Alectinib for choroidal metastasis in a patient with crizotinib-resistant ALK rearranged positive non-small cell lung cancer.
Choroidal metastasis is rare in cancer patients. Small molecules of molecular targeted agents for lung cancer with actionable mutations were reported to be palliated for symptoms caused by choroidal metastasis. Visual disturbance by choroidal metastasis significantly decreases quality of life during the patient's remaining lifespan; therefore, radiotherapy or laser photocoagulation is proposed with consensus. However, improvement in survival with matched molecular targeted agents for oncogenic driver mutations reminds us to also be concerned with late treatment toxicities. A 30-year-old female patient previously treated with crizotinib harboring ALK rearranged non-small cell lung cancer complained of visual disturbance, fever, and bone pains undergoing anti-PD-1 antibody treatment. A decreased proportion of ALK fusion was demonstrated by fluorescence in situ hybridization in liver metastasis compared to the primary site in a chemo-naïve state. She was diagnosed with low vision, choroidal metastasis and retinal detachment. Therefore, she started alectinib treatment and both her ocular and systemic symptoms were palliated in a week. Later, she temporarily discontinued alectinib because of skin rash although the choroidal metastasis and retinal detachment resolved and she regained low vision completely at 2 weeks. She obtained partial response with alectinib for more than 5 months after recovering from skin rash.


Serum concentration of adipocytokines in prepubertal vegetarian and omnivorous children.
THE AIM of our study was to investigate associations between serum adipocytokines status and anthropometric parameters as well as total energy and macronutrient intake in vegetarian, normal-weight omnivorous and obese omnivorous children. We examined 90 healthy prepubertal children aged 4-10 years who had been referred to the Department of Nutrition at the Institute of Mother and Child in Warsaw for dietary consultation. Patients with endocrine disorders or genetic syndromes, as well as those who were taking medications that could affect growth, pubertal development or nutritional status were excluded. Children were divided into groups: vegetarians (n=30), normal-weight omnivores (n=30) and obese omnivores (n=30). Anthropometric measurement (weight, height) was performed in all children and body mass index (BMI) was calculated. A whole body dual-energy X-ray absorptiometry (DXA) scan was performed to determine fat mass, the percentage of body fat and lean body mass using a Lunar Prodigy (GE, USA). Dietary constituents were assessed by questionnaire (nutrient intake from a 3-day period: 2 weekdays and 1 weekend day) and calculated using the nutritional computer program Dietetyk2®. Serum total cholesterol, high-density and low-density lipoproteins, and triglycerides concentrations were assessed by standard enzymatic methods. Serum levels of leptin, soluble leptin receptor and adiponectin were determined by immunoenzymatic assays. There were no significant differences in body weight, height, BMI and lean mass values between vegetarians and normal-weight children on traditional mixed diet. Children on vegetarian diet had lower fat mass (p<0.05) and fat mass/lean mass ratio (p<0.05) than normal-weight omnivores. However, omnivorous children with simple obesity had significantly higher body weight, height, BMI, fat and lean mass in comparison to vegetarian as well to normal-weight omnivorous children. The fat mass/lean mass ratio in obese children was about 2.5-fold higher than in normal-weight subjects on traditional diet. Total energy and percentage of energy from macronutrients in diets of all children were within the recommended daily intake. Children on vegetarian diet was related with lower fat and higher carbohydrates intake in comparison to their omnivorous peers. Vegetarian children had significantly lower mean total cholesterol (151.5±18.0 mg/dL), low-density lipoprotein (81.0±13.6 mg/dL) and triglycerides (61.6±20.5 mg/dL) than omnivores, especially the obese ones (165.0±22.3 mg/dL, 94.7±19.2 mg/dL, 82.4±32.3 mg/dL, respectively). These differences were statistically significant (p<0.05). Serum concentration of leptin was significantly lower in vegetarian children (3.0±2.1 ng/ml) compared with omnivores (6.8±3.4 ng/ml in normal weight versus 37.8±12.7 ng/ml in obese) (p<0.0001). However, serum soluble leptin receptor as well as adiponectin were at higher levels in vegetarians than in omnivores (p<0.001 and p<0.05, respectively). We observed that serum leptin levels positively and soluble leptin receptor negatively correlated with body mass index and fat mass in prepubertal children. Moreover, leptin levels negatively correlated with its soluble receptor and with adiponectin. In children different kinds of diet might modify not only body mass and lipid profile but also serum concentration of adipocytokines. Determination of leptin and its soluble receptor, as well as adiponectin levels may be clinically useful in the medical and nutritional care of obese as well as vegetarian prepubertal children.


Multivariate Analysis in Metabolomics.
Metabolomics aims to provide a global snapshot of all small-molecule metabolites in cells and biological fluids, free of observational biases inherent to more focused studies of metabolism. However, the staggeringly high information content of such global analyses introduces a challenge of its own; efficiently forming biologically relevant conclusions from any given metabolomics dataset indeed requires specialized forms of data analysis. One approach to finding meaning in metabolomics datasets involves multivariate analysis (MVA) methods such as principal component analysis (PCA) and partial least squares projection to latent structures (PLS), where spectral features contributing most to variation or separation are identified for further analysis. However, as with any mathematical treatment, these methods are not a panacea; this review discusses the use of multivariate analysis for metabolomics, as well as common pitfalls and misconceptions.


Different Sources of Fiber Intake and Risk of 17 Specific Cancers and All Cancers Combined: Prospective Study of 364,856 Participants in UK Biobank.
Inverse associations between dietary fiber (DF) and colorectal cancer risk are well-established. However, evidence is limited in relation to other cancer sites. This study, of 364,856 participants from UK Biobank, aimed to evaluate the associations between total and source-specific partial DF and risk of 17 specific cancers and all cancers combined. Partial DF was derived from baseline touch-screen questionnaire data on cereal, bread, fruit and vegetable intake. The outcomes were incident cancer at 17 sites and all cancers combined. Cox proportional hazard models were applied. Over a median 8.8-year follow-up period, 30,725 people were diagnosed with cancer. After adjusting for sociodemographic and lifestyle factors, those in the highest quintile of DF compared to the lowest quintile (<9.6 vs ≥19.1 g/day) had 10% lower risk of cancer overall, with the greatest risk reductions observed for cervical (HR: 0.33, 0.14; 0.82), esophageal (HR: 0.66, 0.52; 0.84), lung (HR: 0.67, 0.59; 0.76), bladder (HR: 0.72, 0.56; 0.91) and kidney (HR: 0.75, 0.61; 0.92) cancers. Associations between DF and lung cancer were observed only in current and ex-smokers. Higher dietary fiber intake, in particular cereal fiber and fruit and vegetable fiber, was associated with a lower risk of overall and multiple site-specific cancers.


'Intelligent' lockdown, intelligent effects? Results from a survey on gender (in)equality in paid work, the division of childcare and household work, and quality of life among parents in the Netherlands during the Covid-19 lockdown.
The COVID-19 pandemic is more than a public health crisis. Lockdown measures have substantial societal effects, including a significant impact on parents with (young) children. Given the existence of persistent gender inequality prior to the pandemic, particularly among parents, it is crucial to study the societal impact of COVID-19 from a gender perspective. The objective of this paper is to use representative survey data gathered among Dutch parents in April 2020 to explore differences between mothers and fathers in three areas: paid work, the division of childcare and household tasks, and three dimensions of quality of life (leisure, work-life balance, relationship dynamics). Additionally, we explore whether changes take place in these dimensions by comparing the situation prior to the lockdown with the situation during the lockdown. We use descriptive methods (crosstabulations) supported by multivariate modelling (linear regression modelling for continuous outcomes; linear probability modelling (LPM) for binary outcomes (0/1 outcomes); and multinomial logits for multinomial outcomes) in a cross-sectional survey design. Results show that the way in which parents were impacted by the COVID-19 pandemic reflects a complex gendered reality. Mothers work in essential occupations more often than fathers, report more adjustments of the times at which they work, and experience both more and less work pressure in comparison to before the lockdown. Moreover, mothers continue to do more childcare and household work than fathers, but some fathers report taking on greater shares of childcare and housework during the lockdown in comparison to before. Mothers also report a larger decline in leisure time than fathers. We find no gender differences in the propensity to work from home, in perceived work-life balance, or in relationship dynamics. In conclusion, we find that gender inequality in paid work, the division of childcare and household work, and the quality of life are evident during the first lockdown period. Specifically, we find evidence of an increase in gender inequality in relation to paid work and quality of life when comparing the situation prior to and during the lockdown, as well as a decrease in gender inequality in the division of childcare and household work. We conclude that the unique situation created by restrictive lockdown measures magnifies some gender inequalities while lessening others. The insights we provide offer key comparative evidence based on a representative, probability-based sample for understanding the broader impact of lockdown measures as we move forward in the COVID-19 pandemic. One of the limitations in this study is the cross-sectional design. Further study, in the form of a longitudinal design, will be crucial in investigating the long-term impact of the COVID-19 pandemic on gender inequality.


Sirtuin and metabolic kidney disease.
Sirtuin is a nicotinamide adenine dinucleotide-dependent deacetylase. One of its isoforms, Sirt1, is a key molecule in glucose, lipid, and energy metabolism. The renal protective effects of Sirt1 are found in various models of renal disorders with metabolic impairment, such as diabetic nephropathy. Protective effects include the maintenance of glomerular barrier function, anti-fibrosis effects, anti-oxidative stress effects, and regulation of mitochondria function and energy metabolism. Various target molecules subject to direct deacetylation or epigenetic gene regulation have been identified as effectors of the renal protective function of sirtuin. Recently, it was demonstrated that Sirt1 expression decreases in proximal tubules before albuminuria in a mouse model of diabetic nephropathy, and that albuminuria is suppressed in proximal tubule-specific mice overexpressing Sirt1. These findings suggest that decreased Sirt1 expression in proximal tubular cells causes abnormal nicotine metabolism and reduces the supply of nicotinamide mononucleotide from renal tubules to glomeruli. This further decreases expression of Sirt1 in glomerular podocytes and increases expression of a tight junction protein, claudin-1, which results in albuminuria. Activators of the sirtuin family of proteins, including resveratrol, may be important in the development of new therapeutic strategies for treating metabolic kidney diseases, including diabetic nephropathy.


