signaling, Mcu-/- macrophages are deficient in phagosomal reactive oxygen species (ROS) production and defective at killing fungi. Mice lacking MCU in their myeloid cells are highly susceptible to disseminated candidiasis. In essence, this study reveals an elegant design principle that MCU-dependent Ca2+ signaling is an electrometabolic switch to fuel phagosome killing.


Leukaemia arising in donor cells following allogeneic bone marrow transplantation for beta thalassaemia demonstrated by immunological, DNA and molecular cytogenetic analysis.
Combined DNA analysis, molecular cytogenetic and immunological techniques have been used to identify the donor origin of common acute lymphoblastic leukaemia (cALL) which arose in a male patient with beta thalassaemia major, 5 years after an allogeneic bone marrow transplant from his HLA-matched sister. The necessity of using multiple techniques in this and similar cases is emphasized and the possible mechanisms for the development of donor leukaemia and the leukaemic transformation of donor cells are discussed.


Seroepidemiology of Peste des Petits ruminants in sheep and goats in the selected district of Horu Guduru Zone, Western Ethiopia.
Peste des Petits Ruminants (PPR) is an acute, highly contagious, economically important transboundary viral disease of small ruminants. The objectives of this cross-sectional study were to estimate the seroprevalence and associated risk factors of PPR in small ruminants in selected districts of Horo Guduru Zone, Western Ethiopia. A total of 806 blood samples, corresponding to 124 flocks comprised of 387 sheep and 419 goats, were collected using multi-stage sampling. The sera were tested using competitive Enzyme-Linked Immunosorbent Assay (c-ELISA). A pre-tested questionnaire was used to collect data on potential risk factors for PPRV infection. Pearson's Chi-Square and logistic regression analyses were used to see the association of the seroprevalence with potential risk factors. The flock-level overall seroprevalence of PPR was 27.42% (95% confidence interval [CI]: 19.79-36.15%). An overall animal level seroprevalence of 5.71% (95% CI: 4.21-7.54%) was recorded with 6.98% (95% CI: 4.65-10.00%) seroprevalence in sheep and 4.53% (95% CI: 2.75-6.99%) in goats. There was a significant association between the seroprevalence and risk factors that were sharing common grazing land (P = 0.032), the introduction of newly purchased animals into the flock (P = 0.011), and uncontrolled animal movements in goats (P = 0.018). Sharing common grazing land with other flocks in goats (P = 0.026) and midland altitude in sheep (P = 0.029) were the other predictors of PPR. The seropositivity in unvaccinated small ruminants suggests the circulation of the virus. Therefore, awareness creation, vaccination, strengthening the disease surveillance system and large-scale epidemiological and molecular studies are suggested.


Dextramycine (the dextraisomer of chloramphenicol) as an inhibitor of the induction of lung adenomas in mice.
Dextramycine as well as leftrotating isomer (chloramphenicol--levomycetin) diminished the blastomogenic effect of urethane which is known to induce lung adenomas in mice.


Photochemical regeneration of flavoenzymes - An Old Yellow Enzyme case-study.
Direct, NAD(P)H-independent regeneration of Old Yellow Enzymes represents an interesting approach for simplified reaction schemes for the stereoselective reduction of conjugated C=C-double bonds. Simply by illuminating the reaction mixtures with blue light in the presence of sacrificial electron donors enables to circumvent the costly and unstable nicotinamide cofactors and a corresponding regeneration system. In the present study, we characterise the parameters determining the efficiency of this approach and outline the current limitations. Particularly, the photolability of the flavin photocatalyst and the (flavin-containing) biocatalyst represent the major limitation en route to preparative application.


Atrial fibrillation ablation.
Atrial fibrillation is the commonest cardiac arrhythmia, with significant morbidity related to symptoms, heart failure, and thromboembolism, which is associated with excess mortality. Over the past 10 years, many centers worldwide have reported high success rates and few complications after a single ablation procedure in patients with paroxysmal atrial fibrillation. Recent studies indicate a short-term and long-term superiority of catheter ablation as compared with conventional antiarrhythmic drug therapy in terms of arrhythmia recurrence, quality of life, and arrhythmia progression. As a result, catheter ablation is evolving to a front-line therapy in many patients with atrial fibrillation. However, in patients with persistent long-standing atrial fibrillation catheter ablation strategy is more complex and time-consuming, frequently requiring repeat procedures to achieve success rates as high as in paroxysmal atrial fibrillation. In the near future, however, with growing experience and evolving technology, catheter ablation of atrial fibrillation may be extended also to patients with long-standing atrial fibrillation.


