Identification of the ultrahigh-risk subgroup in neuroblastoma cases through DNA methylation analysis and its treatment exploiting cancer metabolism.
Neuroblastomas require novel therapies that are based on the exploitation of their biological mechanism. To address this need, we analyzed the DNA methylation and expression datasets of neuroblastomas, extracted a candidate gene characterizing the aggressive features, and conducted functional studies. Based on the DNA methylation data, we identified a subgroup of neuroblastoma cases with 11q loss of heterozygosity with extremely poor prognosis. PHGDH, a serine metabolism-related gene, was extracted as a candidate with strong expression and characteristic methylation in this subgroup as well as in cases with MYCN amplification. PHGDH inhibition suppressed neuroblastoma cell proliferation in vitro and in vivo, indicating that the inhibition of serine metabolism by PHGDH inhibitors is a therapeutic alternative for neuroblastoma. Inhibiting the arginine metabolism, which is closely related to serine metabolism using arginine deiminase, had a combination effect both in vitro and in vivo, especially on extracellular arginine-dependent neuroblastoma cells with ASS1 deficiency. Expression and metabolome analyses of post-dose cells confirmed the synergistic effects of treatments targeting serine and arginine indicated that xCT inhibitors that inhibit cystine uptake could be candidates for further combinatorial treatment. Our results highlight the rational therapeutic strategy of targeting serine/arginine metabolism for intractable neuroblastoma.


Cystathionine beta-synthase p.S466L mutation causes hyperhomocysteinemia in mice.
Missense mutations in the cystathionine beta-synthase (CBS) gene are the most common cause of clinical homocystinuria in humans. The p.S466L mutation was identified in a homocystinuric patient, but enzymatic studies with recombinant protein show this mutant to be highly active. To understand how this mutation causes disease in vivo, we have created mice lacking endogenous mouse CBS and expressing either wild-type (Tg-hCBS) or p.S466L (Tg-S466L) human CBS under control of zinc inducible metallothionein promoter. In the presence of zinc, we found that the mean serum total homocysteine (tHcy) of Tg-S466L mice was 142+/-55 microM compared to 16+/-13 microM for hCBS mice. Tg-S466L mice also had significantly higher levels of total free homocysteine and S-adenosylhomocysteine in liver and kidney. Only 48% of Tg-S466L mice had detectable CBS protein in the liver, whereas all the Tg-hCBS animals had detectable protein. Surprisingly, CBS mRNA was significantly elevated in Tg-S466L animals compared to Tg-hCBS, implying that the reduction in p.S466L protein was occurring due to posttranscriptional mechanisms. In Tg-S466L animals with detectable liver CBS, the enzyme formed tetramers and was active, but lacked inducibility by S-adenosylmethionine (AdoMet). However, even in Tg-S466L animals that had in vitro liver CBS activity equivalent to Tg-hCBS animals there was significant elevation of serum tHcy. Our results show that p.S466L causes homocystinuria by affecting both the steady state level of CBS protein and by reducing the efficiency of the enzyme in vivo.


The physical burdens of secrecy.
The present work examined whether secrets are experienced as physical burdens, thereby influencing perception and action. Four studies examined the behavior of people who harbored important secrets, such as secrets concerning infidelity and sexual orientation. People who recalled, were preoccupied with, or suppressed an important secret estimated hills to be steeper, perceived distances to be farther, indicated that physical tasks would require more effort, and were less likely to help others with physical tasks. The more burdensome the secret and the more thought devoted to it, the more perception and action were influenced in a manner similar to carrying physical weight. Thus, as with physical burdens, secrets weigh people down.


Segmental organization of spinal reflexes mediating autonomic dysreflexia after spinal cord injury.
Spinal cord injuries above mid-thoracic levels can lead to a potentially life-threatening hypertensive condition termed autonomic dysreflexia that is often triggered by distension of pelvic viscera (bladder or bowel). This syndrome is characterized by episodic hypertension due to sudden, massive discharge of sympathetic preganglionic neurons in the thoracolumbar spinal cord. This hypertension is usually accompanied by bradycardia, particularly if the injury is caudal to the 2nd to 4th thoracic spinal segments. The development of autonomic dysreflexia is correlated with aberrant sprouting of peptidergic afferent fibers into the spinal cord below the injury. In particular, sprouting of nerve growth factor-responsive afferent fibers has been shown to have a major influence on dysreflexia, perhaps by amplifying the activation of disinhibited sympathetic neurons. Using a model of noxious bowel distension after complete thoracic spinal transection at the 4th thoracic segment in rats, we selectively altered C-fiber sprouting, at specified spinal levels caudal to the injury, with microinjections of adenovirus encoding the growth-promoting nerve growth factor or the growth-inhibitory semaphorin 3A. This was followed by assessment of physiological responses to colorectal distension and subsequent histology. Additionally, anterograde tract tracers were injected into the lumbosacral region to compare the extent of labeled propriospinal rostral projections in uninjured cords to those in cords after complete 4th thoracic transection. In summary, overexpression of chemorepulsive semaphorin 3A impeded C-fiber sprouting in lumbosacral segments and mitigated hypertensive autonomic dysreflexia, whereas the opposite results were obtained with nerve growth factor overexpression. Furthermore, compared to naïve rats, there were significantly more labeled lumbosacral propriospinal projections rostrally after thoracic injury. Collectively, our findings suggest that distension of pelvic viscera increases the excitation of expanded afferent terminals in the disinhibited lumbosacral spinal cord. This, in turn, triggers excitation and sprouting of local propriospinal neurons to relay visceral sensory stimuli and amplify the activation of sympathetic preganglionic neurons in the thoracolumbar cord, to enhance transmission in the spinal viscero-sympathetic reflex pathway. These responses are manifested as autonomic dysreflexia.


Is suicide mortality associated with neighbourhood social fragmentation and deprivation? A Dutch register-based case-control study using individualised neighbourhoods.
Neighbourhood social fragmentation and socioeconomic deprivation seem to be associated with suicide mortality. However, results are inconclusive, which might be because dynamics in the social context are not well-represented by administratively bounded neighbourhoods at baseline. We used individualised neighbourhoods to examine associations between suicide mortality, social fragmentation, and deprivation for the total population as well as by sex and age group. Using a nested case-control design, all suicides aged 18-64 years between 2007 and 2016 were selected from longitudinal Dutch register data and matched with 10 random controls. Indices for social fragmentation and deprivation were calculated annually for 300, 600 and 1000 metre circular buffers around each subject's residential address. Suicide mortality was significantly higher in neighbourhoods with high deprivation and social fragmentation. Accounting for individual characteristics largely attenuated these associations. Suicide mortality remained significantly higher for women living in highly fragmented neighbourhoods in the fully adjusted model. Age-stratified analyses indicate associations with neighbourhood fragmentation among women in older age groups (40-64 years) only. Among men, suicide risk was lower in fragmented neighbourhoods for those aged 18-39 years and for short-term residents. In deprived neighbourhoods, suicide risk was lower for men aged 40-64 years and long-term residents. Associations between neighbourhood characteristics and suicide mortality were comparable across buffer sizes. Our findings suggest that next to individual characteristics, the social and economic context within which people live may both enhance and buffer the risk of suicide.


Auditory and visual refractory period effects in children and adults: an ERP study.
This developmental study was designed to investigate event-related potential (ERP) refractory period effects in the auditory and visual modalities in children and adults and to correlate these electrophysiological measures with standard behavioral measures. ERPs, accuracy, and reaction time were recorded as school-age children and adults monitored a stream of repetitive standard stimuli and detected occasional targets. Standards were presented at various interstimulus intervals (ISIs) in order to measure refractory period effects on early sensory components. As has been reported previously in adults, larger components for standards with longer ISIs were observed for an auditory N1 and the visual occipital P1 and P2 in adults. Remarkably similar effects were observed in children. However, only children showed refractory effects on the amplitude of the visual N1 and P2 measured at anterior sites. Across groups, behavioral accuracy and reaction time were correlated with latencies of auditory N1 and visual P2 across ISI conditions. The results establish a normal course of development for auditory and visual ERP refractory period effects across the 6- to 8-year-old age range and indicate similar refractoriness in the neural systems indexed by ERPs in these paradigms in typically developing children and adults. Further, the results suggest that electrophysiological measures and standard behavioral measures may at least in part index similar processing in the present paradigms. These findings provide a foundation for further investigation into atypical development, particularly in those populations for which processing time deficits have been implicated such as children with specific language impairment or dyslexia.


Open-loop and closed-loop optokinetic nystagmus in squirrel monkeys (Saimiri sciureus) and in man.
Horizontal optokinetic nystagmus (OKN) was measured in 3 normal Squirrel monkeys by means of the electromagnetic search coil technique. Binocular and monocular stimulation of each eye to the left and right by moving vertical stripe patterns of 2.37 or 15 degree period were applied at angular velocities of 0.5 to 400 deg/s. After measurement of horizontal OKN under normal conditions, open-loop OKN gain was determined by monocular stimulation of an eyeball immobilized by means of retrobulbar injections of 11 units botulinum toxin (BoTx type A) and compared with the pre-injection data or with monocular stimulation of the other eye, which remained mobile. In normal Squirrel monkeys gain of optokinetic nystagmus reached values between 0.8 and 0.97 at angular velocities below 1.5 deg/s. Gain under these conditions was related to stimulus angular velocities Vs, i.e. Ge = Ve/Vs. A slightly higher gain was found for binocular than for monocular stimulation. No significant differences were found in OKN when monocular stimulation in the naso-temporal and in the temporo-nasal direction was applied. The upper cut-off angular velocity (-3 dB-point) reached values of 180-230 deg/s, significantly above those observed in man under similar stimulus conditions. Monocular optokinetic stimulation of an immobilized eye led to vigorous optokinetic nystagmus and OKAN of the other eye, whereby maximum gain (Gi = Ve/Vr) was found to be between 20 and 30 at lower retinal stimulus velocities (2-5 deg/s). Gain was related to retinal stimulus velocity Vr. Increase in Vr above 10 deg/s led to a decrease in gain with a slope of about 20 dB per decade. Measurement of gain of closed-loop OKN related to retinal stimulus velocity Vr (which was determined by the difference between Vs and Ve) led to a similar dependence of OKN as in closed-loop stimulus conditions. Differences in sensitivity between the temporal and the nasal visual hemifield stimulation evoking horizontal open-loop OKN are described. Directional selectivity appeared in these experiments. Open-loop OKN data from a human subject are reported. With highly attentive horizontal optokinetic gaze nystagmus, Ve depended on the duration of the pursuit phases of OKN. Ve accelerated with the duration of the individual slow phase of OKN and was reset by each backward saccade (of the covered mobile eye). OKN gain was considerably smaller when the subject intentionally pursued as many stripes as possible of the 1.15 degree period stripe pattern (gain related to Vr about 1.5-3).(ABSTRACT TRUNCATED AT 400 WORDS)


Wind drives fast changes of light climate in a large, shallow re-established lake.
With ever greater frequency, wetlands and shallow lakes that had been diverted for agriculture are being re-established to reduce nutrient loss and greenhouse gas emission, as well as to increase biodiversity. Here, we investigate drivers of water column light attenuation (Kd) at multiple time scales and locations in Lake Fil, Denmark, during the first five years after its re-establishment in 2012. We found that Kd was generally high (overall mean: 3.4 m-1), with resuspended sediment particles and colored dissolved organic matter being the main contributors. Using daily time series of light attenuation recorded at four stations, we used a generalized additive model to analyze the influence of wind speed and direction on Kd. This model explained a high proportion of the variation (R2 = 0.62, RMSE = 0.74 m-1, and MAE = 0.55 m-1) and showed that higher wind speed increased Kd on the same day and, with smaller influence, on the next day. Furthermore, we found a significant influence of wind direction and an interaction between wind speed and wind direction, a combination that suggests that short-term variations in light climate depends on the interplay between wind direction and sources of particles. Wind from non-prevailing directions thus influence Kd more, as it can activate previously deposited particles. The maximum colonization depths of submerged vegetation occurred at ~2-6% of sub-surface light from 2014 to 2016 and peaked at 1.2 m in 2016. The fast, day-to-day variation of Kd in Lake Fil reveals the importance of wind on light climate and in turn biological elements such as phytoplankton and submerged macrophyte development in shallow lakes. The implications are essential for the prior planning and management of future lake re-establishment.