Effectiveness of an Individualized Training Based on Force-Velocity Profiling during Jumping.
Ballistic performances are determined by both the maximal lower limb power output (Pmax ) and their individual force-velocity (F-v) mechanical profile, especially the F-v imbalance (FVimb ): difference between the athlete's actual and optimal profile. An optimized training should aim to increase Pmax and/or reduce FVimb . The aim of this study was to test whether an individualized training program based on the individual F-v profile would decrease subjects' individual FVimb and in turn improve vertical jump performance. FVimb was used as the reference to assign participants to different training intervention groups. Eighty four subjects were assigned to three groups: an "optimized" group divided into velocity-deficit, force-deficit, and well-balanced sub-groups based on subjects' FVimb , a "non-optimized" group for which the training program was not specifically based on FVimb and a control group. All subjects underwent a 9-week specific resistance training program. The programs were designed to reduce FVimb for the optimized groups (with specific programs for sub-groups based on individual FVimb values), while the non-optimized group followed a classical program exactly similar for all subjects. All subjects in the three optimized training sub-groups (velocity-deficit, force-deficit, and well-balanced) increased their jumping performance (12.7 ± 5.7% ES = 0.93 ± 0.09, 14.2 ± 7.3% ES = 1.00 ± 0.17, and 7.2 ± 4.5% ES = 0.70 ± 0.36, respectively) with jump height improvement for all subjects, whereas the results were much more variable and unclear in the non-optimized group. This greater change in jump height was associated with a markedly reduced FVimb for both force-deficit (57.9 ± 34.7% decrease in FVimb ) and velocity-deficit (20.1 ± 4.3%) subjects, and unclear or small changes in Pmax (-0.40 ± 8.4% and +10.5 ± 5.2%, respectively). An individualized training program specifically based on FVimb (gap between the actual and optimal F-v profiles of each individual) was more efficient at improving jumping performance (i.e., unloaded squat jump height) than a traditional resistance training common to all subjects regardless of their FVimb . Although improving both FVimb and Pmax has to be considered to improve ballistic performance, the present results showed that reducing FVimb without even increasing Pmax lead to clearly beneficial jump performance changes. Thus, FVimb could be considered as a potentially useful variable for prescribing optimal resistance training to improve ballistic performance.


An Improved HRPE-Based Transcriptional Output Reporter to Detect Hypoxia and Anoxia in Plant Tissue.
Oxygen levels in plant tissues may vary, depending on metabolism, diffusion barriers, and environmental availability. Current techniques to assess the oxic status of plant cells rely primarily on invasive microoptodes or Clark-type electrodes, which are not optimally suited for experiments that require high spatial and temporal resolution. In this case, a genetically encoded oxygen biosensor is required instead. This article reports the design, test, and optimization of a hypoxia-signaling reporter, based on five-time repeated hypoxia-responsive promoter elements (HRPE) driving the expression of different reporter proteins. Specifically, this study aimed to improve its performance as a reporter of hypoxic conditions by testing the effect of different untranslated regions (UTRs) at the 5' end of the reporter coding sequence. Next, we characterized an optimized version of the HRPE promoter (HRPE-Ω) in terms of hypoxia sensitivity and time responsiveness. We also observed that severe oxygen deficiency counteracted the reporter activity due to inhibition of GFP maturation, which requires molecular oxygen. To overcome this limitation, we therefore employed an oxygen-independent UnaG fluorescent protein-coupled to an O2-dependent mCherry fluorophore under the control of the optimized HRPE-Ω promoter. Remarkably, this sensor, provided a different mCherry/UnaG ratiometric output depending on the externally imposed oxygen concentration, providing a solution to distinguish between different degrees of tissue hypoxia. Moreover, a ubiquitously expressed UnaG-mCherry fusion could be used to image oxygen concentrations directly, albeit at a narrow range. The luminescent and fluorescent hypoxia-reporters described here can readily be used to conduct studies that involve anaerobiosis in plants.


Transcription precedes loss of Xist coating and depletion of H3K27me3 during X-chromosome reprogramming in the mouse inner cell mass.
Repression of Xist RNA expression is considered a prerequisite to reversal of X-chromosome inactivation (XCI) in the mouse inner cell mass (ICM), and reactivation of X-linked genes is thought to follow loss of Xist RNA coating and heterochromatic markers of inactivation, such as methylation of histone H3. We analyzed X-chromosome activity in developing ICMs and show that reactivation of gene expression from the inactive-X initiates in the presence of Xist coating and H3K27me3. Furthermore, depletion of Xist RNA coating through forced upregulation of NANOG does not result in altered reactivation kinetics. Taken together, our observations suggest that in the ICM, X-linked gene transcription and Xist coating are uncoupled. These data fundamentally alter our perception of the reactivation process and support the existence of a mechanism to reactivate Xp-linked genes in the ICM that operates independently of loss of Xist RNA and H3K27me3 from the imprinted inactive-X.


Comparing the pathology, clinical and demographic characteristics of younger and older-onset multiple sclerosis.
Older people with multiple sclerosis have a less active radiological and clinical presentation, but many still attain significant levels of disability; but what drives worsening disability in this group? We used data from the UK MS Register to characterise demographics and clinical features of late-onset multiple sclerosis (LOMS; symptom onset at ≥50 years), compared to adult-onset MS (AOMS; onset18-49 years). We performed a pathology study of a separate MS cohort with a later onset (n=18, mean age of onset 54 years) versus AOMS (n=23, age of onset 30 years). In the Register cohort there were 1608 (9.4%) with LOMS. When compared with AOMS, there was a lower proportion of females, a higher proportion of primary progressive MS, a higher level of disability at diagnosis (median MS impact scale 36.7 v 28.3, p<0.001), and a higher proportion of gait-related initial symptoms. People with LOMS were less likely to receive a high efficacy disease modifying treatment and attained substantial disability sooner. Controlling for age of death and sex, neuron density in the thalamus and pons decreased with onset-age, whilst actively demyelinating lesions and compartmentalised inflammation was greatest in AOMS. Only neuron density, and not demyelination or the extent of compartmentalised inflammation, correlated with disability outcomes in older-onset MS. The more progressive nature of older-onset MS is associated with significant neurodegeneration but infrequent inflammatory demyelination. These findings have implications for the assessment and treatment of MS in older people. This article is protected by copyright. All rights reserved.


Quality by design-guided development of a capillary electrophoresis method for the simultaneous chiral purity determination and impurity profiling of tamsulosin.
Analytical Quality by Design principles using the design of experiments were applied for the development of a capillary electrophoresis method for the determination of enantiomeric purity and chemically related impurities of tamsulosin. From initial scouting experiments, a dual cyclodextrin (CD) system composed of sulfated β-CD and carboxymethyl-α-CD was selected as the chiral selector. A fractional factorial resolution V+ design was used for the identification of the critical process parameters, while a face-centered central composite design and Monte Carlo simulations were employed for final optimization and defining the design space of the method. The experimental conditions of the working point were: 30 mM sodium phosphate buffer, pH 3.0, containing 40 mg/mL sulfated β-CD and 7 mg/mL carboxymethyl-α-CD, capillary temperature 18°C, applied voltage -23 kV. Following the assessment of robustness by applying a Plackett-Burman design, the method was validated according to the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use guideline Q2(R1). The method allowed the quantification of the chiral impurity and three other related impurities at the 0.1 % level with acceptable accuracy and precision.


Preventive effect of reduced glutathione on contrast-induced nephropathy in elderly patients undergoing coronary angiography or intervention: a randomized, controlled trial.
Coronary angiography can be a high-risk condition for the incidence of contrast-induced nephropathy (CIN) in elderly patients. Reduced glutathione, under a variety of mechanisms, may prevent CIN in this procedure. We prospectively examined whether hydration with reduced glutathione is superior to hydration alone for prevention of CIN in an elderly Han Chinese population. A total of 505 patients (271 males and 234 females) aged 75 years or older who underwent non-emergency coronary angiography or an intervention were randomly divided into two groups. The treatment group received hydration with reduced glutathione (n=262) and the control group received hydration alone (n=243). Serum creatinine and blood urea nitrogen levels were measured prior to coronary angiography and 48 h after this procedure. The primary endpoint was occurrence of CIN, which was defined as 25% or 44.2 µmol/L above baseline serum creatinine levels 48 h after the procedure. The overall incidence of CIN was 6.49% in the treatment group and 7.41% in the control group, with no significant difference between the groups (P=0.68). In subgroup analysis by percutaneous coronary intervention, no significant differences were found between the two groups. In summary, reduced glutathione added to optimal hydration does not further decrease the risk of CIN in elderly patients undergoing coronary angiography or an intervention.


Hd3a, RFT1 and Ehd1 integrate photoperiodic and drought stress signals to delay the floral transition in rice.
Plants show a high degree of developmental plasticity in response to external cues, including day length and environmental stress. Water scarcity in particular can interfere with photoperiodic flowering, resulting in the acceleration of the switch to reproductive growth in several species, a process called drought escape. However, other strategies are possible and drought stress can also delay flowering, albeit the underlying mechanisms have never been addressed at the molecular level. We investigated these interactions in rice, a short day species in which drought stress delays flowering. A protocol that allows the synchronization of drought with the floral transition was set up to profile the transcriptome of leaves subjected to stress under distinct photoperiods. We identified clusters of genes that responded to drought differently depending on day length. Exposure to drought stress under floral-inductive photoperiods strongly reduced transcription of EARLY HEADING DATE 1 (Ehd1), HEADING DATE 3a (Hd3a) and RICE FLOWERING LOCUS T 1 (RFT1), primary integrators of day length signals, providing a molecular connection between stress and the photoperiodic pathway. However, phenotypic and transcriptional analyses suggested that OsGIGANTEA (OsGI) does not integrate drought and photoperiodic signals as in Arabidopsis, highlighting molecular differences between long and short day model species.


Precipitation inequality exacerbates streamflow inequality, but dams moderate it.
Access to clean water is a fundamental human right, yet millions worldwide face the dire consequences of water scarcity and inadequate sanitation. Water inequality, characterized by disparities in access and availability of water resources, has emerged as a critical global challenge with far-reaching social, economic, and environmental implications. Using a globally representative observational streamflow dataset and Gini coefficients, this study investigates how streamflow inequality, which has a large impact on inequality of water availability, varies spatially and temporally, and its relationship with different underlying catchment characteristics. This study finds that watersheds in arid climates exhibit a higher degree of streamflow inequality than polar and equatorial ones. Africa experiences the highest streamflow inequality, followed by Australia, while South America experiences relatively lower streamflow inequality. Around 19.6 % of the catchments in Australia display an increasing trend in streamflow inequality, pointing to worsening conditions. Conversely, South America experiences a decreasing trend in streamflow inequality in 18.3 % of its catchments during the same period. It is also found that a more evenly distributed precipitation within the catchment and higher dam storage capacity corresponds to more evenly distributed streamflow availability throughout the year. This study enhances our understanding of streamflow inequality worldwide, which will aid policy formulation to foster sustainable development.