Endoscopically assisted reconstruction of chronic Achilles tendon ruptures and re-ruptures using a semitendinosus autograft is a viable alternative to pre-existing techniques.
Achilles tendon ruptures are termed chronic after a delay in treatment for more than 4 weeks. The literature advocates surgical treatment with reconstruction to regain ankle push-off strength. The preferred technique is, however, still unknown and is often individualized. This study aims to present the technique and clinical outcome of an endoscopically assisted free semitendinosus reconstruction of chronic Achilles tendon rupture and Achilles tendon re-ruptures with delayed representation. It is hypothesized that the presented technique is a viable and safe alternative for distal Achilles tendon ruptures and ruptures with large tendon gaps. Twenty-two patients (13 males and 9 females) with a median (range) age of 64 (34-73) treated surgically with endoscopically assisted Achilles tendon reconstruction using a semitendinosus autograft were included. The patients were evaluated at 12 months post-operatively for Achilles tendon Total Rupture Score (ATRS), calf circumference, Achilles Tendon Resting Angle (ATRA), heel-rise height and repetitions together with tendon length determined by ultrasonography, concentric heel-rise power and heel-rise work. The patients reported a median (range) ATRS of 76 (45-99) out of 100. The median (range) ATRA on the injured side was 60° (49°-75°) compared with 49.5° (40-61°), p < 0.001, on the non-injured side. Eighteen out of 22 patients were able to perform a single-leg heel-rise on the non-injured side. Sixteen patients out of those 18 (89%) were also able to perform a single heel-rise on the injured side. They did, however, perform significantly lower number of repetitions compared with the non-injured side with a median (range) heel-rise repetitions of 11 (2-22) compared with 26 (2-27), (p < 0.001), and a median (range) heel-rise height of 5.5 cm (1.0-11.0 cm) compared with 9.0 cm (5.0-11.5 cm), (p < 0.001). The median calf circumference was 1.5 cm smaller on the injured side, 37.5 cm compared with 39 cm, when medians were compared. The median (range) tendon length of the injured side was 24.8 cm (20-28.2 cm) compared with 22 cm (18.4-24.2 cm), (p < 0.001), on the non-injured side. The study shows that endoscopically assisted reconstruction using a semitendinosus graft to treat chronic Achilles tendon ruptures and re-ruptures with delayed representation produces a satisfactory outcome. The technique can restore heel-rise height in patients with more distal ruptures or large tendon defects and is therefore a viable technique for Achilles tendon reconstruction. IV.


Inhibition of ornithine-decarboxylase produced by S(+) and R(-) ibuprofen in rats.
The differences between the S(+) and R(-) ibuprofen enantiomers in anti-inflammatory activity were assayed by measuring the release of 14CO2 in rats treated with labelled 14COOH-ornithine. Furthermore we investigated in vitro the inhibitory activity on ornithine-decarboxylase and the anti-inflammatory activity of R(-) and S(+) ibuprofen by using the carrageenin-induced paw oedema test in the rat.


Connections among symptoms of obsessive-compulsive disorder and posttraumatic stress disorder: a case series.
Theoretical, clinical, and empirical implications of the functional connections between symptoms of obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) are abundant. As such, four cases are presented here of men and women who met criteria for comorbid OCD and PTSD. All had been diagnosed with treatment-resistant OCD and were seeking treatment from an OCD specialty clinic or institute, all reported a history of traumatic experiences prior to the onset of OCD, and all appeared to demonstrate negative treatment outcomes. Upon examination, it appeared that symptoms of OCD and PTSD were connected such that decreases in OCD-specific symptoms related to increases in PTSD-specific symptoms, and increases in OCD-specific symptoms related to decreases in PTSD-specific symptoms. Speculations about the function of OCD symptoms in relation to post-traumatic psychopathology are put forth; and theoretical, research, and treatment implications are discussed.


Dynamic landslide susceptibility analysis that combines rainfall period, accumulated rainfall, and geospatial information.
Worldwide, catastrophic landslides are occurring as a result of abnormal climatic conditions. Since a landslide is caused by a combination of the triggers of rainfall and the vulnerability of spatial information, a study that can suggest a method to analyze the complex relationship between the two factors is required. In this study, the relationship between complex factors (rainfall period, accumulated rainfall, and spatial information characteristics) was designed as a system dynamics model as variables to check the possibility of occurrence of vulnerable areas according to the rainfall characteristics that change in real-time. In contrast to the current way of predicting the collapse time by analysing rainfall data, the developed model can set the precipitation period during rainfall. By setting the induced rainfall period, the researcher can then assess the susceptibility of the landslide-vulnerable area. Further, because the geospatial information features and rainfall data for the 672 h before the landslide's occurrence were combined, the results of the susceptibility analysis could be determined for each topographical characteristic according to the rainfall period and cumulative rainfall change. Third, by adjusting the General cumulative rainfall period (DG) and Inter-event time definition (IETD), the preceding rainfall period can be adjusted, and desired results can be obtained. An analysis method that can solve complex relationships can contribute to the prediction of landslide warning times and expected occurrence locations.


End-of-life Heart Failure Care in the United States.
Heart failure (HF) is increasingly common in the United States and is associated with a high degree of morbidity and mortality. As patients approach the end of life there is a significant increase in health care resource use. Patients with end-stage HF have a unique set of needs at the end of life, including symptoms such as dyspnea, uremia, and depression, as well as potentially deactivating implantable defibrillators and mechanical circulatory support devices. Improved palliative care services for patients with HF may improve quality of life and decrease health care resource use near the end of life.