Positron emission tomography imaging of a novel Anxa1-targeted peptide 18 F-Al-NODA-Bn-p-SCN-GGGRDN-IF7 in A431 cancer mouse models.
Annexin 1 (Anxa1) is a highly specific surface marker of tumor vasculature in the lung and prostate solid tumors. The IF7 peptide was modified with a hydrophilic linker, GGGRDN, and coupled with a new bifunctional chelating agent NODA-Bn-p-SCN. The resulting peptides (NODA-Bn-p-SCN-GGGRDN-IF7) were successfully labeled with Al18 F. The targeting characteristics of the radiolabeled peptides were evaluated in the Anxa1 positive A431 tumor model. Micro-positron emission tomography (micro-PET) imaging revealed that the A431 tumors were clearly visualized (5.74 ± 1.13%ID/g, 3.92 ± 0.78%ID/g and 1.30 ± 0.43%ID/g at 0.5, 1, and 2 h post-injection, respectively). Anxa1 binding specificity was also demonstrated by reduced tumor uptake after co-injection with excessive unlabeled GGGRDN-IF7 peptide at 30, 60, and 120 min post-injection. 18 F-Al-NODA-Bn-p-SCN-GGGRDN-IF7 might be a potential PET imaging agent for detecting Anxa1 levels in cancers due to the favorable characteristics such as convenient synthesis, specific Anxa1 targeting, and good tumor uptakes.


Endothelin and sex hormones modulate the fibronectin synthesis by cultured human skin scleroderma fibroblasts.
To evaluate the influence of endothelin-1 (ET-1) and sex hormones on cell proliferation and extracellular matrix (ECM) synthesis (ie, fibronectin, laminin) by cultured normal and scleroderma (SSc) human skin fibroblasts (FBs). Primary cultures of FBs were treated with ET-1 and sex hormones (17beta-oestradiol or testosterone) for 24 h. Cell growth was analysed by methiltetrazolium salt test, ECM synthesis was evaluated by immunocytochemistry and western blot, both at 24 h. In normal FBs, ET-1 and 17beta-oestradiol, as well as their combination, increased cell growth (p<0.001, p<0.001, p<0.01 vs untreated cells (control), respectively) and fibronectin synthesis (p<0.05, p<0.05, p<0.01 vs control, respectively). By contrast, testosterone either alone or in combination with ET-1 did not influence cell proliferation, but decreased fibronectin synthesis (p<0.05, testosterone vs control). In SSc FBs, ET-1 and 17beta-oestradiol alone or their combination induced an increased fibronectin synthesis (p<0.05, p<0.05, p<0.01 vs control, respectively). Unexpectedly, testosterone induced an increase of fibronectin synthesis (p<0.05 vs control). ET-1 and 17beta-oestradiol seem to exert a profibrotic effect in normal and SSc culture FBs and might suggest their synergistic effect in the pathogenesis of the fibrotic process in SSc.


Obstetric and neonatal outcomes after antipsychotic medication exposure in pregnancy.
Antipsychotic medications are used by increasing numbers of women of reproductive age. The safety of these medications during pregnancy has not been well described. We undertook a systematic review and meta-analysis of the adverse obstetric and neonatal outcomes associated with exposure to antipsychotics during pregnancy. PubMed, Reprotox, and ClinicalTrials.gov were searched to identify potential studies for inclusion. Case-control or cohort studies estimating adverse birth outcomes associated with antipsychotic exposure during pregnancy were included. Pooled odds ratios (ORs) were used for dichotomous outcomes and weighted mean differences were used for neonatal birth weight and gestational age. Thirteen cohort studies, including 6,289 antipsychotic-exposed and 1,618,039 unexposed pregnancies, were included. Antipsychotic exposure was associated with an increased risk of major malformations (absolute risk difference [ARD] 0.03, 95% confidence interval [CI] 0.00-0.05, P=.04, Z=2.06), heart defects (ARD 0.01, 95% CI 0.00-0.01, P<.001, Z=3.44), preterm delivery (ARD 0.05, 95% CI 0.03-0.08, P<.001, Z=4.10), small-for-gestational-age births (ARD 0.05, 95% CI 0.02-0.09, P=.006, Z=2.74), elective termination (ARD 0.09, 95% CI 0.05-0.13, P<.001, Z=4.69), and decreased birth weight (weighted mean difference -57.89 g, 95% CI -103.69 to -12.10 g, P=.01). There was no significant difference in the risk of major malformations (test for subgroup differences: χ²=0.07, degrees of freedom=1, P=.79) between typical (OR 1.55, 95% CI 1.21-1.99, P=.006) and atypical (OR 1.39, 95% CI 0.66-2.93, P=.38) antipsychotic medications. Antipsychotic exposure was not associated with risk of large-for-gestational-age births, stillbirth, and spontaneous abortion. Although antipsychotic exposure during pregnancy was associated with increased risk of adverse obstetric and neonatal outcomes, this association does not necessarily imply causation. This analysis was limited by the small number of included studies and limited adjustment in studies for possible confounders. Women requiring antipsychotic treatment during pregnancy appear at higher risk of adverse birth outcomes, regardless of causation, and may benefit from close monitoring and minimization of other potential risk factors during pregnancy.


Simultaneous determination of imigliptin and its three metabolites in human plasma and urine by liquid chromatography coupled to tandem mass spectrometry.
A specific and sensitive method was firstly developed using high performance liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS) to simultaneously quantify imigliptin (KBP-3853) and its three metabolites (KBP-3926, KBP-3902, KBP-5493) in human plasma and urine. Solid-phase extraction (SPE) and direct dilution were used to extract imigliptin and its three metabolites from plasma and urine, respectively. The extracts were injected onto a SymmetryShield RP8 column with a gradient elution of acetonitrile and water containing 5mM ammonium acetate (pH 7). Ionization of KBP-3853, KBP-3926, KBP-3902, KBP-5493, and XZP-3244 (internal standard, IS) was performed using an electrospray ionization (ESI) source in positive mode and detection was carried out with multiple reaction monitoring (MRM) mode. The lower limits of quantitation (LLOQ) of KBP-3853/KBP-3926/KBP-3902/KBP-5493 in human plasma and urine were 0.500/0.500/0.500/0.500ng/mL and 20.0/20.0/10.0/10.0ng/mL, respectively. Inter- and intra-batch precision of imigliptin and its three metabolites were less than 15% and the accuracy was within 85-115% for both plasma and urine. The extraction recoveries of all analytes at three concentration levels were consistent. The specificity, matrix effect, linearity and stabilities under various conditions were validated for imigliptin and its three metabolites in human plasma and urine. In conclusion, the validation results showed that this method was robust, specific, and sensitive and it can successfully fulfill the requirement of clinical pharmacokinetic study of imigliptin hydrochloride in Chinese healthy subjects.


Primary Aorto-Appendicular Fistula Accompanied by Infected Penetrating Aortic Ulcer - Case Report.
Primary aorto-appendicular fistulas are extremely rare in clinical practice, and there are only 3 such cases reported in the available literature. The aim of this study is to present the case of a 68-year-old female patient with primary aorto-appendicular fistula accompanied by infected penetrating aortic ulcer (PAU). At the time of her hospital admission, the patient did not demonstrate any typical symptoms. Multidetector computed tomography imaging of aorta was performed during an additional preoperative examination and the PAU of the infrarenal aortic segment was detected. Other pathological changes were not found. The intraoperative findings confirmed the presence of the PAU firmly attached to the appendix and surrounding signs of inflammation. Appendectomy and partial resection of the PAU were performed, along with aortic reconstruction, using a Dacron tube graft and right renal artery reattachment. During the postoperative period, there were no complications, and the patient was discharged on the 10th postoperative day. Control medical examination and color duplex ultrasonography were performed 18 months after the surgery and they provided satisfactory results.


Variations during leaf development of the relative amounts of two bean (Phaseolus vulgaris) chloroplast tRNAs(Phe) which differ in their minor nucleotide content.
Bean (Phaseolus vulgaris cv. Saxa) chloroplasts contain two tRNA(Phe) species, namely tRNA(Phe)1 and tRNA(Phe)2. By sequence determination, we show that tRNA(Phe)2 is identical to the previously sequenced tRNA(Phe)1 except for two undermodified nucleotides. By reversed-phase chromatography analyses, we demonstrate that the relative amounts of these two chloroplast tRNAs(Phe) vary during leaf development: in etiolated leaves the undermodified tRNA(Phe)2 only represents 15% of total chloroplast tRNA(Phe), during development and greening it increases to reach 60% in 8-day-old leaves, and it then decreases to 9% in senescing leaves.


Tmem138 is localized to the connecting cilium essential for rhodopsin localization and outer segment biogenesis.
Photoreceptor connecting cilium (CC) is structurally analogous to the transition zone (TZ) of primary cilia and gates the molecular trafficking between the inner and the outer segment (OS). Retinal dystrophies with underlying CC defects are manifested in a broad array of syndromic conditions known as ciliopathies as well as nonsyndromic retinal degenerations. Despite extensive studies, many questions remain in the mechanism of protein trafficking across the photoreceptor CC. Here, we genetically inactivated mouse Tmem138, a gene encoding a putative transmembrane protein localized to the ciliary TZ and linked to ciliopathies. Germline deletion of Tmem138 abolished OS morphogenesis, followed by rapid photoreceptor degeneration. Tmem138 was found localized to the photoreceptor CC and was required for localization of Ahi1 to the distal subdomain of the CC. Among the examined set of OS proteins, rhodopsin was mislocalized throughout the mutant cell body prior to OS morphogenesis. Ablation of Tmem138 in mature rods recapitulated the molecular changes in the germline mutants, causing failure of disc renewal and disintegration of the OS. Furthermore, Tmem138 interacts reciprocally with rhodopsin and a related protein Tmem231, and the ciliary localization of the latter was also altered in the mutant photoreceptors. Taken together, these results suggest a crucial role of Tmem138 in the functional organization of the CC, which is essential for rhodopsin localization and OS biogenesis.