Comparison of PI-RADS v1 and v2 for multiparametric MRI detection of prostate cancer with whole-mount histological workup as reference standard.
The aim of this study was to compare Prostate Imaging Reporting and Data System (PI-RADS) versions v1 and v2 for the detection of prostate cancer (PCa) in multiparametric MRI (mpMRI) using whole-mount histological workup as reference standard. MRI data of 40 patients with positive transrectal ultrasound-guided biopsy were analyzed retrospectively by two blinded readers (5 and 4 years' experience) with PI-RADS v1 and v2 for cancer-suspicious lesions. Prior to radical prostatectomy, patients had undergone IRB-approved mpMRI at 3 T according to PI-RADS recommendations: T2-weighted (T2w), diffusion-weighted (DWI) and dynamic contrast-enhanced (DCE) imaging. The reference standard was provided by whole-mount sections of the prostatectomy specimens. Versions v1 and v2 were compared with respect to sensitivity and positive predictive value (PPV) per lesion. Subgroups stratified by tumor location (peripheral vs. transition zone) and aggressiveness (high vs. low grade) were also analyzed. We also evaluated the concordance of the dominant MRI sequence in v2 (DWI or T2w) and the highest individual score under v1. Interobserver agreement for PI-RADS v1 and v2 was assessed by Cohen's kappa statistics. Reader 1 (R1) described 66 and Reader 2 (R2) 72 MRI lesions. The average Gleason score of 58 PCa lesions was 6.5 (range: 6 = 3 + 3 to 8 = 4 + 4), most of them (65.5%) located in the peripheral zone. PI-RADS v2 showed a trend towards lower sensitivities, but differences were not significant for both readers: R1 72.4% (v1) vs. 63.8% (v2) (P = 0.426) and R2 77.6% (v1) vs. 69.0% (v2) (P = 0.402). The trends were more pronounced in the transition zone and for low-grade cancers but remained insignificant (p-values from 0.313 to 0.691). Likewise, the apparent PPV differences, overall as well as in each zone, were not significant. Agreement between high-score v1 and dominant v2 sequence was 48% for R1 and 53% for R2. Cohen's κ of PCa detection for two readers was 0.48 for both v1 and v2. Our findings indicate that the simplified, zone-specific approach of PI-RADS v2 (2015) for MRI assessment of prostate cancer may not necessarily be better than the original v1 criteria (2012). In specific cases, a strict interpretation of v2 criteria may even lead to false-negative findings. Therefore, the current PI-RADS criteria should be reconsidered, despite the low statistical evidence here.


Is hydroxypyridonate 3,4,3-LI(1,2-HOPO) a good competitor of fetuin for uranyl metabolism?
Uranium is widespread in the environment, resulting both from natural occurrences and anthropogenic activities. Its toxicity is mainly chemical rather than radiological. In the blood it is transported as uranyl UO22+ cation and forms complexes with small ligands like carbonates and with some proteins. From there it reaches the skeleton, its main target organ for accumulation. Fetuin is a serum protein involved in biomineralization processes, and it was demonstrated to be the main UO22+-binder in vitro. Fetuin's life cycle ends in bone. It is thus suspected to be a key protagonist of U accumulation in this organ. Up to now, there has been no effective treatment for the removal of U from the body and studies devoted to the interactions involving chelating agents with both UO22+ and its protein targets are lacking. The present work aims at studying the potential role of 3,4,3-LI(1,2-HOPO) as a promising chelating agent in competition with fetuin. The apparent affinity constant of 3,4,3-LI(1,2-HOPO) was first determined, giving evidence for its very high affinity similar to that of fetuin. Chromatography experiments, aimed at identifying the complexes formed and quantifying their UO22+ content, and spectroscopic structural investigations (XAS) were carried out, demonstrating that 3,4,3-LI(1,2-HOPO) inhibits/limits the formation of fetuin-uranyl complexes under stoichiometric conditions. But surprisingly, possible ternary complexes stable enough to remain present after the chromatographic process were identified under sub-stoichiometric conditions of HOPO versus fetuin. These results contribute to the understanding of the mechanisms accounting for U residual accumulation despite chelation therapy after internal contamination.


Clinical characteristics and long-term outcome of surgery for hypothalamic hamartoma in children with refractory epilepsy.
Hypothalamic hamartomas (HH) are ectopic masses of neuronal and glial tissue most commonly presenting with medically refractory gelastic seizures with evolution to other seizure types. They are also associated with cognitive and behavioral problems to varying extent. Surgery has been found to improve quality of life in more than 50% of patients. To evaluate the clinical characteristics and long-term outcome of surgery in children with HH and refractory epilepsy. A retrospective analysis of presurgical, surgical, and postsurgical data of six children who underwent surgery for HH and had at least 3 years follow-up was performed. SIX CHILDREN (MALE: female = 5:1) aged 3-16 years (at the time of surgery) underwent surgical resection of HH for refractory epilepsy. At last follow-up (range 3-9 years), three children were in Engel's class I, two in Class II, and one in class III outcome. Significant improvement in behavior, quality of life was noted in four children; while the change in intelligence quotient (IQ) was marginal. Medically refractory epilepsy associated with behavioral and cognitive dysfunction is the most common presentation of HH. Open surgical resection is safe with favorable outcome of epilepsy in 50% with significant improvement in behavior and marginal change in cognitive functions.


Spruce budworm (Choristoneura fumiferana) pheromone chemistry and behavioral responses to pheromone components and analogs.
This paper reviews the sex pheromone chemistry and pheromone-mediated behavior of the spruce budworm and related coniferophagous (Choristoneura) budworms. InC. fumiferana, temporal changes in pheromone-gland monounsaturated fatty acids (pheromone precursors) enable the prediction of the primary sex pheromone components. This technique may also be applicable for predicting additional pheromone components. Tetradecanal (14∶ Ald), previously shown to enhance close-range precopulatory behavior, lowers the threshold of response by males for upwind flight to a pheromone-component source. Spruce budworm males maintain upwind flight to 95∶5 (E/Z)-1,12-pentadecadiene (diolefin analog) after initiating upwind flight to a primary-component pheromone source (95∶5E/Z11-14∶Ald). This is the first demonstration of apparently normal male flight responses to a pheromone analog.


[Influencing factors and kinetics of oxidation of bisphenol A in water with sodium hypochlorite].
The degradation and its kinetics of sodium hypochlorite oxidation of an endocrine disruptor-bisphenol A (BPA) were studied. The influencing factors were investigated, such as chlorine dosage, initial concentration of BPA, pH value, bromide ion concentration and temperature etc. The results showed that the degradation of BPA by sodium hypochlorite followed pseudo-first-order kinetics. The pH value influenced the degradation of BPA greatly. The pseudo-first-order rate constant of the reaction between BPA and HOCl reached the maximum value of 0.544 3 min(-1) during pH 8 - 9. Moreover, the bromine ion in water would accelerate the degradation of BPA, and the whole reaction did not follow the rule of pseudo-first-order kinetics. The temperature influenced the reaction greatly, and it followed Van' t Hoff Rule. The removal efficiency of BPA would increase with increasing temperature.


C-fibres provide a source of masking inhibition to primary somatosensory cortex.
Capsaicin was applied to the exposed radial nerve of adult flying foxes (n = 5) and cats (n = 2) while recording in primary somatosensory cortex from a single neuron with a receptive field on digits 1 or 2. Within four minutes of application of capsaicin the borders of these receptive fields dramatically expanded. In a further four flying foxes it was shown, with subcutaneous delivery just proximal to the receptive fields, that capsaicin need affect only afferents from the region of a neuron's receptive field to induce expansion. Capsaicin applied directly to a nerve, or subcutaneously in high concentrations, is a selective neurotoxin that rapidly prevents the propagation of action potentials in most C-fibres. The result provides a partial explanation for experiments involving the specific and complete denervation of receptive fields of neurons in primary somatosensory cortex. Such denervation does not lead to unresponsiveness but to immediate sensitivity to stimulation of areas surrounding the original fields. Thus it appears that some subclass of capsaicin-sensitive C-fibres provides a primary source for the masking inhibition that normally limits the extent of the receptive fields of cortical neurons.


Singular contributions of fish neuroendocrinology to mammalian regulatory peptide research.
During the past 20 years, several bioactive peptides have been identified in teleost fishes that subsequently have been shown to play important regulatory roles in mammalian physiology. The urophysis, corpuscles of Stannius and Brockmann body are anatomical structures particular to fish that have no obvious counterpart in mammals. Extracts and/or cDNA libraries prepared from these tissues have been used to identify for the first time urotensin II (U-II), urotensin-I (U-I), stanniocalcin and glucagon-like peptide-1 (GLP-1). Although U-II and U-I were originally regarded as exclusively the products of the teleost urophysis, the peptides have a wide phylogenetic distribution across the vertebrate lineage, including mammals. U-II is localized to motor neurones in the human spinal cord and is a potent vasoconstrictor that may be implicated in the pathogenesis of heart failure. The human ortholog of urotensin-I is urocortin which is synthesized in selected regions of the brain and is the endogenous ligand for the CRF type 2 receptor. Urocortin is believed to important in mediating the effects of stress on appetite. Stanniocalcin is involved in maintaining calcium and phosphate homeostasis in teleost fish. An ortholog of stanniocalcin has a widespread distribution in mammalian tissues and is postulated to regulate renal phosphate excretion and to protect neurons against damage during cerebral ischemia. The biological actions and therapeutic potential of GLP-1 in humans are now fully appreciated but the peptide was first identified as a domain in a preproglucagon cDNA prepared from anglerfish Brockmann bodies. In contrast to mammalian preproglucagons, GLP-1 is present in anglerfish preproglucagon as the bioactive, truncated sequence [corresponding to human GLP-1(7-37)] rather than the inactive, N-terminally extended form [corresponding to GLP-1(1-37)]. Failure to appreciate the significance of this fact retarded progress in the field for several years.


