Association between particulate matter containing EPFRs and neutrophilic asthma through AhR and Th17.
Epidemiological data associate high levels of combustion-derived particulate matter (PM) with deleterious respiratory outcomes, but the mechanism underlying those outcomes remains elusive. It has been acknowledged by the World Health Organization that PM exposure contributes to more than 4.2 million all-cause mortalities worldwide each year. Current literature demonstrates that PM exacerbates respiratory diseases, impairs lung function, results in chronic respiratory illnesses, and is associated with increased mortality. The proposed mechanisms revolve around oxidative stress and inflammation promoting pulmonary physiological remodeling. However, our previous data found that PM is capable of inducing T helper cell 17 (Th17) immune responses via aryl hydrocarbon receptor (Ahr) activation, which was associated with neutrophilic invasion characteristic of steroid insensitive asthma. In the present study, we utilized a combination of microarray and single cell RNA sequencing data to analyze the immunological landscape in mouse lungs following acute exposure to combustion derived particulate matter. We present data that suggest epithelial cells produce specific cytokines in the aryl hydrocarbon receptor (Ahr) pathway that inform dendritic cells to initiate the production of pathogenic T helper (eTh17) cells. Using single-cell RNA sequencing analysis, we observed that upon exposure epithelial cells acquire a transcriptomic profile indicative of increased Il-17 signaling, Ahr activation, Egfr signaling, and T cell receptor and co-stimulatory signaling pathways. Epithelial cells further showed, Ahr activation is brought on by Ahr/ARNT nuclear translocation and activation of tyrosine kinase c-src, Egfr, and subsequently Erk1/2 pathways. Collectively, our data corroborates that PM initiates an eTh17 specific inflammatory response causing neutrophilic asthma through pathways in epithelial, dendritic, and T cells that promote eTh17 differentiation during initial PM exposure.


cDNA Display: A Stable and Simple Genotype-Phenotype Coupling Using a Cell-Free Translation System.
A cDNA display method was developed based on the mRNA display method to increase its stability and efficiency for the directed evolution of various kinds of peptides and proteins. In this method, the puromycin-linker is a key molecule to realize smart genotype-phenotype coupling. A recently improved puromycin-linker and its use were explained in detail for the in vitro selection of peptides and proteins using the cDNA display method.


Diagnosis and treatment of vulvar carcinoma in situ with anal involvement in young women. Two case reports and literature review.
The diagnostic procedure and therapy of carcinoma in situ of the vulva and the anal region are presented by reporting two cases of young women. The rising incidence of the multifocal lesions with a high recurrence rate after treatment is discussed and the relevant literature is reviewed.


Embryolethality of bromofenofos in rats.
Bromofenofos, an organophosphorus anthelmintic, was suspended in deionized water and administered once daily to pregnant rats by gastric intubation on days 8 through 15 of pregnancy in doses of 0, 2.5, 5, 10 and 20 mg/kg. The dams were killed on day 21 of pregnancy, and the number of implants, resorptions and live fetuses was counted. All fetuses were weighed and examined by routine teratological methods. As the results showed, this compound was highly embryolethal in the 20 mg/kg group; approx. 91% of the implants were resorbed at this dose level. Although none of the fetuses were externally malformed in any group, the incidence of skeletal and internal malformations was significantly increased in fetuses in the 20 mg/kg group. Skeletal malformations observed at this dose level were bipartite vertebral centra and wavy ribs. Internal malformations involved anophthalmia, hydronephrosis and hypoplasia of the uterus.


Mantle Cell Lymphoma: A Rare Vallecular Tumour.
Vallecular lymphoma is an extremely rare tumour of oropharynx. We report a case of 61-year-old gentleman presented with severe dysphagia and globus sensation for two months. Patient underwent endoscopic transoral tumour debulking for diagnostic and therapeutic purpose. Histopathologically, patient was diagnosed as mantle cell lymphoma (MCL). In this case report, atypical presentation of the disease, histopathological features and its current treatments are discussed.