Coupling of microplastic contamination in organisms and the environment: Evidence from the tidal flat ecosystem of Hangzhou Bay, China.
Microplastics are a new type of contaminant, widely defined as fragmented plastics with the longest dimension or diameter less than 5 mm, that are widely distributed, difficult to degrade, and easily adsorb other pollutants. Estuaries are key habitats where terrestrial microplastics flow in water runoff and import into the ocean. The ubiquitous use of plastics has resulted in a massive amount of plastic waste that is released and accumulated in bay ecosystems, posing serious ecological impacts. The study of microplastic contamination in Hangzhou Bay, the estuary of the Qiantang River, has important theoretical value in ecology and environmental science. Microplastic contamination in the tidal flats and organisms of Hangzhou Bay is serious and microplastic characteristics (type, size, and polymer type) in organisms were significantly correlated with those in the environmental media. Spatial autocorrelation was found in the abundance of microplastics in marine and tidal flat sediments of Hangzhou Bay, China, but no spatial autocorrelation was found in the sediment environment as a whole. The microplastic abundance in each organism in this study was not statistically correlated by weight or by individual count with its corresponding trophic level (P = 0.239 > 0.05; P = 0.492 > 0.05, respectively). Our study suggests a coupling relationship of microplastic contamination between organisms and the environment and can provide essential data and a scientific foundation for the study of microplastics pollution in Hangzhou Bay, as well as provide important evidence for the ecological and health risk assessment of microplastics.


Scanning electron microscopy reveals deleterious effects of Moringa oleifera seed exuded proteins on root-knot nematode Meloidogyne incognita eggs.
Plant seeds can exudate active molecules with inhibitory effects against several soil pathogens, including nematodes. This study aimed to characterize and evaluate the nematicidal properties against Meloidogyne incognita of exuded proteins from Moringa oleifera seeds. M. oleifera seeds were soaked in distilled water, and exudates were harvested and analyzed for the presence of defense proteins and anthelmintic activity. Enzymatic assays revealed the existence of PR-proteins such as β-1,3-glucanases (0.18 ± 0.003 nkatal mg-1 of protein), chitinases (0.22 ± 0.004 nkatal mg-1 of protein), proteases (261.30 ± 6.405 AU mg-1 of protein min-1), serine (190.30 ± 5.574 IA mg-1 of protein) and cysteine (231.70 ± 0.923 IA mg-1 of protein), protease inhibitors. The exuded proteins presented ovicidal activity and caused 100% mortality of second-stage juveniles (J2s). Scanning electron microscopy (SEM) revealed deleterious effects on M. incognita eggs, such as invaginations, cracks, scratched surface, and loss of internal content. These findings confirm the presence of anthelmintic proteins in M. oleifera seed exudate, possibly involved in plant defense during seed germination. Besides this, the exuded proteins exhibited strong biotechnological potential for use in the biocontrol of M. incognita infections, which are responsible for millions of dollars in staple crop losses every year.


The personality trait self-directedness predicts the amygdala's reaction to appetizing cues in fMRI.
Personality and neural response to food cues in various mesolimbic brain structures have been linked to eating disorders. We investigated the question of whether personality traits in healthy individuals correlate with the brain activation induced on confrontation with appetizing visual stimuli. Personality was assessed in 27 normal-weight participants (14 women, mean age=26.0, SD=3.3 years) with the Temperament and Character Inventory (TCI). After an overnight fast, participants viewed blocks of pictures, half containing appetizing food and the other half showing scrambled pictures as control. After each block, participants rated their appetite. Brain activation was measured using a 3T MR scanner. Food compared to control stimuli elicited a significantly higher appetite rating, as well as strong activation in the ventral and dorsal visual stream, the fusiform gyrus and consecutive limbic centres such as the parahippocampal gyrus, the amygdala, the thalamus, the insula, the ventral striatum and the orbitofrontal cortex. In a region-of-interest analysis, the TCI trait self-directedness was negatively correlated with mean blood oxygenation level dependent (BOLD) signal change in the right amygdala (r=-.43, p=.025). Ultimately, amygdala reactivity might provide a risk factor for the development of eating disorders.


Delayed presentation of haemorrhagic disease of the newborn.
Six infants with delayed presentation of haemorrhagic disease of the newborn are described. All were full-term infants who had no underlying disease, but did not receive prophylactic doses of vitamin K at birth and were breast-fed. Two infants have been left with permanent handicaps as a result of this uncommon, but preventable, disorder.


Ionic events during the volume response of human peripheral blood lymphocytes to hypotonic media. I. Distinctions between volume-activated Cl- and K+ conductance pathways.
Human peripheral blood lymphocytes (PBL), when placed into hypotonic media, first swell and then shrink back to their original volumes because of a rapid KCl leakage via volume-activated K+ and anion permeation pathways. By using gramicidin, a cation channel-forming ionophore, cation transport through the cell membrane can be shunted so that the salt fluxes and thus the volume changes are limited by the rate of the net anion movements. The "gramicidin method," supplemented with direct measurements of volume-induced ion fluxes, can be used to assess the effects of drugs and of various treatments on cation and anion permeabilities. It is demonstrated that quinine and cetiedil are much more effective blockers of volume-induced K+ transport than of Cl- transport, while dipyridamole, DIDS, and NIP-taurine inhibit only volume-induced Cl- movement. Oligomycins block both cation and anion transport pathways, oligomycin A being more effective in inhibiting K+ transport and oligomycin C preferentially blocking Cl- movement. Ca depletion of PBL abolishes volume-induced K+ transport but has no effect on Cl- transport. Repletion of cell calcium by ionophore A23187 immediately restores rapid K+ transport without significantly affecting volume-induced Cl- transport. These observations, taken together with other reported information, can be best explained by a model in which cell swelling activates independent Cl- and K+ conductance pathways, the latter being similar in properties to the Ca2+-activated K+ transport observed in various cell membranes.