Interactions of phencyclidine with crayfish muscle membranes. Sensitivity to calcium channel antagonists and other drugs.
[3H]Phencyclidine ( [3H]PCP) bound to crayfish abdominal muscle membranes at pH 7.4 with two affinities (Kd of 0.96 nM for 0.38 pmole/mg of protein, and 18.9 nM for 7.6 pmoles/mg of protein). Binding affinities increased at higher pH, suggesting that binding may be due mostly to the un-ionized form of [3H]PCP. This high-affinity [3H]PCP binding was sensitive to the actions of trypsin, protease, and dicyclohexylcarbodiimide, but insensitive to phospholipase A, concanavalin A,N-ethylmaleimide, and dithiothreitol. Calcium channel antagonists were most potent in inhibiting the high-affinity [3H]PCP binding with the following descending order of potencies: bepridil greater than nicardipine = diltiazem = verapamil greater than cinnarizine greater than (+)-D-600 greater than (-)-D-600 greater than 4-NO2-nifedipine greater than 2-NO2-nifedipine. The binding was also highly sensitive to several PCP analogues, antipsychotics, piperocaine , and tilorone, and moderately sensitive to d-tubocurarine, atropine, imipramine, nortryptyline , and tetracaine. Although verapamil and nifedipine inhibited the action potential of crayfish muscle, PCP did not and actually prolonged slightly the falling phase of the action potential. Although it is unlikely that the [3H]PCP binding protein in crayfish muscles is a Ca2+ channel, it is possible that it may be a K+ channel.


Effects of tetrodotoxin and anaesthetics on brain metabolism and transport during anoxia.
1. Tetrodotoxin, at concentrations at which it abolishes generation of action potentials in the nervous system, enhances by about 300% the rate of anaerobic glycolysis of brain-cortex slices from adult rats, or from adult and infant guinea pigs. This occurs to a greater extent in Ca(2+)-deficient incubation media than in Ca(2+)-rich media. Tetrodotoxin has no accelerative effect on cerebral aerobic glycolysis. 2. Tetrodotoxin does not affect the rate of anaerobic glycolysis of 2-day-old rat brain-cortex slices, nor that of adult rat kidney medulla, nor that of an extract of an acetone-dried powder of brain. 3. Tetrodotoxin does not affect the rate of penetration of glucose into brain slices. 4. Its effect is not apparent if it is added 10min or later after the onset of anoxia. 5. Its effect diminishes as the concentration of K(+) in the incubation medium is increased while that of Na(+) is decreased. 6. Its salient effect, at the onset of anoxia, is to diminish influx of Na(+) into, and efflux of K(+) from, the brain slices. 7. Substances that promote cerebral influx of Na(+), e.g. protoveratrine, sodium l-glutamate, diminish the accelerative action of tetrodotoxin. 8. It is concluded that tetrodotoxin exerts its effect on anaerobic glycolysis by suppressing, at the onset of anoxia, the generation of action potentials and thereby the accompanying influx of Na(+) and efflux of K(+). It is suggested that glycolytic stimulation occurs because a rate-limiting step, e.g. operation of pyruvate kinase, is stimulated by K(+) and depressed by Na(+). 9. Local anaesthetics behave in a manner similar to that of tetrodotoxin in enhancing cerebral anaerobic glycolysis. 10. Sodium Amytal has a marked effect at relatively high concentration. 11. Tetrodotoxin diminishes efflux of amino acids, particularly glutamate and aspartate, at the onset of anoxia.


A Study on the Leptospirosis Outbreak Among US Marine Trainees in Okinawa, Japan.
The US Marines operate the Jungle Warfare Training Center (JWTC) in Northern Okinawa, where leptospirosis is endemic. The JWTC endurance course involves prolonged fresh and stagnant water exposures in a simulated jungle warfare environment. Since a leptospirosis outbreak in 1987, JWTC has required prophylactic use of doxycycline at 200 mg weekly during exposure to the endurance course. This policy is based on a 1982 study in a similar environment in Panama. In August and September of 2014, an outbreak of leptospirosis occurred among 81 Marines training at JWTC. We analyzed data from the largest reported outbreak of leptospirosis among US military members. Two hundred and thirty nine US Marines who completed the endurance course were interviewed by trained personnel regarding their exposures and use of prophylactic medication utilizing a standardized questionnaire. All available personnel who went through the course during the outbreak period were interviewed regardless of whether or not they became ill. The Armed Forces Health Surveillance Branch's case definition was used to identify cases. Eighty-one cases in 239 personnel were identified (attack rate = 33.9%). Exposures linked to being a case were swallowing water in the stagnant pond (attack rate ratio [ARR] = 2.3, 95% confidence interval [CI] = 1.4-3.7), cuts on the body (ARR = 1.5, 95% CI = 1.01-2.11), and insect bites (ARR = 2.0, 95% CI = 1.2-3.4). Exposures not linked to being a case were taking doxycycline before the exposure (ARR = 3.2, 95% CI = 0.5-22.2), taking doxycycline after the exposure (ARR = 0.9, 95% CI = 0.6-1.3), and swallowing water in the natural stream (ARR = 1.3, 95% CI = 0.9-1.9). Attack rate data indicate that whether or not personnel took pre- or post-exposure doxycycline made no difference statistically. Increased internal exposure (via swallowing water or through broken skin) increased risk of symptomatic disease. This new study combined with a growing body of literature should prompt researchers to re-examine recommendations for those with significant water exposure in areas with high leptospirosis levels.


Geographic concentration of SARS-CoV-2 cases by social determinants of health in metropolitan areas in Canada: a cross-sectional study.
Understanding inequalities in SARS-CoV-2 transmission associated with the social determinants of health could help the development of effective mitigation strategies that are responsive to local transmission dynamics. This study aims to quantify social determinants of geographic concentration of SARS-CoV-2 cases across 16 census metropolitan areas (hereafter, cities) in 4 Canadian provinces, British Columbia, Manitoba, Ontario and Quebec. We used surveillance data on confirmed SARS-CoV-2 cases and census data for social determinants at the level of the dissemination area (DA). We calculated Gini coefficients to determine the overall geographic heterogeneity of confirmed cases of SARS-CoV-2 in each city, and calculated Gini covariance coefficients to determine each city's heterogeneity by each social determinant (income, education, housing density and proportions of visible minorities, recent immigrants and essential workers). We visualized heterogeneity using Lorenz (concentration) curves. We observed geographic concentration of SARS-CoV-2 cases in cities, as half of the cumulative cases were concentrated in DAs containing 21%-35% of their population, with the greatest geographic heterogeneity in Ontario cities (Gini coefficients 0.32-0.47), followed by British Columbia (0.23-0.36), Manitoba (0.32) and Quebec (0.28-0.37). Cases were disproportionately concentrated in areas with lower income and educational attainment, and in areas with a higher proportion of visible minorities, recent immigrants, high-density housing and essential workers. Although a consistent feature across cities was concentration by the proportion of visible minorities, the magnitude of concentration by social determinant varied across cities. Geographic concentration of SARS-CoV-2 cases was observed in all of the included cities, but the pattern by social determinants varied. Geographically prioritized allocation of resources and services should be tailored to the local drivers of inequalities in transmission in response to the resurgence of SARS-CoV-2.


Effects of chronic exposure to clothianidin on the earthworm Lumbricus terrestris.
Although neonicotinoids are targeted at insects, their predominant use as a seed dressing and their long persistence in soils mean that non-target soil organisms such as earthworms are likely to be chronically exposed to them. Chronic exposure may pose risks that are not evaluated in most toxicity tests. We experimentally tested the effect of field-realistic concentrations of a commonly used neonicotinoid, clothianidin, on mortality, weight gain, and food consumption to assess the impacts of chronic exposure over four months on fitness of L. terrestris individuals. We undertook three separate experiments, each with different exposure routes: treated soil only (experiment A), treated food and soil combined (experiment B) and treated food only (experiment C). Mortality was negatively affected by exposure from treated soil only with greatest mortality observed in the groups exposed to the two highest concentrations (20 ppb and 100 ppb), but no clear effect on mortality was found in the other two experiments. When clothianidin was present in the food, an anti-feedant effect was present in months one and two which subsequently disappeared; if this occurs in the field, it could result in reduced rates of decomposition of treated crop foliage. We found no significant effects of any treatment on worm body mass. We cannot rule out stronger adverse effects if worms come into close proximity to treated seeds, or if other aspects of fitness were examined. Overall, our data suggest that field-realistic exposure to clothianidin has a significant but temporary effect on food consumption and can have weak but significant impacts on mortality of L. terrestris.


A method to exhaust anesthetic gases when using the Loosco system for children with an expiratory valve according to the Waters' principle.
A description is presented of a method to eliminate anesthetic gases when using the Loosco system for children with an expiratory valve according to the Waters' principle. From practical experience we have gained the strong impression that this convenient device meets the requirements we have formulated. Exact gas-chromatographic determinations are still in progress, and the results will be published as soon as possible.


Seasonal changes of C and N non-structural compounds in the stem sapwood of adult sessile oak and beech trees.
We assessed the pools of non-structural nitrogen compounds (NSNC) through a year, thereby addressing the question of whether mature sessile oak [Quercus petraea (Matt.) Liebl.] and beech (Fagus sylvatica L.), which differ in wood anatomy and growth patterns, exhibit contrasting seasonal dynamics of NSNC pools as previously shown for non-structural carbohydrate (NSC) pools. Seasonal fluctuations of NSNC (amino acids and soluble proteins) and NSC (starch and soluble sugars) pools were analyzed in the inner and the outer stem sapwood. In oak, NSC showed marked seasonal variation within the stem sapwood (accumulation during winter and decrease during bud burst and early wood growth), whereas in beech seasonal fluctuations in NSC were of minor amplitude. Even if the distribution and intensity of the NSNC pools differed between the two species, NSNC of the stem sapwood did not show seasonal variation. The most significant change in NSNC pools was the seasonal fluctuation of protein composition. In both species, two polypeptides of 13 kDa (PP13) and 26 kDa (PP26) accumulated during the coldest period in parallel with starch to sugar conversion and disappeared with the onset of spring growth. The absence of seasonal changes in total soluble protein concentration suggests that the polypeptides are involved in the internal nitrogen (N) cycling of the stem rather than in N storage and remobilization to the other growing organs of the tree.