Education for cardiac arrest--Treatment or prevention?
In-hospital cardiac arrests (IHCA) occur infrequently and individual staff members working on general wards may only rarely encounter one. Mortality following IHCA is high and the evidence for the benefits of many advanced life support (ALS) interventions is scarce. Nevertheless, regular, often frequent, ALS training is mandatory for many hospital medical staff and nurses. The incidence of pre-cardiac arrest deterioration is much higher than that of cardiac arrests, and there is evidence that intervention prior to cardiac arrest can reduce the incidence of IHCA. This article discusses a proposal to reduce the emphasis on widespread ALS training and to increase education in the recognition and response to pre-arrest clinical deterioration.


[Use of health resources and costs associated with the diagnosis and treatment of each episode of deep vein thrombosis and bleeding in patients undergoing orthopaedic surgery for hip or knee].
To determine the use of healthcare resources and costs associated with the diagnosis and treatment of thrombosis and bleeding patients who have undergone elective hip or knee replacement surgery, in routine clinical practice conditions. This multicentre observational and retrospective study extracted data from the medical records of three Spanish public hospitals (2010). Patients ≥ 40 years who had received prophylaxis-anticoagulation were included. They were randomised into three groups: a) control (no hospital complications), b) bleeding, and c) thrombosis. General variables, use of resources and costs were analysed. logistic regression and ANCOVA for model correction, (P<.05) was included. A total of 141 patients (control: 60; bleeding: 60; and thrombosis: 21), with a mean age 68.7 (SD: 10.4) years, and 68.1% females were identified. Hip arthroplasty was more frequent (71.6%). The bleeding risk was associated with age (OR=1.1) and thrombosis with COPD (OR=1.8); P<.05). The average length of stay for the thrombosis, bleeding and control groups was 13.9, 11.5 and 7.4 days, respectively; P<.001). The total costs for each group were €10,484.3; €8,766.4 and €6,496.1 respectively; P<.05. All grouped results were comparable between them according to the hospital analysed and the type of replacement. Costs were higher for thrombosis and bleeding patients, respectively. Costs were associated with length of stay and hospital-acquired infections.


Hyperendemic malaria transmission in areas of occupation-related travel in the Peruvian Amazon.
Plasmodium vivax and Plasmodium falciparum cause a significant illness burden in Peru. Anopheline indices for populated communities in the peri-Iquitos region of Loreto have been reported to be remarkably low, with entomological inoculation rates (EIR) estimated at one to 30 infective bites per year based on a few studies in close proximity to the urban centre of Iquitos and surrounding deforested areas. Local reports suggest that a large number of the reported cases are contracted outside of populated communities in undeveloped riverine areas frequented by loggers and fishermen. To better understand vectorial capacity in suspected high malaria transmission zones in a rural district near Iquitos, Peru, mosquito collections were conducted at different points in the seasonality of malaria transmission in 21 sites frequented by occupational labourers. Prevalence of Plasmodium spp in vectors was determined by circumsporozoite protein ELISA on individual mosquitoes. Slide surveillance was performed for humans encountered in the zone. In total, of 8,365 adult female mosquitoes examined, 98.5% were identified as Anopheles darlingi and 117 (1.4%) tested positive for sporozoites (P. falciparum, P. vivax VK210 or P. vivax VK247). Measured human biting rates at these sites ranged from 0.102 to 41.13 bites per person per hour, with EIR values as high as 5.3 infective bites per person per night. Six percent of the 284 blood films were positive for P. vivax or P. falciparum; however, 88% of the individuals found to be positive were asymptomatic at the time of sampling. The results of this study provide key missing indices of prominent spatial and temporal heterogeneity of vectorial capacity in the Amazon Basin of Peru. The identification of a target human subpopulation as a principal reservoir and dispersion source of Plasmodium species has important implications for vaccine development and the delivery of effective targeted malaria control strategies.


A novel CD4+ T-helper lymphocyte epitope in the VP3 protein of hepatitis A virus.
Prediction analysis of TH-cell epitopes in the VP3 capsid protein of the hepatitis A virus (HAV) revealed the occurrence of a putative TH epitope in the 102-121 region complying with all the algorithms tested. To confirm these predictions, spleen T lymphocytes obtained from BALB/c mice previously immunised with HAV, were stimulated in vitro with different concentrations of synthetic peptides 102-121 and 110-121 of VP3. The ability of these peptides to stimulate CD4+ T-helper lymphocytes proliferation was evaluated by an immunological flow cytometry detection of bromodeoxyuridine incorporation. Using this method, it is concluded that the amino terminal part of the VP3 102-121 sequence contains a T cell epitope.


Juvenile hormone promotes locust fat body cell polyploidization and vitellogenesis by activating the transcription of Cdk6 and E2f1.
Juvenile hormone (JH) is known to promote cell polyploidization for insect vitellogenesis and egg production, but the underlying mechanisms remain poorly understood. Using the migratory locust Locusta migratoria as a model system, we report here that the expression of cyclin-dependent kinase 6 (Cdk6) and adenovirus E2 factor-1 (E2f1), the core mediators in cell cycle progression is regulated by JH and its receptor Methoprene-tolerant (Met). JH acts through its receptor complex comprised of Met and Taiman to directly activate the transcription of Cdk6 and E2f1. Depletion of Cdk6 or E2f1 results in significantly decreased ploidy, precocious mitotic entry and increased cell numbers in the fat body, accompanied by substantial reduction of Vitellogenin gene expression, blocked ovarian growth and arrested oocyte maturation. These findings indicate a crucial role of Cdk6 and E2f1 in JH-regulated polyploidization and vitellogenesis as well as a novel regulatory machinery for endocycling in insects.


YAG laser meloplasty and blepharoplasty.
Twenty-eight patients have undergone facelift and blepharoplasty in which the YAG laser scalpel was used. The laser is able to produce an incision with excellent hemostasis. The patients in this series demonstrated markedly diminished blood loss during surgery and reduced bruising, swelling, pain, and discomfort postoperatively. Contralateral procedures done with the laser on one side and conventional surgery on the other side demonstrated greater benefit on the laser side.


Human serum resistance of metacyclic forms of Trypanosoma brucei brucei, T. brucei rhodesiense and T. brucei gambiense.
Resistance against the lytic action of human serum has been tested among metacyclic and bloodstream forms of Trypanosoma brucei brucei, T.b. rhodesiense and T.b. gambiense stocks and clones. The resistance was determined by applying an in vitro human serum resistance test. Whereas the majority of T.b. gambiense metacyclic forms exhibited stable human serum resistance, T.b. rhodesiense metacyclics showed inconsistent resistance within a minority of parasites, which tended to diminish completely with prolonged passages in rodents. Infection of tsetse flies with in vivo or in vitro selected human serum resistant forms did not significantly increase the proportion of resistant parasites among extruded metacyclic forms. In a T.b. rhodesiense stock which never showed human serum resistance in the metacyclic forms, human serum resistance reappeared after a 2-day cultivation period in the presence of a mammalian serum. These results reflect important phenotypic dynamics and may lead to a better understanding of the epidemiology of African human sleeping sickness.


Are Mechanical Prostheses Valid Alternatives to the Ross Procedure in Young Children Under 6 Years Old?
Aortic valve replacement in young children is associated with technical difficulties and potential morbidity. In contrast to the versatile Ross operation, mechanical prostheses (MP) are uncommonly used. We examined transplant-free survival and cardiac reoperation among 124 young children (aged 1-6 years) who underwent the Ross operation (n = 84) or MP (n = 40) for congenital disease (1982-2003) using the Pediatric Cardiac Care Consortium database. We explored variables influencing outcomes. Children who received MP were operated in an earlier era and were more likely to have aortic regurgitation, conotruncal abnormalities, prior aortic valve surgery, and to need Konno annular enlargement. Although no significant differences were found in hospital mortality (1.2% vs 5.0%, P = .24) or 15-year transplant-free survival (94.1% vs 87.5%, P = .16) between Ross and MP recipients, survival diverged with later follow-up (91.3% vs 68.9%, respectively, at 25 years; P = .01). On multivariable regression analysis the association of MP use and transplant-free survival changed over time (hazard ratios, 0.8 [95% confidence interval, 0.1-4.4; P = .78] vs 6.0 [95% confidence interval, 0.6-63.1; P = .13], respectively) before and after 17 years. Cumulative incidence of cardiac reoperation at 10 years was 37.7% and 53.6% after the Ross procedure and MP, respectively (P = .05). The most common reoperation after the Ross procedure was conduit replacement and pacemaker ± automated internal cardiac defibrillator and after MP was pacemaker ± automated internal cardiac defibrillator and redo aortic valve replacement. Over the study period there was a trend for increased Ross utilization. Interestingly MP use was associated with comparable operative mortality and survival up to 17 years, albeit with higher need for redo aortic valve replacement. On longer follow-up survival diverged with increased attrition in the MP group, likely because of late valve- and reoperation-related complications.


Salmonella osteomyelitis after internal fixation of fracture.
A patient with Salmonella group D (Salmonella enteritidis) acute osteomyelitis of an operated femur is described. The patient failed to respond to chloramphenicol therapy and aztreonam therapy. The local infection that complicated the presence of a foreign body was eradicated only with the removal of the foreign body, an internal fixation plate.


Pyomyositis associated with hematological malignancy: case report and review of the literature.
Pyomyositis occurs most commonly in patients with various immunosuppressive diseases. However, the association of pyomyositis with an underlying hematological malignancy has not been reviewed. We present herein a relevant case and also review the available literature regarding the association of non-tropical pyomyositis and hematological malignancies. The case patient, a 46-year old female, had non-tropical pyomyositis of the iliopsoas and obturator muscles due to Staphylococcus aureus and underlying Hodgkin's disease. Forty-four patients with pyomyositis and an associated hematological malignant disease have been reported in the literature. The most common types of hematological oncology diseases found were acute lymphocytic leukemia (present in 11/44 patients (25%)) and multiple myeloma (7/44 patients (15.9%)). Staphylococcus aureus was the most common cause of pyomyositis (26 out of 44 patients (59.1%)). The muscles of the thigh were most commonly affected (18/44 patients (40.9%)). Medical therapy with antibiotics and surgical drainage were employed in 25/44 (56.8%) of the patients. Thirty out of 44 (68.2%) of the patients had a successful outcome. Death occurred in 5/44 (11.4%) patients. In cases of pyomyositis, the physician should consider an underlying hematological malignancy.