Effective gene expression prediction from sequence by integrating long-range interactions.
How noncoding DNA determines gene expression in different cell types is a major unsolved problem, and critical downstream applications in human genetics depend on improved solutions. Here, we report substantially improved gene expression prediction accuracy from DNA sequences through the use of a deep learning architecture, called Enformer, that is able to integrate information from long-range interactions (up to 100 kb away) in the genome. This improvement yielded more accurate variant effect predictions on gene expression for both natural genetic variants and saturation mutagenesis measured by massively parallel reporter assays. Furthermore, Enformer learned to predict enhancer-promoter interactions directly from the DNA sequence competitively with methods that take direct experimental data as input. We expect that these advances will enable more effective fine-mapping of human disease associations and provide a framework to interpret cis-regulatory evolution.


[Intrapulmonary sarcoid, presenting as tumor or as multiple pulmonary nodules with and without cavities (author's transl)].
Eight cases of nodular, partially cavitary intrapulmonary--mainly acute--sarcoid mimicking metastatic disease or cavitary disease of other etiology are presented to point out the fact that sarcoid can occur in this form. Almost all these patients were young and asymptomatic with the lesions discovered incidentally on the chest films taken for other reasons. The pulmonary nodules and cavities present differential diagnostic problems; with the concomitant--or previous--presence of hilar or mediastinal lymph-adenopathy and the finding of unsharp borders of the nodules somewhat supporting the diagnosis of sarcoid.


Bacterial meningitis--1982.
The etiologic agents in bacterial meningitis vary with time, geography, and patient age. Predominant pathogens are Escherichia coli, group B streptococci, Listeria monocytogenes, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae. Approximately 70 percent of all cases occur in children under the age of five. The case-fatality rate in the United States in 1978 was 13.6 percent, but it is known that underreporting of cases, and therefore of case-fatalities, occurs. Prevention by vaccine appears to be the ultimate solution, but until a vaccine is developed emphasis should be on rapid diagnosis, improved management, and proper choice of antibiotic.


Short courses of high-dose inhaled budesonide and serum IgG subclass levels in healthy volunteers.
The incidence of systemic side effects of inhaled budesonide increases at doses exceeding 2000 micrograms/day. This study was carried out to investigate whether high-dose inhaled budesonide affects serum IgG subclass concentrations in healthy adult volunteers. Two groups of 10 subjects each inhaled 2.4 mg of budesonide per day in a double-blind, crossover study of morning (8:00 AM and noon, group A) and diurnal (8:00 AM and 8:00 PM, group B) dosing schedules for 4 weeks each, separated by a 2-week washout period. The budesonide was inhaled through a pressurized metered-dose inhaler, mounted on a 750 ml Nebuhaler (ASTRA Pharmaceuticals, Lund, Sweden). The IgG subclass levels were determined at baseline and every 2 weeks until the end of the study period (10 weeks). There were no statistically significant changes in the serum IgG subclass concentrations over the 10-week study period in group A, group B, or groups A and B combined. Inhalation of budesonide, 2.4 mg/day, through a large-volume spacer for repeated 1-month periods does not influence serum IgG subclass concentrations in healthy adults, suggesting that budesonide does not cause systemic humoral immunosuppression when given at therapeutic doses.


Molecular Dissection of Structural Variations Involved in Antithrombin Deficiency.
Inherited antithrombin deficiency, the most severe form of thrombophilia, is predominantly caused by variants in SERPINC1. Few causal structural variants have been described, usually detected by multiplex ligation-dependent probe amplification or cytogenetic arrays, which only define the gain or loss and the approximate size and location. This study has done a complete dissection of the structural variants affecting SERPINC1 of 39 unrelated patients with antithrombin deficiency using multiplex ligation-dependent probe amplification, comparative genome hybridization array, long-range PCR, and whole genome nanopore sequencing. Structural variants, in all cases only affecting one allele, were deleterious and caused a severe type I deficiency. Most defects were deletions affecting exons of SERPINC1 (82.1%), but the whole cohort was heterogeneous, as tandem duplications, deletion of introns, or retrotransposon insertions were also detected. Their size was also variable, ranging from 193 bp to 8 Mb, and in 54% of the cases involved neighboring genes. All but two structural variants had repetitive elements and/or microhomologies in their breakpoints, suggesting a common mechanism of formation. This study also suggested regions recurrently involved in structural variants causing antithrombin deficiency and found three structural variants with a founder effect: the insertion of a retrotransposon, duplication of exon 6, and a 20-gene deletion. Finally, nanopore sequencing was determined to be the most appropriate method to identify and characterize all structural variants at nucleotide level, independently of their size or type.