Synthesis of urea picket porphyrins and their use in the elucidation of the role buried solvent plays in the selectivity and stoichiometry of anion binding receptors.
The synthesis of alpha,alpha-5,10-diurea and alpha,alpha,alpha-5,10,15-triurea picket porphyrins are detailed in this report. In previous reports, these porphyrins, along with alpha,alpha,alpha,alpha-5,10,15,20-tetraurea picket porphyrin, were used to demonstrate the important role one buried solvent molecule plays in the selectivity and stoichiometry of binding inorganic anions. Building on prior work, this report discusses the results of acetate anion binding studies between tetra- and diurea picket porphyrins (the latter does not contain a buried solvent molecule in the anion-receptor complex), compares differences in thermodynamic data obtained from van't Hoff plots of a porphyrin anion receptor able to utilize buried solvent in its binding motif with one that does not, and compares the crystal structure of a tetraurea porphyrin 1-chloride anion complex that contains buried solvent with new X-ray crystal structures of tetraurea porphyrin 1-dichloride or bisdihydrogenphosphate anion complexes that contain no buried solvent. Data from our previous work, and the work described herein, demonstrates that one buried solvent molecule provides stability to the receptor-anion complex that is similar in energy to a moderately strong hydrogen bond.


Risk of radiation-associated intracranial malignancy after stereotactic radiosurgery: a retrospective, multicentre, cohort study.
A major concern of patients who have stereotactic radiosurgery is the long-term risk of having a secondary intracranial malignancy or, in the case of patients with benign tumours treated with the technique, the risk of malignant transformation. The incidence of stereotactic radiosurgery-associated intracranial malignancy remains unknown; therefore, our aim was to estimate it in a population-based study to assess the long-term safety of this technique. We did a population-based, multicentre, cohort study at five international radiosurgery centres (Na Homolce Hospital, Prague, Czech Republic [n=2655 patients]; Ruber International Hospital, Madrid, Spain [n=1080], University of Pittsburgh Medical Center, Pittsburgh, PA, USA [n=1027]; University of Virginia, Charlottesville, VA, USA [n=80]; and NYU Langone Health System, New York, NY, USA [n=63]). Eligible patients were of any age, and had Gamma Knife radiosurgery for arteriovenous malformation, trigeminal neuralgia, or benign intracranial tumours, which included vestibular or other benign schwannomas, WHO grade 1 meningiomas, pituitary adenomas, and haemangioblastoma. Patients were excluded if they had previously had radiotherapy or did not have a minimum follow-up time of 5 years. The primary objective of the study was to estimate the incidence of stereotactic radiosurgery-associated intracranial malignancy, including malignant transformation of a benign lesion or development of radiation-associated secondary intracranial cancer, defined as within the 2 Gy isodose line. Estimates of age-adjusted incidence of primary CNS malignancies in the USA and European countries were retrieved from the Central Brain Tumor Registry of the United States (CBTRUS) and the International Agency for Research on Cancer (IARC) Global Cancer statistics. Of 14 168 patients who had Gamma Knife stereotactic radiosurgery between Aug 14, 1987, and Dec 31, 2011, in the five contributing centres, 4905 patients were eligible for the analysis (had a minimum follow-up of 5 years and no history of previous radiation therapy). Diagnostic entities included vestibular schwannomas (1011 [20·6%] of 4905 patients), meningiomas (1490 [30·4%]), arteriovenous malformations (1089 [22·2%]), trigeminal neuralgia (565 [11·5%]), pituitary adenomas (641 [13·1%]), haemangioblastoma (29 [0·6%]), and other schwannomas (80 [1·6%]). With a median follow-up of 8·1 years (IQR 6·0-10·6), two (0·0006%) of 3251 patients with benign tumours were diagnosed with suspected malignant transformation and one (0·0002%) of 4905 patients was considered a case of radiosurgery-associated intracranial malignancy, resulting in an incidence of 6·87 per 100 000 patient-years (95% CI 1·15-22·71) for malignant transformation and 2·26 per 100 000 patient-years (0·11-11·17) for radiosurgery-associated intracranial malignancy. Two (0·0004%) of 4905 patients developed intracranial malignancies, which were judged unrelated to the radiation field. Overall incidence of radiosurgery-associated malignancy was 6·80 per 100 000 patients-years (95% CI 1·73-18·50), or a cumulative incidence of 0·00045% over 10 years (95% CI 0·00-0·0034). The overall incidence of 6·8 per 100 000, which includes institutions from Europe and the USA, after stereotactic radiosurgery was found to be similar to the risk of developing a malignant CNS tumour in the general population of the USA and some European countries as estimated by the CBTRUS and IARC data, respectively. These data show that the estimated risk of an intracranial secondary malignancy or malignant transformation of a benign tumour in patients treated with stereotactic radiosurgery remains low at long-term follow-up, and is similar to the risk of the general population to have a primary CNS tumour. Although prospective cohort studies with longer follow-up are warranted to support the results of this study, the available evidence suggests the long-term safety of stereotactic radiosurgery and could support physicians counselling patients on Gamma Knife stereotactic radiosurgery. None.


Symbiotic characteristics of cysteine and methionine auxotrophs of Sinorhizobium meliloti.
Twenty one cysteine and 13 methionine auxotrophs of Sinorhizobium meliloti Rmd201 were obtained by random mutagenesis with transposon Tn5. The cysteine auxotrophs were sulfite reductase mutants and each of these auxotrophs had a mutation in cysI/cysJ gene. The methionine auxotrophs were metA/metZ, metE and metF mutants. One hundred per cent co-transfer of Tn5-induced kanamycin resistance and auxotrophy from each Tn5-induced auxotrophic mutant indicated that each mutant cell most likely had a single Tn5 insertion. However, the presence of more than one Tn5 insertions in the auxotrophs used in our study cannot be ruled out. All cysteine and methionine auxotrophs induced nodules on alfalfa plants. The nodules induced by cysteine auxotrophs were fully effective like those of the parental strain-induced nodules, whereas the nodules induced by methionine auxotrophs were completely ineffective. The supplementation of methionine to the plant nutrient medium completely restored symbiotic effectiveness to the methionine auxotrophs. These results indicated that the alfalfa host provides cysteine but not methionine to rhizobia during symbiosis. Histological studies showed that the defective symbiosis of methionine auxotrophs with alfalfa plants was due to reduced number of infected nodule cells and incomplete transformation of bacteroids.


Health perceptions of young adults living with recessive limb-girdle muscular dystrophy.
The aim of this study was to describe health perceptions related to sense of coherence among young adults living with recessive limb-girdle muscular dystrophy. Limb-girdle muscular dystrophy refers to a group of progressive muscular disorders that may manifest in physical disability. The focus in health care is to optimize health, which requires knowledge about the content of health as described by the individual. A descriptive study design with qualitative and quantitative data were used. Interviews were conducted between June 2012-November 2013 with 14 participants aged 20-30 years. The participants also answered the 13-item sense of coherence questionnaire. Qualitative data were analysed with content analysis and related to self-rated sense of coherence. Health was viewed as intertwined physical and mental well-being. As the disease progressed, well-being was perceived to be influenced not only by physical impairment and mental strain caused by the disease but also by external factors, such as accessibility to support and attitudes in society. Factors perceived to promote health were having a balanced lifestyle, social relations and meaningful daily activities. Self-rated sense of coherence varied. The median score was 56 (range 37-77). Those who scored ≥56 described to a greater extent satisfaction regarding support received, daily pursuits and social life compared with those who scored <56. Care should be person-centred. Caregivers, with their knowledge, should strive to assess how the person comprehends, manages and finds meaning in daily life. Through dialogue, not only physical, psychological and social needs but also health-promoting solutions can be highlighted.


The role of matrix gla protein in ossification and recovery of the avian growth plate.
Extracellular matrix mineralization is an essential physiologic process in bone, teeth, and hypertrophic cartilage. Matrix Gla protein (MGP), an inhibitor of mineralization, is expressed by chondrocytes and vascular smooth muscle cells to inhibit calcification of those soft tissues. Tibial dyschondroplasia (TD), a skeletal abnormality apparent as a plug of non-vascularized, non-mineralized, white opaque cartilage in the tibial growth plate of avian species can serve as a good model for studying process and genes involved in matrix mineralization and calcification. In this work, we studied the involvement of MGP in the development of TD, as well as in the processes of spontaneous and induced recovery from this syndrome. First, we found that during normal bone development, MGP is expressed in specific time and locations, starting from wide-spread expression in the yet un-ossified diaphysis during embryonic development, to specific expression in hypertrophic chondrocytes adjacent to the chondro-osseous junction and the secondary ossification center just prior to calcification. In addition, we show that MGP is not expressed in the impaired TD lesion, however when the lesion begins to heal, it strongly express MGP prior to its calcification. Moreover, we show that when calcification is inhibited, a gap is formed between the expression zones of MGP and BMP2 and that this gap is closed during the healing process. To conclude, we suggest that MGP, directly or through interaction with BMP2, plays a role as ossification regulator that acts prior to ossification, rather then simple inhibitor.


Splenectomy in sickle cell disease.
Since role of splenectomy in sickle cell disease still remains controversial, this paper evaluates the same in 32 cases of splenectomy in sickle disease patients observed by the author. After proper diagnosis by standard methods the cases were observed for 2-3 years before deciding on splenectomy. Though acute splenic sequestration (53%) and chronic hypersplenism (21.8%) were the main indication. Two cases of splenic abscess and one case with frequent pain attacks were also subjected to splenectomy. There was one immediate post-operative death. The cases were followed up for 1 to > 8 years. While Acute splenic sequestration disappeared, in chronic hypersplenism cases as well as others besides a sense of general well being, steady state hemoglobin rose by > 2G/dl in 81% and significant increase in height and weight was seen in 90% and 61% cases respectively. Frequency of pain attack, fever, anaemia and need for blood transfusion improved in 79% patients. Splenectomy in selected cases appears to be an acceptable procedure in sickle disease.


Middle East coastal ecosystem response to middle-to-late Holocene abrupt climate changes.
The Holocene vegetation history of the northern coastal Arabian Peninsula is of long-standing interest, as this Mediterranean/semiarid/arid region is known to be particularly sensitive to climatic changes. Detailed palynological data from an 800-cm alluvial sequence cored in the Jableh plain in northwest Syria have been used to reconstruct the vegetation dynamics in the coastal lowlands and the nearby Jabal an Nuşayriyah mountains for the period 2150 to 550 B.C. Corresponding with the 4.2 to 3.9 and 3.5 to 2.5 cal kyr BP abrupt climate changes (ACCs), two large-scale shifts to a more arid climate have been recorded. These two ACCs had different impacts on the vegetation assemblages in coastal Syria. The 3.5 to 2.5 cal kyr BP ACC is drier and lasted longer than the 4.2 to 3.9 cal kyr BP ACC, and is characterized by the development of a warm steppe pollen-derived biome (1100-800 B.C.) and a peak of hot desert pollen-derived biome at 900 B.C. The 4.2 to 3.9 cal kyr BP ACC is characterized by a xerophytic woods and shrubs pollen-derived biome ca. 2050 B.C. The impact of the 3.5 to 2.5 cal kyr BP ACC on human occupation and cultural development is important along the Syrian coast with the destruction of Ugarit and the collapse of the Ugarit kingdom at ca. 1190 to 1185 B.C.