Inhibitory effects of podophyllotoxin derivatives on herpes simplex virus replication.
Podophyllotoxin and its derivatives were examined for inhibitory effects on the replication of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), including acyclovir-resistant virus and clinical isolates. Deoxypodophyllotoxin (RD4-6266) proved to be a highly potent and selective inhibitor of all HSV strains in MRC-5 cells. EC50 values of RD4-6283 (in which the methylenedioxy ring A is modified) for HSV-1 and -2 were inferior to those of deoxypodophyllotoxin. However, podorhizol (RD4-6277) and 5'-methoxy-podorhizol (RD4-6276), in which ring C is absent, did not inhibit HSV replication. Moreover, RD4-6266 also inhibited the production of infectious virus particles of HSV-1 KOS strain and HSV-2 G strain. In contrast, none of the podophyllotoxin derivatives were found to have an antiviral effect against influenza A virus, respiratory syncytial virus or human cytomegalovirus in doses not toxic to the cells.


Different strategies for MRI measurements of renal cortical volume.
First, to measure renal cortical volume (Vc) using different MRI methods combined with a semiautomatic segmentation method. Second, to compare MRI measurements of Vc using the semiautomatic segmentation method with a manual segmentation method. Third, to evaluate the reproducibility of Vc measurements. A total of 22 pigs, 13 with healthy kidneys and nine with diseased kidneys, underwent MRI with two non-contrast-agent methods (MRI 100 x 900 and MRI 300 x 1100) and one contrast-agent method (MRI Gd). For each of these methods, Vc was estimated using semiautomatic (Vc(100 x 900), Vc(300 x 1100), and Vc(Gd)), as well as manual (Vc MANUAL) segmentation. Reference volumes were estimated by stereological means (Vc STEREOLOGY). MRI-derived volumes were compared with reference volumes using a two-tailed paired t-test, and variances between methods were visualized with Bland Altman plots. Reproducibilities were analyzed using covariance analysis. Neither measurements of Vc 100 x 900, Vc 300 x 1100, nor Vc Gd differed markedly from Vc STEREOLOGY using semiautomatic segmentation. Vc was comparable when semiautomatic and manual segmentations were performed at the same scan. Reproducibility of MRI estimated Vc values offered intra- and interindividual differences <5%. Vc can in both healthy and diseased kidneys be measured accurately with MRI using both semiautomatic and manual segmentation, and measurements can be obtained with a high reproducibility. Measurements of Vc 100 x 900 may in the future become suitable in patients with chronic renal failure.


Functional outcomes and quality of life after surgically treated tibial plateau fractures.
Tibial plateau fractures (TPF) are uncommon and challenging for orthopedic surgeons with controversial reported outcomes. In this study, we aimed to evaluate the functional outcomes and quality of life (QOL) of patients with surgically treated TPF. A total of 80 consecutive patients and 82 controls participated in this case control study. The patients were all surgically treated in our tertiary center from April 2012 to April 2020. The functional outcome was evaluated using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scale. Moreover, we used the Short Form 36 health survey (SF-36) health survey to evaluate the QOL. No significant difference was observed in the overall mean SF-36 score in the two groups. We found a significant positive correlation between the scores of the SF-36 and WOMAC questionnaires (r = 0.642, p < 0.001) and between the ROM and the WOMAC questionnaire score (r = 0.478, p < 0.001). Further, ROM and SF-36 showed a weak positive correlation (r = 0.248, p = 0.026). Age had a weak negative correlation with the pain subscale of SF-36 (r = - 0.255, p = 0.22), even though it was not correlated with the total score or other subscales (p > 0.05). QoL after TPF is not significantly different from that of a matched control group. Also, neither age nor BMI correlates with the QoL and functional outcome.


[Phototoxic drugs and age-related maculopathy].
To disclose a correlation between age-related macular degeneration (AMD) and long-lasting treatments with potentially phototoxic drugs. Case-control study. The case group was made up of 90 randomized patients, 65 years old or older, with documented AMD, examined in 1998 and 1999. The M/F sex ratio was 0.54, and mean age 79.9 years. The control group was randomized with age- and sex-matched subjects. In both groups, we noted long-lasting oral treatment for hypertension, diabetes mellitus, epilepsy, hyperuricemia, and psychiatric pathologies. All the study group patients underwent a complete ophthalmological examination for visual acuity, contrast sensitivity, biomicroscopy, fundus color and red-free photographs, fluorescein and ICG angiographies. When the study group was compared with the control group, neovascular AMD was positively associated with thiazide diuretics (p<0.001). When the study group was analyzed alone, intake of one or several antihypertensive drugs was positively associated with occult neovascularization and mild to moderate visual loss (p=0.009). Only thiazide diuretic intake was positively associated with severe bilateral loss of vision (p=0.041) and extensive choroidal neovascularization with major subretinal hemorrhages (p=0.022). These findings suggest that severe neovascular AMD is associated with long-term thiazide diuretic treatment.


Effects of photobiomodulation therapy and topical non-steroidal anti-inflammatory drug on skeletal muscle injury induced by contusion in rats-part 1: morphological and functional aspects.
Musculoskeletal injuries are very frequent and are responsible for causing pain and impairment of muscle function, as well as significant functional limitations. In the acute phase, the most prescribed treatment is with non-steroidal anti-inflammatory drugs (NSAIDs), despite their questionable effectiveness. However, the use of photobiomodulation therapy (PBMT) in musculoskeletal disorders has been increasing in the last few years, and this therapy appears to be an interesting alternative to the traditional drugs. The objective of the present study was to evaluate and compare the effects of PBMT, with different application doses, and topical NSAIDs, under morphological and functional parameters, during an acute inflammatory process triggered by a controlled model of musculoskeletal injury induced via contusion in rats. Muscle injury was induced by means of a single trauma to the animals' anterior tibialis muscle. After 1 h, the rats were treated with PBMT (830 nm; continuous mode, with a power output of 100 mW; 3.57 W/cm2; 1 J-35.7 J/cm2, 3 J-107.1 J/cm2, and 9 J-321.4 J/cm2; 10, 30, and 90 s) or diclofenac sodium for topical use (1 g). Morphological analysis (histology) and functional analysis (muscle work) were performed, 6, 12, and 24 h after induction of the injury. PBMT, with all doses tested, improved morphological changes caused by trauma; however, the 9 J (321.4 J/cm2) dose was the most effective in organizing muscle fibers and cell nuclei. On the other hand, the use of diclofenac sodium produced only a slight improvement in morphological changes. Moreover, we observed a statistically significant increase of muscle work in the PBMT 3 J (107.1 J/cm2) group in relation to the injury group and the diclofenac group (p < 0.05). The results of the present study indicate that PBMT, with a dose of 3 J (107.1 J/cm2), is more effective than the other doses of PBMT tested and NSAIDs for topical use as a means to improve morphological and functional alterations due to muscle injury from contusion.


Psychosocial presentation of female bariatric surgery patients after multiple revisional surgeries: A qualitative study.
Bariatric surgery is currently the most viable and cost-effective treatment for obesity. This study aimed to understand, from a female patient's perspective, what contributed to not achieving or maintaining excess weight loss from a primary laparoscopic adjustable gastric band surgery, leading to subsequent multiple revisional bariatric surgeries. The purposive sample of participants ( N = 17 females) were over 18 years, had a primary failed laparoscopic adjustable gastric band and had more than three revisional procedures. Participants were individually interviewed and data were analysed from a grounded theory methodology to build a causal model with the core category of unrealistic expectations of bariatric surgery and other important conceptual categories.


Regulation of atrial natriuretic peptide-stimulated cGMP production in the inner medulla.
Studies were performed to examine the regulation of atrial natriuretic peptide- (ANP) stimulated guanylate cyclase in the the inner medulla. Primary cultures of rat inner medullary collecting tubular cells exposed to 10(-7) M ANP increased cGMP formation to 31.2 +/- 1.8 compared to the basal production of 2.1 +/- 0.6 fm/micrograms protein. This response did not appear to be transduced via a Gi protein, as preincubation with pertussis toxin did not alter the response to 10(-7) M ANP, and saponized cells exposed to 10 microM GTP gamma S did not enhance the response to ANP (77.3 +/- 5.9 vs. 86.7 +/- 6.3 g/micrograms). Likewise, changes in extracellular Ca2+ from 0.5 to 3.0 mM, decrements in intracellular Ca2+ with EGTA or increments in intracellular Ca2+ with ionomycin (5 microM) did not significantly alter the response to ANP. Neither activation of protein kinase A with forskolin (36.5 +/- 5.1) nor of protein kinase C with s,n-1,2-dioctanoylglycerol (33.2 +/- 2.5) altered the response to 10(-7) M ANP (32.2 +/- 3.3, NS). As the inner medullary environment was hypertonic, the effect of altering tonicity was studied. Cells grown for 48 hours in hypertonic media (600 mOsm/kg H2O) displayed enhanced response to 10(-8) and 10(-7) M ANP when osmolality was raised by either Na+ alone or in combination with urea, but not by urea alone. Our studies demonstrate that ANP-stimulated guanylate cyclase is insensitive to alterations in either intra- or extracellular Ca2+, is not subject to inhibition by protein kinase, and does not involve a pertussis-sensitive G protein.(ABSTRACT TRUNCATED AT 250 WORDS)


Spontaneous growth and regulation of noble metal nanoparticles on flexible biomimetic MXene paper for bioelectronics.
Smart and green construction of noble metal nanostructures on two-dimensional nanomaterials-based flexible paper-like materials have gained extensive attention due to the formed hybrid papers have shown great promise in the applications of energy devices, sensing electronics, actuators, and chemical filters. Herein, a cost-effective and environment-friendly strategy to realize the spontaneous growth of noble metal nanoparticles (Au, Pd, and Pt) on flexible biomimetic MXene paper was proposed. The self-defined regulation of formed noble metal nanoparticles could be easily achieved, and the bimetallic (AuPt, PdPt) nanoparticles decorated MXene paper could be obtained at the mean time. These findings bring a simple, efficient and green way for constructing various hybrid MXene paper with outperforming electrocatalytic activities, which was demonstrated by the sensitive detection of superoxide (O2•-) and the good stability and reproducibility after a long-term usage. The outstanding analytical performance of the obtained AuPtNPs/MXene paper in O2•- monitoring leads to a satisfactory application in real-time extracellular biosensing. The investigation for spontaneous growth and regulation of noble metal nanoparticles on flexible biomimetic MXene paper exhibits a huge application potential for constructing high-performance flexible bioelectronics and energy-related devices.