The obstetrician-gynecologist's role in the practical management of polycystic ovary syndrome.
Women with polycystic ovary syndrome come to the gynecologist with a variety of symptoms, including menstrual irregularities, hirsutism, acne, weight gain, obesity, and infertility. An accurate diagnosis requires both confirmation of signs and symptoms of polycystic ovary syndrome and exclusion of other disorders. Once the diagnosis of polycystic ovary syndrome has been established, the presence of concomitant conditions, such as hypertension, dyslipidemia, and diabetes, must be assessed. Because the cause of polycystic ovary syndrome is not clear, treatment options have focused on symptom management. Such treatment options include oral contraceptives, gonadotropin-releasing hormone analogs with "add-back" hormone regimens, antiandrogens, ovulation-inducing agents, electrolysis, nutritional and weight loss counseling, exercise, laparoscopic ovarian drilling, and glucocorticoids. Pathogenic considerations, risk factor assessments, and treatment objectives combine to determine the choice of therapies. It is not clear whether insulin resistance is clinically important or causal in polycystic ovary syndrome symptom complex in all affected women. Polycystic ovary syndrome may be the final common expression of a variety of metabolic or neuroendocrine perturbations. If insulin resistance is a universal feature, it would make sense to treat with an insulin-sensitizing agent in the expectation that symptoms would resolve or improve. If insulin resistance is not the main etiologic factor, however, then insulin-sensitizing agents would be useful as adjunctive agents only for women with clinically important insulin resistance (eg, patients with polycystic ovary syndrome in whom insulin resistance causes hyperglycemia). In such cases an insulin-sensitizing agent could be instituted along with a program of weight loss and exercise.


The isolation of specific genes from the basidiomycete Schizophyllum commune.
We have developed a routine way to isolate genes directly from the basidiomycete fungus, Schizophyllum commune. Plasmid DNA from a genomic gene library was used to isolate five specific genes by complementation of Schizophyllum mutations via transformation. The mutant strains were deficient in the ability to synthesize either adenine (ade2 and ade5), uracil (ura1, encoding orotidine-5'-phosphate decarboxylase; OMPdecase), tryptophan (trp1, encoding indole-3-glycerol phosphate synthetase; IGPS) or para aminobenzoic acid (pab1). In each case, Southern analysis revealed that transformation to prototrophy was concomitant with the integration of vector sequence into the genome of the S. commune mutant. Total DNA from transformants was restricted, religated, and used to transform E. coli. Ampicillin resistant plasmids were recovered from E. coli and tested for their ability to transform the corresponding mutant of S. commune. Plasmids complementing the ade2, ade5, pab1, trp1, and ura1 mutations were recovered.


Iron ore identification method using reflectance spectrometer and a deep neural network framework.
In the first selection stage of iron ore, the ore classification accuracy plays a decisive role in subsequent work. Therefore, how to identify iron ore quickly and accurately is an important task. Traditional chemical, physical and manual identification methods have the disadvantages of high costs and high time consumption. This research proposes a new iron ore identification method, that combines deep learning with visible-infrared reflectance spectroscopy to establish an iron ore classification model. We collected iron ore samples from the Anshan iron ore area and measured the spectral data with a spectrometer. Then, a deep neural network framework is proposed based on the convolution neural network and the improved extreme learning machine algorithm, and an iron ore classification model is established based on the framework. The results show that the proposed model can effectively identify the types of iron ore, and the overall accuracy reaches 98.11%.


Treatment Outcomes of Nevirapine- Versus Efavirenz-Based Highly Active Antiretroviral Therapy Regimens Among Antiretroviral-Naive Adult Patients in Ethiopia: A Cohort Study.
Despite wide use of nevirapine- and efavirenz-based highly active antiretroviral therapy regimens in Ethiopia, their treatment outcome has not been well studied. The objective of this study was to compare treatment outcome of nevirapine- and efavirenz-based regimens. This retrospective cohort study was conducted on antiretroviral-naive adult patients with human immunodeficiency virus (HIV) who had started antiretroviral therapy. Study participants were excluded after treatment failure, regimen change, loss to follow-up, or transfer to other health facility. The outcomes of interest included immunologic recovery, immunologic failure, clinical failure, and treatment failure. There were 1064 HIV patients in the study; an equal proportion (1:1) from both efavirenz- and nevirapine-based regimens was included. Patients in both regimens had similar baseline CD4 cells count ( P = .876). In multivariate analysis, efavirenz-based regimens showed more likelihood of immunologic recovery, whether defined as a CD4 cell count of >200 cells/mm3 (hazard ratio [HR] = 1.31 [95% CI, 1.05-1.59]), >350 cells/mm3 (HR = 1.26 [95% CI, 1.08-1.47]), or >500 cells/mm3 (HR = 1.95 [95% CI, 1.57-2.41]). Moreover, efavirenz-based regimens showed a lower hazard of treatment failure (HR = 0.66 [95% CI, 0.49-0.88]). Although the finding of retrospective study should be interpreted with caution, efavirenz-based regimens were associated with superior treatment outcome.