Carvedilol protects against hepatic ischemia/reperfusion injury in high-fructose/high-fat diet-fed mice: Role of G protein-coupled receptor kinase 2 and 5.
Hepatic ischemia/reperfusion injury (H-IRI) is associated with irreversible liver damage. The current study aimed to investigate the protective effect of carvedilol against H-IRI in high-fructose high-fat diet (HFrHFD)-fed mice and the role of G protein-coupled receptor kinase 2 and 5 (GRK2 and GRK5). Mice were fed HFrHFD for 16 weeks; then mice were subjected to 30 min of ischemia followed by 1 h of reperfusion at the end of feeding period. Carvedilol (20 mg/kg, i.p.) was administered 30 min before ischemia. To explore the role of GRK2 and GRK5 in mediating carvedilol effects, paroxetine (GRK2 inhibitor, 10 mg/kg, i.p.) and amlexanox (GRK5 inhibitor, 25 mg/kg, i.p.) were administered 30 min before carvedilol administration. Liver function, histopathology and hepatic oxidative stress, as well as inflammatory and apoptotic markers were measured at the end of the experiment. In addition, adrenergic receptor downstream signals were measured in the liver. Results showed increased markers of liver injury (ALT and AST) in mice subjected to H-IRI. Moreover, liver injury was associated with slight collagen deposits as revealed by histopathology and elevated hepatic levels of oxidative stress, inflammatory and apoptotic markers. On the other hand, carvedilol protected mice against H-IRI and improved all associated pathological changes. Furthermore, pre-injection of either GRK2 or GRK5 inhibitor did not change carvedilol effects on serum ALT level and liver collagen deposits, while increased its antioxidant, anti-inflammatory and anti-apoptotic effects. In conclusion, carvedilol protects against H-IRI in HFrHFD-fed mice. GRK2 and GRK5 may not play a potential role in mediating this effect.


Association Between Elevated Mean Arterial Blood Pressure and Neurologic Outcome After Resuscitation From Cardiac Arrest: Results From a Multicenter Prospective Cohort Study.
Laboratory studies suggest elevated blood pressure after resuscitation from cardiac arrest may be protective; however, clinical data are limited. We sought to test the hypothesis that elevated postresuscitation mean arterial blood pressure is associated with neurologic outcome. Preplanned analysis of a prospective cohort study. Six academic hospitals in the United States. Adult, nontraumatic cardiac arrest patients treated with targeted temperature management after return of spontaneous circulation. Mean arterial blood pressure was measured noninvasively after return of spontaneous circulation and every hour during the initial 6 hours after return of spontaneous circulation. We calculated the mean arterial blood pressure and a priori dichotomized subjects into two groups: mean arterial blood pressure 70-90 and greater than 90 mm Hg. The primary outcome was good neurologic function, defined as a modified Rankin Scale less than or equal to 3. The modified Rankin Scale was prospectively determined at hospital discharge. Of the 269 patients included, 159 (59%) had a mean arterial blood pressure greater than 90 mm Hg. Good neurologic function at hospital discharge occurred in 30% of patients in the entire cohort and was significantly higher in patients with a mean arterial blood pressure greater than 90 mm Hg (42%) as compared with mean arterial blood pressure 70-90 mm Hg (15%) (absolute risk difference, 27%; 95% CI, 17-37%). In a multivariable Poisson regression model adjusting for potential confounders, mean arterial blood pressure greater than 90 mm Hg was associated with good neurologic function (adjusted relative risk, 2.46; 95% CI; 2.09-2.88). Over ascending ranges of mean arterial blood pressure, there was a dose-response increase in probability of good neurologic outcome, with mean arterial blood pressure greater than 110 mm Hg having the strongest association (adjusted relative risk, 2.97; 95% CI, 1.86-4.76). Elevated blood pressure during the initial 6 hours after resuscitation from cardiac arrest was independently associated with good neurologic function at hospital discharge. Further investigation is warranted to determine if targeting an elevated mean arterial blood pressure would improve neurologic outcome after cardiac arrest.