Functional analysis of the glycero-manno-heptose 7-phosphate kinase domain from the bifunctional HldE protein, which is involved in ADP-L-glycero-D-manno-heptose biosynthesis.
The core oligosaccharide component of the lipopolysaccharide can be subdivided into inner and outer core regions. In Escherichia coli, the inner core consists of two 3-deoxy-d-manno-octulosonic acid and three glycero-manno-heptose residues. The HldE protein participates in the biosynthesis of ADP-glycero-manno-heptose precursors used in the assembly of the inner core. HldE comprises two functional domains: an N-terminal region with homology to the ribokinase superfamily (HldE1 domain) and a C-terminal region with homology to the cytidylyltransferase superfamily (HldE2 domain). We have employed the structure of the E. coli ribokinase as a template to model the HldE1 domain and predict critical amino acids required for enzyme activity. Mutation of these residues renders the protein inactive as determined in vivo by functional complementation analysis. However, these mutations did not affect the secondary or tertiary structure of purified HldE1, as judged by fluorescence spectroscopy and circular dichroism. Furthermore, in vivo coexpression of wild-type, chromosomally encoded HldE and mutant HldE1 proteins with amino acid substitutions in the predicted ATP binding site caused a dominant negative phenotype as revealed by increased bacterial sensitivity to novobiocin. Copurification experiments demonstrated that HldE and HldE1 form a complex in vivo. Gel filtration chromatography resulted in the detection of a dimer as the predominant form of the native HldE1 protein. Altogether, our data support the notions that the HldE functional unit is a dimer and that structural components present in each HldE1 monomer are required for enzymatic activity.


Evaluation of clinical tolerance of local anaesthetic agents.
The clinical tolerance to local anaesthetic drugs can be assessed from a knowledge of their pharmacokinetic behaviour, their absorption properties and the effects produced by controlled i.v. infusions. Pharmacokinetic behavior can be calculated from the plasma concentrations of the drugs injected i.v. in non-toxic doses. Absorption properties can likewise be determined from plasma concentrations following injection at various sites. Acute toxicity can be assessed by i.v. infusion of toxic doses into volunteers. The dosage required to produce symptoms can be compared with other drugs. Such dosage is considerably affected by the rate of injection. The venous plasma concentrations at the height of toxicity are unreliable guides to toxicity. Experiences using the new local anaesthetic etidocaine are reported.


Epidemiology of HIV-associated tuberculosis.
We review literature concerning the epidemiology of HIV-associated tuberculosis (HIV-TB), focusing on articles published between 2007 and 2008. An estimated 1.37 million new cases of HIV-TB occurred in 2007, representing 15% of the total global burden of TB. In addition, an estimated 456 000 HIV-TB deaths accounted for 23% of global HIV/AIDS mortality. Sub-Saharan Africa is the worst affected region with 79% of the disease burden. The epicentre of the coepidemic lies in the south of the continent, with South Africa alone accounting for over one quarter of all cases. A critical overlap between HIV and the global multidrug-resistant TB epidemics is emerging. Although it is as yet unclear whether HIV is driving a disproportionate increase in multidrug-resistant TB cases at a population level, HIV has nevertheless been a potent risk factor for institutional outbreaks, especially in South Africa and eastern Europe. Increasing data have highlighted the risk of TB among HIV-infected healthcare workers in resource-limited settings. However, many studies also show the major benefits to be derived from antiretroviral therapy in high-income and low-income countries. HIV-TB remains a major challenge to global health that requires substantial increases in resource allocation and concerted international action.


Amphiphilic conetworks as regenerative controlled releasing antimicrobial coatings.
Bitelechelic polydimethylsiloxanes (PDMS) and 2-hydroxyethylacrylate (HEA)/acrylic acid(AA) were photopolymerized to give nanophase separated amphiphilic 20-mum-thin coatings covalently attached to glass. The coatings quickly take up the antimicrobial surfactant cetyltrimethylammonium chloride (CTAC). After a 30 min loading period the release of CTAC in water was followed by simultaneously measuring both the antimicrobial activity of the coating's surface against Staphylococcus aureus and the release of the structurally related dye Rhodamine B. Depending on the composition the antimicrobial activity remained up to 3 weeks. The influence of different pH, varying sodium chloride concentrations, and the surfactant Pluronic was investigated. However, even in the cases of 160 mM NaCl and 1 wt.% Pluronic as release medium, the antimicrobial activity remained more than 6 days in case of a coating consisting of 45 wt.% PDMS, 31 wt.% PHEA, and 25 wt.% PAA. Mechanistic investigations revealed that the CTAC-loaded coatings act like contact-active surfaces, i.e., they do not kill microbes in the surrounding solution but only on their surface. This supports our hypothesis that the antimicrobial action is due to a concentration gradient of CTAC on the surface, allowing it to be antimicrobial on contact and to release only very low concentration of the biocide into the surrounding.


Single-antibiotic use for penetrating abdominal trauma.
A prospective randomized study compared the use of moxalactam disodium vs clindamycin phosphate and tobramycin sulfate for treatment of 190 patients with penetrating abdominal trauma. Twenty-seven patients were disqualified because of early death or failure to follow the protocol. The patients in each group were comparable regarding the cause and severity of injury. No significant difference was seen in the incidence of intra-abdominal infection between the moxalactam-treated group (13%) and the clindamycin- and tobramycin-treated group (9%). The intra-abdominal infection rate in patients with colon injuries (21%) was significantly increased when compared with the patients without colon injuries (6%), but the antibiotic regimen did not significantly change the infection rate. No evidence of bleeding problems from moxalactam were noted. Changes in prothrombin and partial thromboplastin times appeared to be related to shock rather than the use of moxalactam. The most severe coagulopathies occurred prior to moxalactam therapy and were seen only in those patients who had shock requiring 10 or more units of blood. Moxalactam is as effective as combination (clindamycin and tobramycin) antimicrobial therapy in patients with penetrating abdominal trauma.


Emergency department physician telemedical triage.
Telemedical physician triage (TPT) is a potential application of telemedicine in the emergency department (ED). We report the technical success, patient satisfaction, and effect on ED throughput metrics (length of stay [LOS] and time to physician evaluation [TPE]) of TPT performed on a mobile platform. Patients underwent standard nursing triage with or without TPT. Technical success is reported as raw data. Patient satisfaction is reported as raw data±standard deviation on a 5-point (low-to-high) scale. LOS and TPE are reported as mean±SD [95% CI] values. Statistical analyses of LOS and TPE are via two-sample t test. One hundred six patients were registered during intervention periods, and TPT was completed in 36 (34%). One hundred ninety-six patients were registered during control periods. The technical success rate was 95%. Average patient satisfaction was 4.7 on a 5-point scale. The primary analysis (106 patients) showed no change in LOS (266±101 [244-288] min versus 258±172 [234-282] min) but a trend toward improved TPE with TPT (35±28 [29-41] min versus 42±31 [38-46] min) (p=0.052). A secondary analysis (36 patients) showed no change in LOS (273±125 [231-316] min versus 258±172 [234-282] min) but improved TPE with TPT (16±15 [11-21] min versus 42±31 [38-46] min) (p<0.0001). TPT in the ED on a mobile platform was technically successful, well accepted by patients, and associated with a decrease in TPE but not LOS.


[Use of autoblood and its components in orthopedics and traumatology].
The results of the autoblood donation in 304 patients with complex surgical operations in orthopedics and traumatology are analyzed. The method of the intraoperation blood loss compensation with own red cells is offered. It should be noted that the red cells must be prepared 2 days and less before the operation. The use of modern methods of autoblood donation allowed to reduce 3 times the requirement in homologous blood.


Methylthioadenosine phosphorylase expression in cutaneous squamous cell carcinoma.
The methylthioadenosine phosphorylase (MTAP) gene is a tumour suppressor gene, located on chromosome 9p21, 100 kb telomeric of the p15 and p16 genes, which are often deleted in tumor cells. The role of MTAP protein expression in the genesis of cutaneous squamous cell carcinoma (SCC) is currently not known. In a previous study we have shown the frequent occurrence of allelic imbalance/loss of heterozygosity (AI/LOH) in cutaneous SCCs using AI/LOH markers flanking the p15, p16, and MTAP genes and demonstrated reduction in p15 and p16 protein expression in comparison to normal human skin. The present study is a continuation to our previous studies, aimed at determining possible roles played by MTAP protein expression in the genesis of cutaneous SCC. The expression of MTAP protein was detected using immunohistochemical approach in 109 micro array cutaneous SCC and 20 normal human skin tissue samples. The expression of MTAP was not significantly different in the cutaneous SCC cases as compared with normal human skin. This may indicate that MTAP protein expression does not contribute to the genesis of cutaneous SCC.


[Mechanism of the pro-oxidant activity of tetracycline].
It was shown on male rats that like ethanol tetracycline increased lipid peroxidation (LPO) in the hepatocyte membranes, evident from increased levels of diene conjugates and malone dialdehyde in the liver homogenates, especially on their combination. The signal amplitude of the EPR-forms of cytochrome P-450 and Cu-, Mo- and Fe-containing proteins did not change, while the content of the EPR-forms of the free radicals increased. High efficiency of antioxidants, such as tocopherol acetate, sodium selenite and tincture of Astragalus L. is indirect evidence of the role of the free radicals in initiation of LPO in tetracycline affections of the liver.