Evaluating the impact of cash transfers on tuberculosis (ExaCT TB): a stepped wedge cluster randomised controlled trial.
Mitigating financial barriers to tuberculosis (TB) diagnosis and treatment is a core priority of the global TB agenda. We evaluated the impact of a cash transfer intervention on completion of TB testing and treatment initiation in Uganda. We conducted a pragmatic complete stepped wedge randomised trial of a one-time unconditional cash transfer at 10 health centres between September 2019 and March 2020. People referred for sputum-based TB testing were enrolled to receive UGX 20 000 (∼USD 5.39) upon sputum submission. The primary outcome was the number initiating treatment for micro-bacteriologically confirmed TB within 2 weeks of initial evaluation. The primary analysis included cluster-level intent-to-treat and per-protocol analyses using negative binomial regression. 4288 people were eligible. The number diagnosed with TB initiating treatment was higher in the intervention period versus the pre-intervention period (adjusted rate ratio (aRR)=1.34) with a 95% CI of 0.62-2.91 (p=0.46), indicating a wide range of plausible true intervention effects. More were referred for TB testing (aRR=2.60, 95% CI 1.86-3.62; p<0.001) and completed TB testing (aRR=3.22, 95% CI 1.37-7.60; p=0.007) per National Guidelines. Results were similar but attenuated in per-protocol analyses. Surveys revealed that while the cash transfer supported testing completion, it was insufficient to address long-term underlying social/economic barriers. While it is uncertain whether a single unconditional cash transfer increased the number of people diagnosed and treated for TB, it did support higher completion of diagnostic evaluation in a programmatic setting. A one-time cash transfer may offset some but not all of the social/economic barriers to improving TB diagnosis outcomes.


Wearable GPS and Accelerometer Technologies for Monitoring Mobility and Physical Activity in Neurodegenerative Disorders: A Systematic Review.
Neurodegenerative disorders (NDDs) constitute an increasing global burden and can significantly impair an individual's mobility, physical activity (PA), and independence. Remote monitoring has been difficult without relying on diaries/questionnaires which are more challenging for people with dementia to complete. Wearable global positioning system (GPS) sensors and accelerometers present a cost-effective and noninvasive way to passively monitor mobility and PA. In addition, changes in sensor-derived outcomes (such as walking behaviour, sedentary, and active activity) may serve as potential biomarkers of disease onset, progression, and response to treatment. We performed a systematic search across four databases to identify papers published within the past 5 years, in which wearable GPS or accelerometers were used to monitor mobility or PA in patients with common NDDs (Parkinson's disease, Alzheimer's disease, motor neuron diseases/amyotrophic lateral sclerosis, vascular parkinsonism, and vascular dementia). Disease and technology-specific vocabulary were searched singly, and then in combination, identifying 4985 papers. Following deduplication, we screened 3115 papers and retained 28 studies following a full text review. One study used wearable GPS and accelerometers, while 27 studies used solely accelerometers in NDDs. GPS-derived measures had been validated against current gold standard measures in one Parkinson's cohort, suggesting that the technology may be applicable to other NDDs. In contrast, accelerometers are widely utilised in NDDs and have been operationalised in well-designed clinical trials.


In-vivo dosimetry from total body irradiation patients (2000-2006): results and analysis.
In-vivo dosimetry is an important technique to ensure accuracy of delivered dose during total body irradiation (TBI). We present an analysis of semiconductor diode dosimetry, constituting seven years of dosimetry data from eighty-six patients who underwent total body irradiation. For lateral field irradiation, the mean exit dose, averaged over five anatomical sites (head, sternal notch, chest, abdomen and pelvis) and as a percentage of the planned dose was 95.7% (SD 7.8%). For AP/PA irradiation, the mean exit dose averaged over five anatomical sites and as a percentage of the planned dose was 95.5% (SD 9.8%). We propose a number of possible reasons for these differences, including patient setup variations, movement of the patient and diodes during treatment, imprecise placement of planned bolus material, inaccurate inhomogeneity corrections and modelling by the treatment planning system.


Modelling the transfer of 14C from the atmosphere to grass: a case study in a grass field near AREVA-NC La Hague.
Radioactive (14)C is formed as a by-product of nuclear power generation and from operation of nuclear fuel reprocessing plants like AREVA-NC La Hague (North France), which releases about 15 TBq per year of (14)C into the atmosphere. Since the autumn of 2006, (14)C activity concentrations in samples from the terrestrial environment (air, grass and soil) have been monitored monthly on grassland 2 km downwind of the reprocessing plant. The monitoring data provides an opportunity to validate radioecology models used to assess (14)C transfer to grassland ecosystems. This article compares and discusses the ability of two different models to reproduce the observed temporal variability in grass (14)C activity in the vicinity of AREVA-NC La Hague. These two models are the TOCATTA model which is specifically designed for modelling transfer of (14)C and tritium in the terrestrial environment, and PaSim, a pasture model for simulating grassland carbon and nitrogen cycling. Both TOCATTA and PaSim tend to under-estimate the magnitude of observed peaks in grass (14)C activity, although they reproduce the general trends. PaSim simulates (14)C activities in substrate and structural pools of the plant. We define a mean turn-over time for (14)C within the plant, which is based on both experimental data and the frequency of cuts. An adapted PaSim result is presented using the 15 and 20 day moving average results for the (14)C activity in the substrate pool, which shows a good match to the observations. This model reduces the Root Mean Square Error (RMSE) by nearly 40% in comparison to TOCATTA.


[The value of supracricoid partial laryngectomy in moderately advanced laryngeal cancer (T3-T4a)].
Transoral laser microsurgery (TLM) is the method of choice for partial laryngectomy in Germany. In advanced stages, chemoradiotherapy is increasingly indicated for organ preservation. This report considers the indications for and outcomes of supracricoid partial laryngectomy (SPL), also known as crico-hyoido-(epiglotto)-pexy, as an option for surgical organ preservation in moderately advanced laryngeal cancer (T3-T4a), in the well-defined gap between TLM and chemoradiotherapy protocols in Germany. Retrospective evaluation of functional and oncological outcomes of all SPLs conducted between 2008 and 2014. During this period, 17 SPLs with resection of rpT2 (n = 2), (r)pT3 (n = 11), and (r)pT4a (n = 4) were performed with resection of one arytenoid. Mean age was 58 years (range 47-75 years). In 5 patients, SPL was for a first or second local recurrence after TLM or open partial laryngectomy. Adjuvant radiotherapy was received by 7 patients staged pT4a or pN+. Salvage laryngectomy with adjuvant radiotherapy was required by 2 patients. The remaining patients (n = 15) had a mean tumor-free follow-up of 4 years with a functional intact larynx: these patients can eat and drink, have a closed tracheotomy, and a good voice. After 3 years tumor-free follow-up with a functional intact larynx, 2 patients died due to cardiac comorbidity at the age of 76 years. SPL is a rare but valuable option for surgical larynx preservation in stage pT3-4a laryngeal cancer.


Remediation effect of mercapto-palygorskite combined with manganese sulfate on cadmium contaminated alkaline soil and cadmium accumulation in pak choi (Brassica chinensis L.).
Cadmium pollution in alkaline soil in some areas of northern China seriously threatens agricultural production and human health, but there are few materials and methods to remediate cadmium pollution in alkaline soil. Therefore, it is necessary to further study the economic and adaptive remediation and regulation techniques of cadmium pollution in alkaline soil. In the study, a pot experiment was conducted to study the effects of MP and MnSO4 combined treatment on the immobilization effect of cadmium contaminated alkaline soils. The results showed that LM and HM treatments in different periods had little effect on the content of extractable Cd fraction in soil without MP treatment, but the EXC-Cd content in the soil with Mn(15) was lower than that in the soil with Mn(29). The EXC-Cd content under MP+ LM and MP + HM treatments reduced by 3%-7% and 7%-9%, respectively. The OX-Cd content increased by 13%-16% after MP + Mn treatment. The content of DTPA-Cd decreased by 17.9%-28.6% under MP + Mn treatment except for MP + HM(15). Under the treatment of MP, LM(29), HM, MP + LM and MP + HM, the content of Cd in shoots of pak choi were decreased by 27.2%, 13.1%, 19.8%-27.9%, 28.5%-54.2% and 34.2%-41.1%, respectively. Compared with CK, the TFCd values in HM(15), LM(29), HM(29), MP + LM(29) and MP + HM(29) treatments were reduced to 35.7%, 41.1%, 35.7%, 42.9% and 37.5%, respectively, while no statistical difference was observed in other treatments. There was no significant difference in BCFCd between MP(15) and LM(15), but the BCFCd was significantly decreased. For MP + MnSO4 treatment group, the content of Mn oxides in soil was negatively correlated with the content of EXC-Cd (P < 0.05) and positively correlated with the content of OX-Cd (P < 0.05).


Amido-Bridged Nucleic Acid-Modified Antisense Oligonucleotides Targeting SYT13 to Treat Peritoneal Metastasis of Gastric Cancer.
Patients with peritoneal metastasis of gastric cancer have dismal prognosis, mainly because of inefficient systemic delivery of drugs to peritoneal tumors. We aimed to develop an intraperitoneal treatment strategy using amido-bridged nucleic acid (AmNA)-modified antisense oligonucleotides (ASOs) targeting synaptotagmin XIII (SYT13) and to identify the function of SYT13 in gastric cancer cells. We screened 71 candidate oligonucleotide sequences according to SYT13-knockdown efficacy, in vitro activity, and off-target effects. We evaluated the effects of SYT13 knockdown on cellular functions and signaling pathways, as well as the effects of intraperitoneal administration to mice of AmNA-modified anti-SYT13 ASOs. We selected the ASOs (designated hSYT13-4378 and hSYT13-4733) with the highest knockdown efficiencies and lowest off-target effects and determined their abilities to inhibit cellular functions associated with the metastatic potential of gastric cancer cells. We found that SYT13 interfered with focal adhesion kinase (FAK)-mediated intracellular signals. Intraperitoneal administration of hSYT13-4378 and hSYT13-4733 in a mouse xenograft model of metastasis inhibited the formation of peritoneal nodules and significantly increased survival. Reversible, dose- and sequence-dependent liver damage was induced by ASO treatment without causing abnormal morphological and histological changes in the brain. Intra-abdominal administration of AmNA-modified anti-SYT13 ASOs represents a promising strategy for treating peritoneal metastasis of gastric cancer.


Ultrasonic tissue characterization for patients with Chagas' disease.
This study was undertaken to test the hypothesis that ultrasonic tissue characterization, as evaluated by intensity and cardiac cyclic variation of integrated backscatter (IBS), could identify early myocardial involvement in Chagas' disease. We evaluated 69 participants, age 15 to 73 years (mean +/- SD: 49 +/- 12 years), who were divided as following: 19 control subjects; 13 patients with the indeterminate form of Chagas' disease; 7 patients with the digestive form; and 30 patients with the cardiac form. IBS images were obtained in parasternal short-axis (basal, papillary muscle, apical) view and analyzed in 12 left ventricular (LV) segments (anterior, lateral, posterior, and septal). The following IBS variables were evaluated: (1) the corrected coefficient (CC) of IBS, obtained by dividing IBS intensity, in each cardiac segment, by IBS intensity measured in a rubber phantom using the same equipment adjustments at the same depth; and (2) magnitude of cardiac cyclic variation (MCV) of IBS, as measured by the peak-to-peak difference between maximal and minimal values of IBS in cardiac cycle. The CC of IBS was increased (P <.05) for patients with the cardiac form who had LV segments with normal wall motion as compared with control subjects, in 4 of 12 segments evaluated (basal anterior, midposterior and midseptal, anterior apical), whereas the remaining chagasic groups were comparable with controls subjects. The CC of IBS tended to increase with worsening of LV segmental wall motion. MCV showed a large individual variability and had a large mean value (P <.05) in just 1 of 12 segments evaluated, when patients with the cardiac form were compared with control subjects. No correlation was observed between the magnitude of LV dysfunction and MCV of IBS. (1) the CC of IBS was able to provide early differentiation of cardiac involvement for patients with Chagas' disease who had LV segments with normal wall motion; (2) increase of CC of IBS with worsening of LV segmental wall motion suggests a relationship between the acoustic properties of myocardial tissue and grading of myocardial fibrosis; (3) MCV was not able to differentiate patients with Chagas' disease from control subjects; and (4) patients with the indeterminate form of Chagas' disease were not differentiated from control subjects by any of the IBS techniques evaluated in this study.