Apathy and cognitive performance in older adults with depression.
Recent studies have linked apathy to frontal lobe dysfunction in persons with dementia, but few studies have explored this relationship in older, depressed persons without dementia. We examined the association between apathy and cognitive function in a group of older persons with major depression using standardized neuropsychological tests. We hypothesized that presence of apathy in depression is associated with poorer frontal executive performance. We analyzed data from 89 older adults with major depression. We defined apathy using four items from the Hamilton Psychiatric Rating Scale for Depression which reflect the clinical state of apathy, including 'diminished work/interest,' 'psychomotor retardation,' 'anergy' and 'lack of insight.' Apathy most strongly correlated with two verbal executive measures (Stroop C and FAS), a nonverbal executive measure (Wisconsin Card Sorting Test-Other Responses), and a measure of information processing speed (Stroop B). Apathy was not associated with age, sex, education, medical illness burden, Mini-Mental State Examination score and Full Scale IQ score. Stepwise regression analyses of significant cognitive tests showed that apathy alone or apathy plus depression severity, age, or education accounted for a significant amount of the variance. The results of this study provide support for an apathy syndrome associated with poorer executive function in older adults with major depression.


Deep Recursive Embedding for High-Dimensional Data.
Embedding high-dimensional data onto a low-dimensional manifold is of both theoretical and practical value. In this article, we propose to combine deep neural networks (DNN) with mathematics-guided embedding rules for high-dimensional data embedding. We introduce a generic deep embedding network (DEN) framework, which is able to learn a parametric mapping from high-dimensional space to low-dimensional space, guided by well-established objectives such as Kullback-Leibler (KL) divergence minimization. We further propose a recursive strategy, called deep recursive embedding (DRE), to make use of the latent data representations for boosted embedding performance. We exemplify the flexibility of DRE by different architectures and loss functions, and benchmarked our method against the two most popular embedding methods, namely, t-distributed stochastic neighbor embedding (t-SNE) and uniform manifold approximation and projection (UMAP). The proposed DRE method can map out-of-sample data and scale to extremely large datasets. Experiments on a range of public datasets demonstrated improved embedding performance in terms of local and global structure preservation, compared with other state-of-the-art embedding methods. Code is available at https://github.com/tao-aimi/DeepRecursiveEmbedding.


Effects of shoulder position on axillary nerve positions during the split lateral deltoid approach.
The axillary nerve may be injured during percutaneous fixation of proximal humerus fractures. This study investigated the kinematic behavior of the superior and inferior borders of the axillary nerve under varying shoulder positions. This information may reduce iatrogenic neurologic injury during fracture reduction and hardware placement. The lateral deltoid approach was performed on 7 fresh frozen shoulders. The inferior and superior borders of the axillary nerve were tagged. Screws were placed in the anterior, middle, and posterior acromion as landmarks. Three-dimensional distances of the inferior and superior border of the nerve were measured to the mid-acromion while the shoulder was placed in combinations of forward flexion, vertical abduction, and humeral rotation. The distances were compared by repeated measures ANOVA statistical analysis. The distance from the mid-acromion to the superior border of the axillary nerve was 66.6 mm (+/-5.7), and to the inferior axillary nerve was 75.7 mm (+/-5.8) with the shoulder in neutral position. Vertical abduction to 60 degrees significantly moved the superior and inferior borders of the axillary nerve to a distance of 53.9 (+/-7.7) and 61.6 mm (+/-8.1), respectively (P < 0.005). Forward flexion had no significant effect on the position of the axillary nerve (P > 0.5). The longest distance from the mid-acromion to the inferior border of the axillary nerve was 86 mm with the arm forward flexed. The main determinant of axillary nerve position with respect to the acromion is vertical abduction. Axillary nerve position is essentially unaffected by varying degrees of humeral rotation and forward flexion. Vertical glenohumeral abduction to 60 degrees is required to move the nerve significantly closer to the acromion.