Lovastatin and phenylacetate inhibit the induction of nitric oxide synthase and cytokines in rat primary astrocytes, microglia, and macrophages.
This study explores the role of mevalonate inhibitors in the activation of NF-kbeta and the induction of inducible nitric oxide synthase (iNOS) and cytokines (TNF-alpha, IL-1beta, and IL-6) in rat primary astrocytes, microglia, and macrophages. Lovastatin and sodium phenylacetate (NaPA) were found to inhibit LPS- and cytokine-mediated production of NO and expression of iNOS in rat primary astrocytes; this inhibition was not due to depletion of end products of mevalonate pathway (e.g., cholesterol and ubiquinone). Reversal of the inhibitory effect of lovastatin on LPS-induced iNOS expression by mevalonate and farnesyl pyrophosphate and reversal of the inhibitory effect of NaPA on LPS-induced iNOS expression by farnesyl pyrophosphate, however, suggests a role of farnesylation in the LPS-mediated induction of iNOS. The inhibition of LPS-mediated induction of iNOS by FPT inhibitor II, an inhibitor of Ras farnesyl protein transferase, suggests that farnesylation of p21(ras) or other proteins regulates the induction of iNOS. Inhibition of LPS-mediated activation of NF-kbeta by lovastatin, NaPA, and FPT inhibitor II in astrocytes indicates that the observed inhibition of iNOS expression is mediated via inhibition of NF-kbeta activation. In addition to iNOS, lovastatin and NaPA also inhibited LPS-induced expression of TNF-alpha, IL-1beta, and IL-6 in rat primary astrocytes, microglia, and macrophages. This study delineates a novel role of the mevalonate pathway in controlling the expression of iNOS and different cytokines in rat astrocytes, microglia, and macrophages that may be important in developing therapeutics against cytokine- and NO-mediated neurodegenerative diseases.


Cryo-reconstructions of P22 polyheads suggest that phage assembly is nucleated by trimeric interactions among coat proteins.
Bacteriophage P22 forms an isometric capsid during normal assembly, yet when the coat protein (CP) is altered at a single site, helical structures (polyheads) also form. The structures of three distinct polyheads obtained from F170L and F170A variants were determined by cryo-reconstruction methods. An understanding of the structures of aberrant assemblies such as polyheads helps to explain how amino acid substitutions affect the CP, and these results can now be put into the context of CP pseudo-atomic models. F170L CP forms two types of polyhead and each has the CP organized as hexons (oligomers of six CPs). These hexons have a skewed structure similar to that in procapsids (precursor capsids formed prior to dsDNA packaging), yet their organization differs completely in polyheads and procapsids. F170A CP forms only one type of polyhead, and though this has hexons organized similarly to hexons in F170L polyheads, the hexons are isometric structures like those found in mature virions. The hexon organization in all three polyheads suggests that nucleation of procapsid assembly occurs via a trimer of CP monomers, and this drives formation of a T = 7, isometric particle. These variants also form procapsids, but they mature quite differently: F170A expands spontaneously at room temperature, whereas F170L requires more energy. The P22 CP structure along with scaffolding protein interactions appear to dictate curvature and geometry in assembled structures and residue 170 significantly influences both assembly and maturation.


The COMFORT Communication Model: A Nursing Resource to Advance Health Literacy in Organizations.
The COMFORT Model has recently been revised based on feedback from bedside nurses working in palliative care and oncology and includes the following components: Connect, Options, Making Meaning, Family Caregiver, Openings, Relating, and Team. Based on clinical and nonclinical research in hospital, hospice, palliative care, and interdisciplinary education settings, the authors present the updated COMFORT Model. Originally introduced in 2012 to support the work of the nurse, the model is not a linear guide, an algorithm, a protocol, or a rubric for sequential implementation by nurses, but rather a set of communication principles that are practiced concurrently and reflectively during patient/family care. In its restructuring, we focus on the role of health literacy throughout the COMFORT components in relationship to the health literacy attributes of a health care organization. A brief summary of COMFORT components is provided and includes strategies and competencies contributing to a health-literate care organization. Both health literacy and COMFORT are explored using specific communication challenges that underscore the role of the nurse in accomplishing person-centered and culturally responsive care, especially in chronic and terminal illness. The integration of the COMFORT Model into nursing education is proposed.


Modeling preferential attraction to infected hosts in vector-borne diseases.
Vector-borne infectious diseases cause more than 700,000 deaths a year and represent an increasing threat to public health worldwide. Strategies to mitigate the spread of vector-borne diseases can benefit from a thorough understanding of all mechanisms that contribute to viral propagation in human. A recent study showed that Aedes mosquitoes (the vectors for dengue and Zika virus, among others) are preferentially attracted to infected hosts. In order to determine the impact of this factor on viral spread, we built a dedicated agent-based model and parameterized it on dengue fever. We then performed a systematic study of how mosquitoes' preferential attraction for infected hosts affects viral load and persistence of the infection. Our results indicate that even small values of preferential attraction have a dramatic effect on the number of infected individuals and the persistence of the infection in the population. Taken together, our results suggests that interventions aimed at decreasing the preferential attraction of vectors for infected hosts can reduce viral transmission and thus can have public health implications.


Ferroelectric switching and electrochemistry of pyrrole substituted trialkylbenzene-1,3,5-tricarboxamides.
We explore a new approach to organic ferroelectric diodes using a benzene-tricarboxamide (BTA) core connected with C10 alkyl chains to pyrrole groups, which can be polymerized to provide a semiconducting ferroelectric material. The compound possesses a columnar hexagonal liquid crystalline (LC) phase and exhibits ferroelectric switching. At low switching frequencies, an additional process occurs, which leads to a high hysteretic charge density of up to ∼1000 mC/m2. Based on its slow rate, the formation of gas bubbles, and the emergence of characteristic polypyrrole absorption bands in the UV-Vis-NIR, the additional process is identified as the oxidative polymerization of pyrrole groups, enabled by the presence of amide groups. Polymerization of the pyrrole groups, which is essential to obtain semiconductivity, is limited to thin layers at the electrodes, amounting to ∼17 nm after cycling for 21 h. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2017, 55, 673-683.


Hypospadias prevalence by severity and associated risk factors: A population-based active surveillance analysis.
Hypospadias is one of the most common congenital anomalies. Trends of hypospadias prevalence by severity are not well reported. Most prevalence studies consist of pooled data from different countries or states suffer from low data quality due to inconsistent methodologies, limited variables, and lack of categorization of hypospadias severity. The objective of this study is to examine the prevalence of hypospadias by degrees of severity and associated risk factors using combined data sources from a stable and well-defined population. The study population includes infants born with hypospadias to mothers residing in Arkansas from 1997 to 2016. Cases were identified from an active population-based surveillance program of birth defects. Identified hypospadias cases from surveillance data were linked to birth certificate and to a clinical database. These two data sources provide more details on the location of the defect and maternal and infant characteristics. The prevalence and 95% confidence intervals were calculated using total male live births as denominator. Chi-square test was used to assess the association of nominal variables. Logistic regression was used to calculate adjusted odds ratio. A total 3230 hypospadias cases were identified from 1997 to 2016. The overall prevalence is 83.0 per 10,000 male births. A majority of cases (56.7%) were classified as first degree with the others having second degree (22.8%), third degree (4.7%) or not otherwise specified (15.6%). The highest prevalence of hypospadias was observed among Non-Hispanic whites. Higher prevalence also was observed among mothers in the older age group with no prenatal care in the first trimester and with gestational hypertension or diabetes. Premature or small for gestational age infants tend to have higher prevalence across all levels of severity. The number of hypospadias cases increased over time. After maternal age, race and education were adjusted, higher risk persisted for infants of restricted fetal growth, mothers with gestational hypertension or diabetes and the cohort of 2013-2016. There is an increase of hypospadias cases in Arkansas. Several maternal and infant characteristics associated with higher prevalence for all levels of severity are worth further investigation.


Heterogeneous Language Profiles in Patients with Primary Progressive Aphasia due to Alzheimer's Disease.
The logopenic variant of Primary Progressive Aphasia (lvPPA) is associated with underlying Alzheimer's disease (AD) pathology and characterized by impaired single word retrieval and repetition of phrases and sentences. We set out to study whether logopenic aphasia is indeed the prototypic language profile in PPA patients with biomarker evidence of underlying AD pathology and to correlate language profiles with cortical atrophy patterns on MRI. Inclusion criteria: (I) clinical diagnosis of PPA; (II) CSF profile and/or PiB-PET scan indicative for amyloid pathology; (III) availability of expert language evaluation. Based on language evaluation, patients were classified as lvPPA (fulfilling lvPPA core criteria), lvPPA extended (fulfilling core criteria plus other language disturbances), or PPA unclassifiable (not fulfilling lvPPA core criteria). Cortical atrophy patterns on MRI were visually rated and quantitative measurements of cortical thickness were performed using FreeSurfer. We included 22 patients (age 67±7 years, 50% female, MMSE 21±6). 41% were classified as lvPPA, 36% as lvPPA extended with additional deficits in language comprehension and/or confrontation naming, and 23% as PPA unclassifiable. By both qualitative and quantitative measurements, patients with lvPPA showed mild global cortical atrophy on MRI, whereas patients with lvPPA extended showed more focal cortical atrophy, predominantly at the left tempo-parietal side. For PPA unclassifiable, qualitative measurements revealed a heterogeneous atrophy pattern. Although most patients fulfilled the lvPPA criteria, we found that their language profiles were heterogeneous. The clinical and radiological spectrum of PPA due to underlying AD pathology is broader than pure lvPPA.


Deep sleep and parietal cortex gene expression changes are related to cognitive deficits with age.
Age-related cognitive deficits negatively affect quality of life and can presage serious neurodegenerative disorders. Despite sleep disruption's well-recognized negative influence on cognition, and its prevalence with age, surprisingly few studies have tested sleep's relationship to cognitive aging. We measured sleep stages in young adult and aged F344 rats during inactive (enhanced sleep) and active (enhanced wake) periods. Animals were behaviorally characterized on the Morris water maze and gene expression profiles of their parietal cortices were taken. Water maze performance was impaired, and inactive period deep sleep was decreased with age. However, increased deep sleep during the active period was most strongly correlated to maze performance. Transcriptional profiles were strongly associated with behavior and age, and were validated against prior studies. Bioinformatic analysis revealed increased translation and decreased myelin/neuronal pathways. The F344 rat appears to serve as a reasonable model for some common sleep architecture and cognitive changes seen with age in humans, including the cognitively disrupting influence of active period deep sleep. Microarray analysis suggests that the processes engaged by this sleep are consistent with its function. Thus, active period deep sleep appears temporally misaligned but mechanistically intact, leading to the following: first, aged brain tissue appears capable of generating the slow waves necessary for deep sleep, albeit at a weaker intensity than in young. Second, this activity, presented during the active period, seems disruptive rather than beneficial to cognition. Third, this active period deep sleep may be a cognitively pathologic attempt to recover age-related loss of inactive period deep sleep. Finally, therapeutic strategies aimed at reducing active period deep sleep (e.g., by promoting active period wakefulness and/or inactive period deep sleep) may be highly relevant to cognitive function in the aging community.