The use of silver nitrate-incorporated amniotic membrane as a temporary dressing.
Human amniotic membrane is one of the most effective biological dressings used in burn treatment. Since 1978, we have been using human amniotic membrane incorporating 0.5 per cent silver nitrate. Studies in 96 patients using this method showed that the silver-incorporated membranes gave a better therapeutic effect than plain amniotic membranes. It was noted that 0.5 per cent silver nitrate incorporated into the membranes increased their manageability, provided easier application to the burned area and created a bactericidal effect, therefore reducing the risk of contamination and infection. One of the main advantages of wound coverage with amniotic membrane is that it does not appear to discourage re-epithelization, reduces fluid, protein, heat and energy loss, increases mobility and most important this may be the ideal wound cover next to the patient's own skin. Therefore, we highly recommend the use of 0.5 per cent silver nitrate-incorporated amniotic membrane, since it is readily available and freely obtainable, has low preparation and storage costs that make it an ideal dressing to use, especially in countries where economic factors prevent the purchase of other types of dressings.


The chemical composition and membrane stability activity of some herbs used in local therapy for anemia.
The chemical composition and the membrane stabilizing activity of the decoctions of the dry Hibiscus sabdariffa Linn. (Malvaceae) calyx (Sobo in a Nigerian language), Theobroma cacao Linn. (N.O. Sterculiaceae) root (cocoa) and the dry stalk of white and red cultivars of Sorghum bicolor (L.) Moench (Poaceae) were determined. These herbs are often used locally for the management of anemia. Ash content was from 3.5 to 7.2%, tannin 7-46 mg/kg catechin equivalent, ascorbic acid content 250-625 mg/kg and total anthocyanin 57-150 mg/kg cyanidin-3-glucoside equivalent. Phytate was not detected in any sample but alkaloids and saponins were present except in Sobo. The decoctions contained 0.2-2.0% of the herbs' total tannin content while the pH was 3.2-6.7. Iron and zinc content was highest in Sobo while Theobroma cacao root contained the highest calcium and magnesium. Solubility and mineral availability were highest in the decoction of Sobo and lowest but available in Theobroma cacao root decoction. The decoction of Theobroma cacao exhibited a high membrane stabilizing activity while those of Sorghum bicolor and Hibiscus sabdariffa were only average. The study indicated that the herbal decoctions could provide some minerals and also help to stabilize the red blood cells from stress injury.


Relative importance of climate changes at different time scales on net primary productivity-a case study of the Karst area of northwest Guangxi, China.
Climate changes are considered to significantly impact net primary productivity (NPP). However, there are few studies on how climate changes at multiple time scales impact NPP. With MODIS NPP product and station-based observations of sunshine duration, annual average temperature and annual precipitation, impacts of climate changes at different time scales on annual NPP, have been studied with EEMD (ensemble empirical mode decomposition) method in the Karst area of northwest Guangxi, China, during 2000-2013. Moreover, with partial least squares regression (PLSR) model, the relative importance of climatic variables for annual NPP has been explored. The results show that (1) only at quasi 3-year time scale do sunshine duration and temperature have significantly positive relations with NPP. (2) Annual precipitation has no significant relation to NPP by direct comparison, but significantly positive relation at 5-year time scale, which is because 5-year time scale is not the dominant scale of precipitation; (3) the changes of NPP may be dominated by inter-annual variabilities. (4) Multiple time scales analysis will greatly improve the performance of PLSR model for estimating NPP. The variable importance in projection (VIP) scores of sunshine duration and temperature at quasi 3-year time scale, and precipitation at quasi 5-year time scale are greater than 0.8, indicating important for NPP during 2000-2013. However, sunshine duration and temperature at quasi 3-year time scale are much more important. Our results underscore the importance of multiple time scales analysis for revealing the relations of NPP to changing climate.


Protein kinase C delta stimulates apoptosis by initiating G1 phase cell cycle progression and S phase arrest.
Overexpression of protein kinase C delta (PKCdelta) stimulates apoptosis in a wide variety of cell types through a mechanism that is incompletely understood. PKCdelta-deficient cells are impaired in their response to DNA damage-induced apoptosis, suggesting that PKCdelta is required to mount an appropriate apoptotic response under conditions of stress. The mechanism through which it does so remains elusive. In addition to effects on cell survival, PKCdelta elicits pleiotropic effects on cellular proliferation. We now provide the first evidence that the ability of PKCdelta to stimulate apoptosis is intimately linked to its ability to stimulate G(1) phase cell cycle progression. Using an adenoviral-based expression system to express PKCalpha,-delta, and -epsilon in epithelial cells, we demonstrate that a modest increase in PKCdelta activity selectively stimulates quiescent cells to initiate G(1) phase cell cycle progression. Rather than completing the cell cycle, PKCdelta-infected cells arrest in S phase, an event that triggers caspase-dependent apoptotic cell death. Apoptosis was preceded by the activation of cell cycle checkpoints, culminating in the phosphorylation of Chk-1 and p53. Strikingly, blockade of S phase entry using the phosphatidylinositol 3-kinase inhibitor LY294002 prevented checkpoint activation and apoptosis. In contrast, inhibitors of mitogen-activated protein kinase cascades failed to prevent apoptosis. These findings demonstrate that the biological effects of PKCdelta can be extended to include positive regulation of G(1) phase cell cycle progression. Importantly, they reveal the existence of a novel, cell cycle-dependent mechanism through which PKCdelta stimulates cell death.


Ideal crop plant architecture is mediated by tassels replace upper ears1, a BTB/POZ ankyrin repeat gene directly targeted by TEOSINTE BRANCHED1.
Axillary branch suppression is a favorable trait bred into many domesticated crop plants including maize compared with its highly branched wild ancestor teosinte. Branch suppression in maize was achieved through selection of a gain of function allele of the teosinte branched1 (tb1) transcription factor that acts as a repressor of axillary bud growth. Previous work indicated that other loci may function epistatically with tb1 and may be responsible for some of its phenotypic effects. Here, we show that tb1 mediates axillary branch suppression through direct activation of the tassels replace upper ears1 (tru1) gene that encodes an ankyrin repeat domain protein containing a BTB/POZ motif necessary for protein-protein interactions. The expression of TRU1 and TB1 overlap in axillary buds, and TB1 binds to two locations in the tru1 gene as shown by chromatin immunoprecipitation and gel shifts. In addition, nucleotide diversity surveys indicate that tru1, like tb1, was a target of selection. In modern maize, TRU1 is highly expressed in the leaf trace vasculature of axillary internodes, while in teosinte, this expression is highly reduced or absent. This increase in TRU1 expression levels in modern maize is supported by comparisons of relative protein levels with teosinte as well as by quantitative measurements of mRNA levels. Hence, a major innovation in creating ideal maize plant architecture originated from ectopic overexpression of tru1 in axillary branches, a critical step in mediating the effects of domestication by tb1.


Endocrine and inflammatory markers as predictors of frailty.
To examine the association of serum concentrations of 25-hydroxyvitamin D [25(OH)D], interleukin-6 (IL-6), C-reactive protein (CRP) and IGF-1 with prevalent and incident frailty. The Longitudinal Aging Study Amsterdam (LASA), a prospective cohort study with 3-yearly measurement cycles. Setting General population-based sample. The respondents were men and women aged 65 and over, who participated at T1 (1995/1996, N = 1720) and T2 (1998/1999, N = 1509). Blood samples were obtained at T1 (N = 1271). Measurements The presence of frailty at T1 and 3-year incidence of frailty. Frailty is defined as the presence of three out of nine frailty indicators. At T1, 242 (19.0%) of all respondents were frail. Those who were frail at T1 had higher CRP and lower 25(OH)D levels. Serum 25(OH)D remained associated with frailty after adjustment for potential confounders with an odd ratios (OR) of 2.60 [95% confidence interval (95% CI) 1.60-4.21] for 25(OH)D < 25 nmol/l and 1.72 (95% CI 1.19-2.47) for 25(OH)D 25-50 nmol/l vs. high levels of 25(OH)D. Of the nonfrail at T1, 125 respondents (14.1%) became frail at T2. After adjustment, moderately elevated CRP levels (3-10 microg/ml) (OR 1.69, 95% CI 1.09-2.63) and low 25(OH)D (OR 2.04, 95% CI 1.01-4.13) were associated with incident frailty. No consistent associations were observed for IL-6 and IGF-1. Low 25(OH)D levels were strongly associated with prevalent and incident frailty; moderately elevated levels of CRP were associated with incident frailty.


Cardioprotection with ICRF-187 (Cardioxane) in patients with advanced breast cancer having cardiac risk factors for doxorubicin cardiotoxicity, treated with the FDC regimen.
A study of cardioprotection with ICRF-187 (Cardioxane, Eurocetus) has been performed in 35 patients with metastatic breast cancer treated with the FDC regimen (5-fluorouracil 500 mg/m2 i.v., day 1; doxorubicin 50 mg/m2 i.v., day 1; cyclophosphamide 500 mg/m2 i.v., day 1). All patients had one or more cardiac risk factors for doxorubicin cardiotoxicity including 24 who had previously received left-chest-wall irradiation. Cardioxane was applied at a dosage of 1000 mg/m2 as a 15-min infusion in Ringer lactate solution 30 min before doxorubicin administration. Cardiological monitoring included left-ventricular ejection fraction (LVEF) determination by echocardiography before treatment and before each cycle following the cumulative doxorubicin dose of 200 mg/m2. Of the 35 patients, 34 were evaluable fore response, and the overall response rate was 19/34 (56%) with 3/34 complete responses and 16/34 partial responses. Statistical analysis of LVEF values in relation to increasing cumulative doxorubicin doses with Wilcoxon's test of equivalent pairs and Friedman's test has demonstrated that no cardiotoxicity was detected up to a cumulative doxorubicin dose of between 800 mg/m2 and 1000 mg/m2, except for 2 patients in whom a decrease of 20% in relation to the LVEF pretreatment level was demonstrated following a cumulative drug dose of 250 mg/m2. Thus Cardioxane provides an effective cardioprotection even in breast cancer patients with cardiac risk factors for doxorubicin cardiotoxicity treated with the FDC regimen.