High aldehyde dehydrogenase 1 activity is related to radiation resistance due to activation of AKT signaling after insulin stimulation in prostate cancer.
The association between type 2 diabetes mellitus and prostate cancer is still under investigation, and the relationship between hyperinsulinemia and prostate cancer stem-like cells (CSCs) is elusive. Here, we investigated the function of insulin/AKT signaling in prostate CSCs. We isolated prostate CSCs as aldehyde dehydrogenase 1-high (ALDH1high) cells from the human prostate cancer 22Rv1 cell line using an ALDEFLUOR assay and established several ALDH1high and ALDH1low clones. ALDH1high clones showed high ALDH1 expression which is a putative CSC marker; however, they showed heterogeneity regarding tumorigenicity and resistance to radiation and chemotherapy. Interestingly, all ALDH1high clones showed lower phosphorylated AKT (Ser473) (pAKT) levels than the ALDH1low clones. PI3K/AKT signaling is a key cell survival pathway and we analyzed radiation resistance under AKT signaling activation by insulin. Insulin increased pAKT levels in ALDH1high and ALDH1low cells; the fold increase rate of pAKT was higher in ALDH1high cells than in ALDH1low cells. Insulin induced resistance to radiation and chemotherapy in ALDH1high cells, and the increased levels of pAKT induced by insulin were significantly related to radiation resistance. These results suggest that ALDH1 suppresses baseline pAKT levels, but AKT can be activated by insulin, leading to treatment resistance.


Psychiatric disorders in child and adolescent offspring of patients with schizophrenia and bipolar disorder: A controlled study.
Early clinical manifestations predating schizophrenia (SZ) and bipolar disorder (BP) have not been fully characterized. Child offspring studies are a valuable opportunity to study the natural history of the illness from its earliest stages. However, there is limited evidence assessing young offspring of SZ and BP simultaneously. We set out to assess rates of psychiatric disorders in child and adolescent offspring of SZ and BP, relative to offspring of community controls, so as to characterize the early phenotype of the disorders comparatively. SZ and BP parents with offspring aged 7-17years were recruited through adult mental health services of two tertiary hospitals. Community control (CC) parents were recruited from the same geographical area. Ninety BP-offspring, 41 SZ-offspring and 107 CC-offspring were assessed using the K-SADS-PL by child psychiatrists blinded to parental status. Differences in prevalence of psychiatric disorders between groups were adjusted for confounders and for sibling correlation using generalised estimating equations. We found a gradient of clinical severity and social disadvantage between SZ, BP and CC-offspring. After adjusting for socio-demographic confounders, SZ and BP-offspring presented higher rates of attention deficit hyperactivity disorder (ADHD) than CC-offspring. ADHD was more prevalent in SZ-offspring than BP-offspring, and BP-offspring presented a higher prevalence of depression than CC-offspring. The higher rates of ADHD in SZ-offspring suggest that abnormal neurodevelopmental processes may exert a stronger influence in SZ than BP. Follow-up of these children will help elucidate the role of ADHD and depression phenotypes in predicting future transition to SZ or BP.


Impact of preoperative patient education on prevention of postoperative complications after major visceral surgery: study protocol for a randomized controlled trial (PEDUCAT trial).
In line with the growing number of surgical procedures being performed worldwide, postoperative complications are also increasing proportionately. Prevention of these postoperative complications is a high medical priority. Preoperative education of patients, including provision of preparatory information about the correct behavior after surgery, could improve the postoperative outcome, but the evidence for this is inconclusive. The aim of the PEDUCAT trial is to evaluate the feasibility and the impact of preoperative patient education on postoperative morbidity, mortality and quality of life in patients scheduled for elective major visceral surgery. PEDUCAT is designed as a cluster-randomized controlled pilot study. The experimental group will visit a standardized preoperative seminar to learn how best to behave after surgery in addition to being given a standard information brochure, whereas the control group will only receive the information brochure. Outcome measures such as postoperative morbidity, postoperative pain, postoperative anxiety and depression, patient satisfaction, quality of life, length of hospital stay and postoperative mortality will be evaluated. Statistical analysis will be based on the intention-to-treat population. Analysis of covariance will be applied for the intervention group comparison, adjusting for age, center and quality of life before surgery. This is a pilot study to show the feasibility of the concept. Nevertheless, the planned sample size of n = 204 is large enough to show an effect with power of 90% and a significance level of 5%. German Clinical Trial Register number: DRKS00004226.


Bone Sequestration as a Consequence of Esophageal Carcinoma Metastasis Detected by 18F-FDG PET/CT.
A bony sequestrum is a single piece of bone present in an area of osteolysis. It is separated from the surrounding bone and is primarily observed in patients with bone infection. We present our radiographic findings on F-FDG PET/CT in a case of esophageal squamous cell carcinoma with a sequestrum in the skull metastasis.