R-factor-mediated resistance to sulfonamides by a plasmid-borne, drug-resistant dihydropteroate synthase.
Evidence was found for the existence of an episome-specified variant of the enzyme dihydropteroate synthase involved in folic acid formation. Since the plasmid-borne enzyme showed a decreased susceptibility for sulfonamide inhibition and was transferable together with resistance to this drug, it is proposed that diploidy for the target enzyme in some cases could be the mechanism of R-factor-mediated resistance to sulfonamides. Two types of evidence were obtained. One was the rescue from temperature sensitivity of bacterial mutants with a lesion in the chromosomal dihydropteroate synthase by the R factor R1dr19 mediating sulfonamide resistance. The other evidence was found by the determination of dihydropteroate forming activity in extracts from R(-) and R(+) bacteria. Cells harboring R1dr19 were found to contain an enzyme activity which was far less susceptible to sulfonamide inhibition than the corresponding activity from R(-) cells.


Macrophages stimulated with IFN-gamma activate NF-kappa B and induce MCP-1 gene expression in primary human endothelial cells.
A novel coculture model was established to study the effects of reactive oxygen (ROS) and reactive nitrogen species (RNS) generated by RAW 264.7 macrophages on NF-kappa B activation and monocyte chemoattractant protein (MCP-1) gene expression in primary human endothelial cells (HUVEC). This model simulates free radical-mediated interactions occurring in the process of cardiovascular diseases. The coculture of macrophages grown on filters and stimulated by IFN-gamma-induced a pro-oxidant environment and resulted in increased DNA binding and NF-kappa B transactivation in HUVEC. Activation of NF-kappa B in endothelial cells was accompanied by an evident increase in the expression of the mRNA encoding for the MCP-1 protein, which stimulates the recruitment of monocytes into the arterial wall. Present data suggest that the influx of stimulated monocytes into the subendothelial space could affect redox-sensitive transcription factors and gene expression in the endothelium, thereby possibly leading to endothelial dysfunction.


Platelet antibodies in immune thrombocytopenic purpura and onyalai.
A prospective study was undertaken to assess the nature, incidence and natural history of platelet antibodies in patients with immune thrombocytopenic purpura (ITP) and patients with onyalai, using an immunofluorescent technique. Twelve patients under 14 years old and 11 patients 14-75 years old with ITP, and 24 patients with onyalai were studied. Alternate younger patients were treated with corticosteroids. Ten of the 12 children with ITP had IgG platelet antibodies in their serum, which disappeared as the platelet count recovered. Steroid therapy did not change the course of the disease or the antibody response. Of the 24 patients with onyalai, 23 had IgG antibodies and 18 had IgM antibodies, which were still present after 14 days and unrelated to their rise in platelet count. Steroid therapy did not affect the platelet count or the antibody titre. The difference in immune response of ITP and onyalai points to a difference in aetiology. The clinical presence of IgM antibodies in onyalai fits the hypothesis that a toxin, possibly acting as a hapten, is responsible for this form of thrombocytopenia.


125I seeds implantation for an elderly patient of skin squamous cell carcinomas with ulcer guided by ultrasound.
The skin squamous cell carcinoma (SCC) is a kind of malignancy of keratinocytes. SCC was originated within the epidermis or relevant appendages, which commonly occurred on sunlight exposure sites, such as the head and neck. This case report described an 85-year-old female patient with skin SCC at the right frontal, accompanied with skin ulcer. This patient suffered from indications that were not suitable for surgical resection, including old age, Alzheimer's disease (AD), lacunar infarction, hydropericardium, and some other concomitant diseases. In addition, the external beam radiotherapy was rejected by the relatives of this patient. Then, the patient received 125I seeds interstitial brachytherapy guided by bedside ultrasound. The tumor response was evaluated based on the response evaluation criteria in solid tumors version 1.1 criteria. Complete response was achieved 4 months after brachytherapy. No complications and recurrence were observed during 8-month follow-up. As the sole modality, the 125I seeds implantation could be a reasonable and safe alternative for treating skin SCC with ulcer, especially for the elderly patients.


Organic Radical Contrast Agents Based on Polyacetylenes Containing 2,2,6,6-Tetramethylpiperidine 1-Oxyl (TEMPO): Targeted Magnetic Resonance (MR)/Optical Bimodal Imaging of Folate Receptor Expressing HeLa Tumors in Vitro and in Vivo(a).
Nitroxides have great potential as magnetic resonance imaging (MRI) contrast agents for tumor detection. Polyacetylenes(PAs) containing 2,2,6,6-tetramethyl-piperidine oxyl (TEMPO) and poly(ethylene glycol) were synthesized via metathesis polymerization of the corresponding substituted acetylenes to be used for targeted bimodal MRI /optical imaging of tumors. The poly(ethylene glycol) in the polyacetylenes enables covalent conjugation of carboxyl fluorescein and folic acid (FA) with hydroxyl groups to develop targeted multifunctional organic radical contrast agents (ORCAs). In vitro studies confirm the excellent binding specificity and subsequent enhanced cellular internalization of the targeted ORCAs (PA-TEMPO-FI-FA) without cytotoxicity. In vivo T1-weighted MRI demonstrates the active tumor targeting ability of PA-TEMPO-FI-FA to generate specific contrast enhancement in mice bearing HeLa tumors. Moreover, longitudinal optical imaging displays high tumor accumulation after 1 h post-injection of PA-TEMPO-FI-FA. These results indicate that multifunctional ORCAs may provide a tumor-targeted delivery platform for further molecular imaging guided cancer therapy.


Behavioral and educational limitations after chemotherapy for childhood acute lymphoblastic leukemia or Wilms tumor.
The improved prognosis of childhood cancer makes monitoring of functional outcome important. The purpose of this study was to evaluate behavioral and educational functioning in survivors of childhood acute lymphoblastic leukemia (ALL) or a Wilms tumor. In this study, children with ALL received central nervous system directed chemotherapy without cranial irradiation. In a multicenter study, behavioral functioning and school performance was examined in 199 children age 4 to 18. Sixty-four children were at least 1 year from finishing treatment with chemotherapy for ALL (n = 28) or a Wilms tumor (n = 36). They were compared with siblings (n = 37) and with a control group of healthy schoolchildren (n = 98). A moderately increased risk of behavioral and educational problems was found in children with ALL but not in children with Wilms tumor. School performance was poorer in children with ALL attending primary school compared with same-age peers; however, the rate of utilization of special education services was low. Teacher-rated behavior and mathematics performance was correlated with attention function in children with ALL. An excess of problem behavior and underperformance at school was found in the ALL high-risk group compared with the standard-risk group. No differences were found between siblings and controls. Evidence is provided of subtle but significant behavioral and educational problems in survivors of childhood ALL, but no dysfunctions in survivors of a Wilms tumor. Careful follow-up of children with ALL treated with chemotherapy only is warranted.


"Stay strong! keep ya head up! move on! it gets better!!!!": resilience processes in the healthMpowerment online intervention of young black gay, bisexual and other men who have sex with men.
Overlapping stigmas related to sexual minority-, race/ethnicity-, and HIV-status pose barriers to HIV prevention and care and the creation of supportive social networks for young, Black, gay, bisexual, and other men who have sex with men (GBMSM). A risk-based approach to addressing the HIV epidemic focuses on what is lacking and reinforces negative stereotypes about already-marginalized populations. In contrast, a strengths-based approach builds on Black GBMSM's existing strengths, recognizing the remarkable ways in which they are overcoming barriers to HIV prevention and care. HealthMpowerment (HMP) is an online, mobile phone optimized intervention that aimed to reduce condomless anal intercourse and foster community among young Black GBMSM (age 18-30). Applying a resilience framework, we analyzed 322 conversations contributed by 48 HMP participants (22/48 living with HIV) on the intervention website. These conversations provided a unique opportunity to observe and analyze dynamic, interpersonal resilience processes shared in response to stigma, discrimination, and life challenges experienced by young Black GBMSM. We utilized an existing framework with four resilience processes and identified new subthemes that were displayed in these online interactions: (1) Exchanging social support occurred through sharing emotional and informational support. (2) Engaging in health-promoting cognitive processes appeared as reframing, self-acceptance, endorsing a positive outlook, and agency and taking responsibility for outcomes. (3) Enacting healthy behavioral practices clustered into modeling sex-positive norms, reducing the risk of acquiring or transmitting HIV, and living well with HIV. (4) Finally, empowering other gay and bisexual youth occurred through role modeling, promoting self-advocacy, and providing encouragement. Future online interventions could advance strengths-based approaches within HIV prevention and care by intentionally building on Black GBMSM's existing resilience processes. The accessibility and anonymity of online spaces may provide a particularly powerful intervention modality for amplifying resilience among young Black GBMSM.


Three-year radiologic follow-up of marginal bone loss around titanium dioxide grit-blasted dental implants with and without fluoride treatment.
This study was conducted to evaluate the influence of fluoride-treated, titanium dioxide grit-blasted implant surfaces on marginal bone levels through radiography at 3 years after functional loading and to determine whether a correlation exists between primary stability and marginal bone levels of implants. Edentulous patients who sought two-implant-retained mandibular overdentures and were available for follow-up were included. Each patient received two implants in the mandible; one implant received fluoride treatment and the other did not. To determine primary stability of the dental implants, resonance frequency analysis was performed at the time of implant placement. Panoramic radiographs were obtained preoperatively, at the time of overdenture connection, and at 6-month and 1- , 2-, and 3-year follow-up examinations. Fifty-two edentulous patients with a mean age of 58 years (range, 40 to 70 years) were enrolled. All implants survived the observation period. No statistically significant differences were observed in the marginal bone levels of implants with and without fluoride treatment at 6 months and 1, 2, and 3 years (P > .05). No significant relationship was found between marginal bone levels and the recorded resonance frequency analysis values of the implants. Fluoride treatment of titanium dioxide grit-blasted implants was not effective in preventing marginal bone loss, and primary stability did not affect marginal bone loss around implants placed in anterior mandibles.


Use of transgenic mice to study the role of apolipoprotein E in lipid metabolism and atherosclerosis.
Insight into the role of apolipoprotein (apo) E in lipoprotein metabolism and atherosclerosis has increased dramatically with the generation and analysis of novel transgenic, knockout and knockin mouse models. Moreover, the recent development and application of somatic gene and cell transfer technologies which can express (or delete) apoE in specific tissues of virtually any mouse model have further added to this increase in knowledge. It is now well established that apoE plays a role in virtually every step in the metabolism of very low-density lipoproteins and in the efflux of cholesterol from macrophages. In this review we will discuss recent insights into the role of apoE in these processes with particular emphasis on the specific effects of variation in apoE structure and quantity.