In vitro cytotoxicity of paclitaxel/beta-cyclodextrin complexes for HIPEC.
Hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising strategy in the treatment of peritoneal carcinomatosis. To perform HIPEC, a tensioactive- and solvent-free paclitaxel formulation consisting of water-soluble paclitaxel/randomly methylated-beta-cyclodextrin (Pac/RAMEB) complexes was developed previously. Using MTT and SRB assays the cytotoxic activity of this formulation versus Taxol, was evaluated as well as the cytotoxicity of the different formulation excipients (RAMEB and Cremophor EL. The possible synergistic effect of heat and paclitaxel-based chemotherapy during HIPEC was also evaluated in vitro. The cytotoxicity assays revealed differences in viability between Cremophor EL and RAMEB treated cells of 40 and 50% for the CaCo-2 human and the CC531s rat colon cancer line, respectively, in favour of RAMEB. Despite the higher cytotoxicity of Cremophor EL, Pac/RAMEB complexes and Taxol were equipotent. Using the MTT and SRB assays the average difference in viability between both cell lines was below 10% and IC50 values showed no significant difference. Hyperthermia after drug administration (41 degrees C during 1h) had no effect on cell viability. These results indicated that it was possible to reformulate paclitaxel with a less cytotoxic vehicle while maintaining the cytotoxic activity of the formulation and that there is no synergism between paclitaxel and heat for in vitro cytotoxicity.


Complementary base-pairing properties of cyclized and linear oligonucleotides.
Oligouridylates of varying chain lengths were synthesized by polynucleotide phosphorylase and cyclized by RNA ligase. Over chain lengths from 7 to 15, the bindings of the cyclized and linear oligomers to polyadenylate were measured on the basis of differential migration of bound and free oligomers on a gel exclusion column. Binding of the cyclized oligomers was found to be far weaker than that of their linear counterparts of equal length. Such a general reduction in base-pairing capacity due to the cyclized conformation, by limiting the strength of unintended base-pairing without obstructing the possible development of strong specific base-pairing, may represent an advantage important to the function and evolution of loop structures in tRNA and other RNA molecules.


Oxidative and reductive transformations of epothilone A.
The C7 hydroxy group of cytotoxic epothilone A was selectively oxidized using PDC. A selective oxidation of the C3 hydroxy group was accomplished with Me2S/(PhCO2)2 after in situ protection of C7-OH. Reduction of epothilone A or of a C5, C7 dioxo derivative with NaBH4 proceeded at the C5 carbonyl group. Oxidation and hydrogenation of the C16-C17 double bond proved to be difficult but it was easily cleaved with ozone and the resulting keto derivative was transformed to epothilone analogs with different side chains.


Macrophage migration inhibitory factor contributes to the development of acute dextran sulphate sodium-induced colitis in Toll-like receptor 4 knockout mice.
Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharides, plays an important role in the innate immune response. In this study, we investigated the role of TLR4 in the development of experimental colitis with regard to the biological actions of macrophage migration inhibitory factor (MIF) using TLR4 null ((-/-)) mice. TLR4(-/-) mice were given 2% dextran sulphate sodium (DSS) in drinking water to induce colitis, which was clinically and histologically as severe as that seen in wild-type (WT) mice. The level of tumour necrosis factor (TNF)-alpha in colon tissues was increased in WT mice but unchanged in TLR4(-/-) mice. The level of myeloperoxidase (MPO) activity in colon tissues was increased by DSS administration in both TLR4(-/-) and WT mice. The expression of MIF was up-regulated in the colons of TLR4(-/-) mice with acute DSS-induced colitis. An anti-MIF antibody significantly suppressed colitis and elevation of matrix metalloproteinase-13 in TLR4(-/-) mice. The current results obtained from TLR4(-/-) mice provide evidence that MIF plays a critical role in the development of acute DSS-induced colitis.


Theoretical design and implementation of a transcutaneous, multichannel stimulator for neural prosthesis applications.
The development of a transcutaneous, implantable, multichannel neural stimulator is described. This was originally dedicated to the stimulation of the auditory nerve in profoundly deaf persons, but is sufficiently flexible in design and operation to be applicable to other areas of neural prosthetics. Control of both the amplitude and time of stimulation for up to fifteen independent channels is possible with a maximum stimulation rate of 1 kHz. Particular attention is given to the design of the transcutaneous link stage which allows both power and data to be transferred to the implanted device using a compact coupling inductor configuration. All circuit timing is derived from a single clock in the external transmitter unit, resulting in stable operation with predictable stimulus output characteristics. The implantable device, realised using thick film hybrid techniques, employs CMOS logic extensively to reduce power consumption. One such device has been implanted in a profoundly deaf volunteer for a period exceeding two years and has continued to operate reliably in conjunction with the complete prosthesis system.


Brain infecting kudoids of Australia's coral reefs, including a description of Kudoa lemniscati n. sp. (Myxosporea: Kudoidae) from Lutjanus lemniscatus (Perciformes: Lutjanidae) off Ningaloo Reef, Western Australia.
A survey of the myxosporean fauna of Australian marine fishes revealed the presence of a number of putative species of Kudoidae (Multivalvulida) forming pseudocysts between the outer meningeal layer and the outer surface of the brains of the lutjanids Caesio cuning, Lutjanus carponotatus, Lutjanus ehrenbergii and Lutjanus fulviflamma and the mugilid Liza vaigiensis from Lizard Island on the Great Barrier Reef, Australia and Lutjanus lemniscatus off Ningaloo Reef, Western Australia. Morphometric data combined with Bayesian inference and maximum likelihood analyses of small subunit (SSU) and large subunit (LSU) ribosomal DNA (rDNA) was used for species identification and to explore relationships among these taxa. The brain-infecting taxa examined here formed a well-supported clade to the exclusion of non-brain infecting species in the phylogenetic analyses. The combined diagnostic approach identified an undescribed taxon, Kudoa lemniscati n. sp., from the brain of L. lemniscatus (Perciformes: Lutjanidae) off Ningaloo Reef, Western Australia, which we describe and characterise here. K. lemniscati n. sp. can be distinguished from all other species of Kudoa based on the combination of the distinct tropism for forming pseudocysts in the brain tissue, spores with 7 or 8 equal shell valves and 7 or 8 polar capsules, spore size and the differences in the SSU and LSU rDNA sequence data relative to other kudoids. Kudoa chaetodoni was found in the lutjanids C. cuning and L. carponotatus, expanding the known host range for this species to include chaetodontids and lutjanids. L. ehrenbergii and L. fulviflamma were infected with Kudoa lethrini off Lizard Island, a parasite previously known only from lethrinids. Specimens putatively identified as Kudoa yasunagai from Liza vaigiensis and Lutjanus ehrenbergii were morphologically similar and genetically identical over the SSU rDNA dataset to previously reported specimens, but differed by 4 to 11 nucleotides over the LSU dataset from the remaining isolates examined here. While these data are not definitive, they suggest the presence of a K. yasunagai complex.


Retrospective analysis of secondary enucleation for uveal melanoma after plaque radiotherapy.
Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Plaque brachytherapy (PRT) is widely accepted as an effective globe-conserving treatment modality for UM. However, local treatment failure and complications lead to the enucleation of irradiated eyes. We conducted this study to explore the causes and long-term prognosis for UM patients who accepted secondary enucleation after plaque radiotherapy. This was a retrospective cohort study. Data of patients who underwent secondary enucleation for UM after plaque radiotherapy, from July 2007 to July 2019, at Beijing Tongren Hospital were analyzed. Kaplan-Meier analysis was performed to assess the probability of indications, metastasis, and metastasis-related death. Cox regression analysis was used to analyze associations of the prognostic factors. Eight hundred and eighty patients were clinically diagnosed with uveal melanoma and initially treated by iodine-125 plaque radiotherapy, 132 of whom underwent secondary enucleation and pathological examination in the same hospital. Fifty-two (39.4%) eyes were enucleated simply because of uncontrollable neovascular glaucoma (NVG). Forty-four (33.3%) patients suffered from tumor recurrence. Tumor non-response occurred in 18 (13.6%) cases. Ten (7.6%) eyes received enucleation entirely due to other types of glaucoma. Failure to preserve the eyes for other reasons occurred in eight (6.1%) patients. At a median follow-up of 58.1 [IQR: 40.9-90.5] months, the systemic spread was detected in 45 (34.1%) patients, and 38 of them died. On multivariate analysis, tumor largest basal diameter (HR 1.15 [95% CI: 1.01, 1.31]), tumor non-response (HR 7.22 [95% CI: 2.63, 19.82]), and recurrence (HR 3.29 [95% CI: 1.54, 7.07]) were risk factors for metastasis. Increased age (HR 1.54 [95% CI: 1.07, 2.23]), tumor non-response (HR 7.91 [95% CI: 2.79, 22.48]), and recurrence (HR 3.08 [95% CI: 1.13, 7.23]) were risk factors for metastasis-related death. NVG was the major reason for secondary enucleation for Chinese UM patients after PRT. Tumor non-response and recurrence were associated with a significantly higher risk of long-term metastasis and metastasis-related death.


Focus on women: linking HIV care and treatment with reproductive health services in the MTCT-Plus Initiative.
Despite important advances in expanding access to antiretroviral therapy in the countries most heavily affected by HIV/AIDS, there has been little consideration of the connections between HIV prevention, care and treatment programmes and reproductive health services. In this paper, we explore the integration of reproductive health services into HIV care and treatment programmes. We review the design and progress of the MTCT-Plus Initiative, which provides HIV care and treatment services to HIV positive women as well as their HIV positive children and partners. By emphasising the long-term follow-up of families and the provision of comprehensive care across the spectrum of HIV disease, MTCT-Plus highlights the potential synergies in linking reproductive health services to HIV care and treatment programmes. While HIV care and treatment programmes in resource-limited settings may not be able to integrate all reproductive health services into a single service delivery model, there is a clear need to include basic reproductive health services, such as access to appropriate contraception and counselling and management of unplanned pregnancies. The integration of these services would be facilitated by greater insight into the reproductive choices of HIV positive women and men, and into how health care providers influence access to reproductive health services of people with HIV and AIDS.