Humoral immune response of a pneumococcal conjugate vaccine: capsular polysaccharide serotype 14-Lysine modified PspA.
Polysaccharide-protein conjugates are so far the current antigens used for pneumococcal vaccines for children under 2 years of age. In this study, pneumococcal surface protein A (PspA) was used as a carrier protein for pneumococcal capsular polysaccharide serotype 14 as an alternative to broaden the vaccine coverage. PspA was modified by reductive amination with formaldehyde in order to improve the specificity of the reaction between protein and polysaccharide, inhibiting polymerization and the gel formation reaction. In the synthesis process, the currently used activator, 1-[3-(dimethylamine)propyl]-3-ethylcarbodiimide hydrochloride (EDAC) was substituted for 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM). BALB/c mice were immunized with either the PS14-mPspA conjugate or the co-administered components in a three dose regimen and sera from the immunized animals were assayed for immunity induced against both antigens: PS14 and mPspA. Modification of more than 70% of lysine residues from PspA (mPspA) did not interfere in the immune response as evaluated by the anti-PspA titer and C3 complement deposition assay. Sera of mice immunized with conjugated PS14-mPspA showed similar IgG titers, avidity and isotype profile as compared to controls immunized with PspA or mPspA alone. The complement deposition was higher in the sera of mice immunized with the conjugate vaccine and the opsonophagocytic activity was similar for both sera. Conjugation improved the immune response against PS14. The anti PS14 IgG titer was higher in sera of mice immunized with the conjugate than with co-administered antigens and presented an increased avidity index, induction of a predominant IgG1 isotype and increased complement deposition on a bacteria with a surface serotype 14. These results strongly support the use of PspA as carrier in a conjugate vaccine where both components act as antigens.


Declining trend of carbon in Finnish cropland soils in 1974-2009.
Soil organic matter not only affects soil properties and productivity but also has an essential role in global carbon (C) cycle. We studied changes in the topsoil C content of Finnish croplands using a dataset produced in nationwide soil monitoring. The monitoring network consisting of fields on both mineral and organic soils was established in 1974 and resampled in 1987, 1998, and 2009. Over the monitoring period from 1974 to 2009, cultivated soils showed a continuous decline in C concentration (g kg(-1) ). In organic soils, C concentration decreased at a mean rate of 0.2-0.3% yr(-1) relative to the existing C concentration. In mineral soils, the relative decrease was 0.4% yr(-1) corresponding to a C stock (kg m(-2) ) loss of 220 kg ha(-1) yr(-1) . The change in management practices in last decades toward increasing cultivation of annual crops has contributed to soil C losses noted in this study. The results, however, suggest that the C losses result partly from other processes affecting cultivated soils such as climatic change or the continuing long-term effect of forest clearance. We estimated that Finnish cropland soils store 161 Tg carbon nationwide in the topmost 15 cm of which 117 Tg is in mineral soils. C losses from mineral soils can therefore total up to 0.5 Tg yearly.


Quantitative comparison of rat hepatocyte functions in two improved culture systems with or without rat liver epithelial cell line.
We quantitatively evaluated two recently-developed novel techniques for hepatocyte cultivation in a dish level; that is, spheroid culture and membrane-supported collagen (CN) gel sandwich culture, in terms of cellular maintenance, albumin secretion and 7-ethoxycoumarin (7EC) metabolism to 7-hydroxycoumarin (7HC) as a marker for cytochrome P450 IA1 activity in the presence and absence of rat liver epithelial cell line (RLEC) during one month of culture, together with conventional coculture with RLEC in CN-coated dishes as a control. RLEC prevented spheroid loss caused by its detachment from the culture dishes often occurring in pure culture. CN-gel sandwich by itself improved remarkably hepatocyte maintenance when compared with CN-gel free systems, thereby resulting in enhancement of overall functional expressions as compared with CN-gel free systems. RLEC in CN-gel sandwhich, however, reduced cellular sustainment probably due to its suppression of hepatocyte growth. Although there were no significant differences in albumin secretion per cell among the five cultures examined, CN-gel sandwich expressed markedly higher 7EC metabolizing activity per cell, where RLEC presence had a preferable influence. Consequently, membrane-supported CN-gel sandwich was the most superior technique for hepatocyte cultivation from the standpont of both cellular maintenance and its functional expressions per cell.


Thermally Activated Geometrical Regioselective E→Z Isomerization-Enabled Cascade Sequences of Conjugated Dienals: Experimental and DFT Studies.
The geometrical regioselective E→Z isomerization of a conjugated alkene under thermal activation pose a challenge due to microscopic reversibility. Herein we report that such reversibility issues can be circumvented by integrating E→Z isomerization with subsequent cyclization cascade, particularly in the absence of commonly employed light, acids, or metal-catalysts. Thus, linearly conjugated dienals in a mixture of toluene-alcohol (2 : 1) solvents or only with alcohol at 60-70 °C can be converted to γ-alkoxybutenolides in moderate to good yields. The intermediary 2Z,4E-isomer can be isolated, which includes the first example of isolating the regioselective isomerization product under thermal conditions. Density functional theory (DFT) studies have been employed to shed light on the feasibility of geometrical alkene isomerization and ensuing cascade sequences. It has been observed that the regioselective 2E,4E→2Z,4E isomerization of dienal is a thermodynamically facile (ΔG <0) process. Structural elucidation further reveals that the presence of a certain charge transfer and a non-covalent interaction may be the primary reasons for the enhanced stability of the 2Z,4E-isomer. The thermodynamic plausibility of the subsequent cascade reaction from the Z-isomer to the anticipated product in the presence of a polar protic solvent (here MeOH) is also explicated. Out of the two probable pathways, the "hemiacetal pathway" involving a relay proton transfer is kinetically more feasible due to the diminished activation barrier than the "conjugate addition pathway".


The personal computer as a clinical research and teaching tool.
The combination of the IBM Personal Computer and Lotus 1-2-3 software has made the personal computer of practical value to the surgeon. Within a month of spare time learning one can become competent in the use of the electronic spread sheet, data manipulation, basic statistics, and graph creation. Special functions, macros, and menus can be written into the program to tailor it to the investigator's individual needs. The software is self instructing, but the help and advice of a professional programmer is invaluable if a problem arises. Slide, table, and manuscript preparation time are minimized, particularly if a word processing package is added, and your secretary will love it!


Detection of Mycoplasma genitalium from male primary urine specimens: an epidemiologic dichotomy with Trichomonas vaginalis.
A total of 2750 male urines subjected to a transcription-mediated amplification (TMA)-based Mycoplasma genitalium assay yielded 188 positive results (6.84%). This rate was similar to Chlamydia trachomatis (6.87%; P = 0.96) and greater than Neisseria gonorrhoeae (4.0%) and Trichomonas vaginalis (2.3%; P < 0.0002). Mean age of M. genitalium-infected males (30.8) was similar to N. gonorrhoeae (P = 0.78) but less than T. vaginalis (mean, 41.6; P < 0.0001). A total of 266 STI clinic encounters had at least 1 sexually transmitted infection (STI); 36.5% of these encounters had sole detection of M. genitalium (P ≤ 0.009 versus sole detection of other STI agents). In 209 community encounters with at least 1 STI, 22.0% exhibited sole detection of M. genitalium (P = 0.0007 versus sole M. genitalium detection in STI clinic males), while 18.7% had sole detection of T. vaginalis (P < 0.0002 versus detection in STI clinic males). TMA-based M. genitalium screening identifies additional cases of nongonococcal urethritis.


SHIP negatively regulates IgE + antigen-induced IL-6 production in mast cells by inhibiting NF-kappa B activity.
We demonstrate in this study that IgE + Ag-induced proinflammatory cytokine production is substantially higher in Src homology-2-containing inositol 5'-phosphatase (SHIP)(-/-) than in SHIP(+/+) bone marrow-derived mast cells (BMMCs). Focusing on IL-6, we found that the repression of IL-6 mRNA and protein production in SHIP(+/+) BMMCs requires the enzymatic activity of SHIP, because SHIP(-/-) BMMCs expressing wild-type, but not phosphatase-deficient (D675G), SHIP revert the IgE + Ag-induced increase in IL-6 mRNA and protein down to levels seen in SHIP(+/+) BMMCs. Comparing the activation of various signaling pathways to determine which ones might be responsible for the elevated IL-6 production in SHIP(-/-) BMMCs, we found the phosphatidylinositol 3-kinase/protein kinase B (PKB), extracellular signal-related kinase (Erk), p38, c-Jun N-terminal kinase, and protein kinase C (PKC) pathways are all elevated in IgE + Ag-induced SHIP(-/-) cells. Moreover, inhibitor studies suggested that all these pathways play an essential role in IL-6 production. Looking downstream, we found that IgE + Ag-induced IL-6 production is dependent on the activity of NF-kappa B and that I kappa B phosphorylation/degradation and NF-kappa B translocation, DNA binding and transactivation are much higher in SHIP(-/-) BMMCs. Interestingly, using various pathway inhibitors, it appears that the phosphatidylinositol 3-kinase/PKB and PKC pathways elevate IL-6 mRNA synthesis, at least in part, by enhancing the phosphorylation of I kappa B and NF-kappa B DNA binding while the Erk and p38 pathways enhance IL-6 mRNA synthesis by increasing the transactivation potential of NF-kappa B. Taken together, our data are consistent with a model in which SHIP negatively regulates NF-kappa B activity and IL-6 synthesis by reducing IgE + Ag-induced phosphatidylinositol-3,4,5-trisphosphate levels and thus PKB, PKC, Erk, and p38 activation.


Mechanism of linear DNA circularization: formation of 'lasso'-like structures of pre-mRNA DNA copies.
An electron microscopic investigation of a DNA product synthesized on the pre-mRNA template using AMV reverse transcriptase in the absence of actinomycin D revealed linear single-stranded and double-stranded molecules, and, also, double-stranded branched as well as 'lasso'-like and circular structures. Models for the formation of such DNA structures are proposed.