A Functional Polymorphism rs145204276 in the Promoter of Long Noncoding RNA GAS5 Is Associated with an Increased Risk of Ischemic Stroke.
Long noncoding RNAs (lncRNAs) play crucial roles in the regulation of pathological process of ischemic stroke (IS) via affecting cell apoptosis, inflammation, cell death, and angiogenesis. LncRNA growth arrest-specific 5 (GAS5) was observed to be up-regulated in IS, acting as a competing endogenous RNA for miR-137 to mediate the Notch1 signaling pathway. In this study, we aimed to whether an insertion/deletion polymorphism (rs145204276) in the promoter of GAS5 was related to the risk of IS. The rs145204276 was genotyped using polymerase chain reaction (PCR)-polyacrylamide gel electrophoresis in 509 patients with IS and 668 healthy controls with frequencies matched to cases regarding age, gender, living area, and ethnicity. The GAS5 expression levels were determined using qPCR and relative luciferase activity was measured using the Dual Luciferase assay system. The presence of del/del genotype and del allele was associated with an increased risk of IS [del/del versus ins/ins: adjusted odds ratio (OR) = 2.06, 95% confidence interval (CI): 1.37-3.11; recessive model: adjusted OR = 2.07, 95% CI: 1.41-3.04; del versus ins: adjusted OR = 1.31, 95% CI: 1.08-1.57]. Results from logistic regression analysis identified risk factors for IS, including hypertension, total cholesterol, triglyceride, low-density lipoprotein cholesterol, and rs145204276 del/del genotype. Furthermore, patients carrying rs145204276 del/del genotype had significantly higher levels of GAS5 and cells transfected with rs145204276 del allele exhibited a larger increase in luciferase activity. These findings indicate that rs145204276 del allele exhibited a significant association with an increased IS susceptibility by elevating the transcriptional activity and subsequently enhancing the expression of lncRNA GAS5.


Biomechanical comparison of different prosthetic reconstructions in total en bloc spondylectomy: a finite element study.
To analyse and compare the biomechanical differences between 3D-printed prostheses, titanium mesh cages and poorly matched titanium mesh cages in total en bloc spondylectomy (TES). The finite element model of T10-L2 for healthy adults was modified to make three models after T12 total spondylectomy. These models were a 3D-printed prosthesis, titanium mesh cage and prosthesis-endplate mismatched titanium mesh cage for reconstruction. The range of motion (ROM), stress distribution of the endplate and internal fixation system of three models in flexion and extension, lateral bending and axial rotation were simulated and analysed by ABAQUS. In flexion, due to the support of the anterior prosthesis, the fixation system showed the maximum fixation strength. The fixation strength of the 3D-printed prosthesis model was 26.73 N·m /°, that of the TMC support model was 27.20 N·m /°, and that of the poorly matched TMC model was 24.16 N·m /°. In flexion, the L1 upper endplate stress of the poorly matched TMC model was 35.5% and 49.6% higher than that of the TMC and 3D-printed prosthesis, respectively. It was 17% and 28.1% higher in extension, 39.3% and 42.5% higher in lateral bending, and 82.9% and 91.2% higher in axial rotation, respectively. The lower endplate of T11 showed a similar trend, but the magnitude of the stress change was reduced. In the stress analysis of the 3D-printed prosthesis and TMC, it was found that the maximum stress was in flexion and axial rotation, followed by left and right bending, and the least stress was in extension. However, the mismatched TMC withstood the maximum von Mises stress of 418.7 MPa (almost twice as much as the buckling state) in rotation, 3 times and 5.83 times in extension, and 1.29 and 2.85 times in lateral bending, respectively. Different prostheses with good endplate matching after total spondylectomy can obtain effective postoperative stable support, and the reduction in contact area caused by mismatch will affect the biomechanical properties and increase the probability of internal fixation failure.


Feasibility of Two High-Intensity Interval Training Protocols in Cancer Survivors.
High-intensity interval training (HIIT) is a time-efficient and promising tool for enhancing physical fitness. However, there is lack of research concerning safety and feasibility of HIIT in cancer survivors. Therefore, two different HIIT protocols were investigated in terms of safety, feasibility, and acute exercise responses. Forty cancer survivors (20 breast and 20 prostate cancer survivors, 62.9 ± 9.2 yr, BMI 27.4 ± 3.9 kg·m, 6 to 52 wk after the end of primary therapy) completed a maximal cardiopulmonary exercise test and two HIIT protocols on a cycle ergometer: 10 × 1 min at peak power output (10 × 1) and 4 × 4 min at 85%-95% peak HR (4 × 4). Safety (adverse events), acute physiological responses (HR, blood lactate concentration) and acute psychological responses (RPE, enjoyment) were recorded. No major but three minor adverse events occurred. Ninety-five percent of participants were able to complete each HIIT protocol. Estimated energy expenditure (159 ± 15 vs 223 ± 45 kcal, P < 0.001), HR (128 ± 20 vs 139 ± 18 bpm; P < 0.001), blood lactate concentration (5.4 ± 1.0 vs 5.9 ± 1.9 mmol·L; P = 0.035), and RPE legs/breathing (13.8 ± 2.0/13.1 ± 2.0 vs 14.6 ± 2.1/14.3 ± 2.0; P = 0.038/0.003) were significantly higher in the 4 × 4. Enjoyment did not differ between protocols (P = 0.301). The two HIIT protocols as single sessions appear safe and in the vast majority of breast and prostate cancer survivors after the end of primary therapy also feasible and enjoyable. The 4 × 4 elicited higher energy expenditure and higher cardio-circulatory and metabolic strain and might therefore be preferred if a high training stimulus is intended.


Risk of lung cancer following exposure to carbon black, titanium dioxide and talc: results from two case-control studies in Montreal.
The International Agency for Research on Cancer (IARC) recently evaluated the carcinogenicity of three poorly soluble weakly-toxic substances: carbon black, titanium dioxide and talc. Though there is evidence of carcinogenity in experimental animals for these substances, the evidence in humans is sparse and equivocal. In the context of two large population based case-control studies of lung cancer carried out in Montreal, we were able to study the possible relationships between the exposure to each of these substances and subsequent risk of lung cancer. We were able to distinguish talc used for industrial purposes from that used for cosmetic purposes. Interviews for Study I were conducted in 1979-1986 (857 cases, 533 population controls, 1,349 cancer controls) and interviews for Study II were conducted in 1996-2001 (1,236 cases and 1,512 controls). Detailed lifetime job histories were elicited, and a team of hygienists and chemists evaluated the evidence of exposure to a host of occupational substances. Lung cancer risk was analysed in relation to each exposure, adjusting for several potential confounders, including smoking. Subjects with occupational exposure to carbon black, titanium dioxide, industrial talc and cosmetic talc did not experience any detectable excess risk of lung cancer. The results are consistent with the recent evaluations of the IARC Monographs.


Edrophonium-induced inward membrane current in single neurons physically isolated from Aplysia californica.
The action of edrophonium on Aplysia neurons was studied using a concentration clamp technique which combines internal perfusion and a rapid drug application. Edrophonium elicited a dose-dependent inward current in the concentration range 10(-6) to 10(-4) M. At higher concentrations (10(-3) and 10(-2) M), the amplitude of the current often decreased and there was a rapid decay of the current. At these high concentrations, the current increased immediately after washing the neuron with normal solution. These results suggest that edrophonium blocks the ion channel which it opens. Removal of Na+ from the external solution greatly reduced the current amplitude by more than 90%. Removal of Ca2+ also reduced the amplitude of the response; however an increase of Ca2+ did not augment the response. These results suggest that Ca2+ does not carry the current, but is necessary for generation of an Na+-dependent inward current. Edrophonium, 10(-2) M, which completely blocked the current it induced within 20 s, did not significantly affect the voltage-dependent Na+ current. Tetrodotoxin, 1 x 10(-6) M, did not affect the edrophonium response. Hexamethonium, 1 x 10(-4) M, did not change the response elicited by edrophonium, while it significantly reduced the ACh response mediated by Na+. In some neurons edrophonium elicited an inward current, but ACh induced an outward current. Therefore the Na+ channels opened by edrophonium appear to be distinct from both the voltage-gated and ACh receptor-operated Na+ channels.


Extended experience benefits spatial mental model development with route but not survey descriptions.
Spatial descriptions symbolically represent environmental information through language and are written in two primary perspectives: survey, analogous to viewing a map, and route, analogous to navigation. Readers of survey or route descriptions form abstracted perspective flexible representations of the described environment, or spatial mental models. The present two experiments investigated the maintenance of perspective in spatial mental models as a function of description perspective and experience (operationalized through repetition), and as reflected in self-paced reading times. Experiment 1 involved studying survey and route descriptions either once or three times, then completing map drawing and true/false statement verification. Results demonstrated that spatial mental models are readily formed with survey descriptions, but require relatively more experience with route descriptions; further, some limited evidence suggests perspective dependence in spatial mental models, even following extended experience. Experiment 2 measured self-paced reading during three successive description presentations. Average reading times over the three presentations reduced more for survey relative to route descriptions, and there was no evidence for perspective specificity in resulting spatial mental models. This supports Experiment 1 findings demonstrating the relatively time-consuming nature of acquiring spatial mental models from route, but not survey descriptions. Results are discussed with regard to developmental, discourse processing, and spatial mental model theory.


Hybrid structured fiber-optic Fabry-Perot interferometer for simultaneous measurement of strain and temperature.
We fabricate and experimentally demonstrate a hybrid structured Fabry-Perot interferometer (FPI) embedded in the middle of a fiber line for simultaneous measurement of axial strain and temperature. The FPI is composed of a silica-cavity cascaded to a spheroidal air-cavity, both of which are formed in a hollow annular core fiber (HACF). The fabrication process of the FPI includes only a fusion splice between a single-mode fiber and a HACF and several electrical arc discharges at the HACF near the splice point. Experimental results show that the strain and temperature sensitivities of the air-cavity can be 5.2 pm/με and 1.3 pm/C°, respectively, and those of the silica-cavity can be 1.1 pm/με and 13 pm/C°, respectively. The different sensitivities of silica-cavity and air-cavity to strain and temperature enable us to implement simultaneous sensing in strain and temperature.


Novel 1,4,5,6-tetrahydrocyclopenta[d]imidazole-5-carboxamide-based JNK3 inhibitors: Design, synthesis, molecular docking, and therapeutic potential in neurodegenerative diseases.
JNK3 is a key factor driving the pathophysiology of neuronal apoptosis. Since demonstrating the therapeutic potential of JNK3 inhibitors in Alzheimer's disease, we aimed to broaden their chemical diversity for drug development. In continuation with our previous research, a series of compounds with the tetrahydrocyclopenta[d]imidazole scaffold as a core moiety was developed as JNK3 inhibitors based on in silico modeling analysis. The biochemical kinase assay results revealed that the JNK3 inhibitory effects and isoform selectivity of the compounds developed in this study were significantly higher than that of previously developed inhibitors. In particular, the IC50 values of compounds 18c, 19c, 22b, and 26c, which exhibited excelled isoform selectivity, against JNK3 were 0.716, 0.564, 0.379, and 0.779 nM, respectively, which were more potent than those of any known JNK3 inhibitors. Additionally, compounds 18c, 18c, 22b, and 22c effectively protected the neuronal cells against amyloid beta-induced apoptosis. Docking studies indicated that the tetrahydrocyclopenta[d]imidazole scaffold retained all the optimal interactions. Meanwhile, BBB PAMPA and ADME prediction suggested that the tested compounds had a favorable BBB permeability and pharmacokinetic profile. Therefore, the tetrahydrocyclopenta[d]imidazole scaffold is a promising candidate for developing JNK3 inhibitors. In particular, compound 22b is a potential starting point for the preclinical optimization of novel JNK3 inhibitors.