A Failure to Communicate: MYOSIN RESIDUES INVOLVED IN HYPERTROPHIC CARDIOMYOPATHY AFFECT INTER-DOMAIN INTERACTION.
Our molecular modeling studies suggest a charge-dependent interaction between residues Glu-497 in the relay domain and Arg-712 in the converter domain of human β-cardiac myosin. To test the significance of this putative interaction, we generated transgenic Drosophila expressing indirect flight muscle myosin with charge reversal mutations in the relay (E496R) or converter (R713E). Each mutation yielded dramatic reductions in myosin Ca-ATPase activity (~80%) as well as in basal (~67%) and actin-activated (~84%) Mg-ATPase activity. E496R myosin-induced in vitro actin-sliding velocity was reduced by 71% and R713E myosin permitted no actin motility. Indirect flight muscles of late pupae from each mutant displayed disrupted myofibril assembly, with adults having severely abnormal myofibrils and no flight ability. To understand the molecular basis of these defects, we constructed a putative compensatory mutant that expresses myosin with both E496R and R713E. Intriguingly, ATPase values were restored to ~73% of wild-type and actin-sliding velocity increased to 40%. The double mutation suppresses myofibril assembly defects in pupal indirect flight muscles and dramatically reduces myofibril disruption in young adults. Although sarcomere organization is not sustained in older flies and flight ability is not restored in homozygotes, young heterozygotes fly well. Our results indicate that this charge-dependent interaction between the myosin relay and converter domains is essential to the mechanochemical cycle and sarcomere assembly. Furthermore, the same inter-domain interaction is disrupted when modeling human β-cardiac myosin heavy chain cardiomyopathy mutations E497D or R712L, implying that abolishing this salt bridge is one cause of the human disease.


Experiences and perspectives of healthcare professionals implementing advance care planning for people suffering from life-limiting illness: a systematic review and meta-synthesis of qualitative studies.
Life-limited patients may lose decision-making abilities during disease progression. Advance care planning can be used as a discussion method for healthcare professionals to understand patients' future care preferences. However, due to many difficulties, the participation rate of healthcare professionals in advance care planning is not high. To explore the facilitators of and barriers to healthcare professionals' provision of advance care planning to life-limited patients to better implement it for this population. We followed ENTREQ and PRISMA to guide this study. We conducted a systematic search of PubMed, Web of Science, Embase, CINAHL, PsycINFO, CNKI, and SinoMed to include qualitative data on the experiences and perspectives of healthcare professionals in different professional fields in providing advance care planning for life-limited patients. The Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research was used to assess the quality of the included studies. A total of 11 studies were included. Two themes were identified: unsupported conditions and facilitative actions. Healthcare professionals regarded cultural concepts, limited time, and fragmented record services as obstacles to implementation. They had low confidence and were overly concerned about negative effects. They needed to possess multiple abilities, learn to flexibly initiate topics, and facilitate effective communication based on multidisciplinary collaboration. Healthcare professionals need an accepting cultural environment to implement advance care planning, a sound legal system, financial support, and a coordinated and shared system to support them. Healthcare systems need to develop educational training programs to increase the knowledge and skills of healthcare professionals and to promote multidisciplinary collaboration to facilitate effective communication. Future research should compare the differences in the needs of healthcare professionals in different cultures when implementing advance care planning to develop systematic implementation guidelines in different cultures.


TOAST criteria applied in acute ischemic stroke.
Etiological subclassification of ischemic stroke has become increasingly important, as new therapeutic agents have been introduced. The aim of this study was to assess the inter-rater reliability of the TOAST classification applied in the acute setting, and further to evaluate the criterion validity of the TOAST classification in discriminating between small vessel disease and other etiologies. From June to December 2001, 38 patients with acute ischemic stroke were included in the present study. All were classified according to the TOAST criteria by two junior registrars shortly after admission. Later, a consensus classification was made based on a comprehensive investigation programme. The inter-rater reliability between the two junior registrars was very good (kappa 0.88). The overall agreement between initial and consensus classifications was fair (kappa 0.30). The TOAST classification discriminated between small vessel disease and other subgroups in most patients (sensitivity 0.93, specificity 0.83). Etiological subclassification of ischemic stroke requires extensive cerebrovascular investigation. Normally, such resources are not available at admission. Nevertheless, the TOAST classification should be used in this setting to help physicians differentiate between small vessel disease and other etiologies of acute stroke, particularly when therapies with possible harmful side effects are considered an option.


Segmental maternal uniparental disomy 7q associated with DLK1/GTL2 (14q32) hypomethylation.
Aberrant methylation at different imprinted loci has been reported for several congenital imprinting disorders, that is, Silver-Russell syndrome (SRS), but the coincidental occurrence of aberrant methylation and uniparental disomy (UPD) has not yet been described. We report on a patient initially diagnosed with SRS carrying a segmental maternal UPD of chromosome 7 [upd(7q)mat]. By further screening the patient's DNA for methylation defects on other chromosomes we identified a hypomethylation of the paternally methylated DLK1/GTL2 locus in 14q32, an epigenotype typically associated with the upd(14)mat phenotype. Detailed clinical analysis confirmed the molecular finding in the patient indicating that the 14q32 epimutation was clinically preponderant. The parallel occurrence of upd(7q)mat and a DLK1/GTL2 hypomethylation in the same patient is a unique finding. Indeed, both disturbances might have occurred coincidentally, but it can also be hypothesized that the upd(7q)mat as the initial genomic mutation represents a trans-acting mutation causing an aberrant methylation in 14q32.