The sol-gel prepared SiO2-CaO-P2O5 composites doped with Metronidazole for application in local delivery systems.
The aim of this study was to evaluate the physical properties, chemical structure and bioactivity of sol-gel processed oxide (SiO(2)-CaO-P(2)O(5)) composites used as controlled release materials for Metronidazole-drug applied in periodontal disease treatment. The obtained composite materials were characterized by Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), the Brunauer-Emmet-Teller (BET) technique and further monitoring in the ultraviolet and visible light regions (UV-Vis) of the in vitro release of the drug over time. Using tetramethoxysilane (TMOS) as a precursor of silica matrix and calcium nitrate tetrahydrate (Ca(NO(3))(2) 4H(2)O), triethyl phosphite (P(OC(2)H(5))(3)) as precursors of CaO and P(2)O(5) respectively, xerogels with different morphology and physical properties were obtained. The applied modifications improved also the bioactivity and changed the profile of the drug release. Based on the presented results of this study, it may be concluded that applied xerogel matrices could be promising candidates for the formulation in local delivery systems.


Determination of noscapine's localization and interaction with the tubulin-α/β heterodimer.
Noscapine, the benzylisoquinoline alkaloid, 5-(4,5-Dimethoxy-3-oxo-1,3-dihydro-isobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-6-ium, has been extensively used as a cough-suppressing medication with low toxicity. It has been recently shown to also have anti-cancer activity in mice and humans. In this work, using in silico analyses, the most probable binding site for noscapine is identified to be at the intradimer region of the α and β subunits of the tubulin heterodimer. By utilization of small molecule docking techniques, and an analysis of the thermodynamically favorable binding modes of noscapine in its binding site, the key residues of tubulin monomers interacting with noscapine are determined. Upon noscapine binding, the conformational change in the tubulin heterodimer along with a potential long-range allosteric effect on both the N and E sites is studied by means of molecular dynamics simulations. Noscapine is found to function as a tubulin-stabilizing agent that interacts strongest with the lateral and longitudinal segments of the tubulin dimer, impacting the interaction between monomers in neighboring protofilaments. We infer that this may act as a depolymerization inhibitor of microtubules. As a result of this study, we have designed novel analogues of noscapine with the ultimate goal of finding agents with increased anti-tumor activity and lower inhibitory concentrations than that of noscapine.


Exercise and heart disease. Epidemiology of the "exercise hypothesis".
The "exercise hypothesis" states that exercise protects against coronary heart disease. Reviewed herein is the epidemiologic evidence for and against the "exercise hypothesis." The weight of evidence supports the view that exercisers have a lower risk of coronary disease, but that vigorous exercise cannot always prevent progression of coronary atherosclerosis and does increase the risk of sudden death in persons with advanced coronary atherosclerosis. It is concluded that the "exercise hypothesis" is plausible, even likely, but still unproved.


An assessment of tumor cell viability after in vitro freezing.
The identification of the minimum lethal temperature for tumor cells in vivo is difficult because of the secondary factors that are associated with the cryoinjury. This study attempts to identify this temperature by a combination of in vitro and in vivo techniques. Suspensions of Walker carcinoma cells were frozen at a rate of 1 degree C/min without cryoprotection, to either -10, -15, -20, -25, -30, -35 or -40 degrees C and held at that temperature for either 0, 10, 20, or 30 min. After spontaneous rewarming viability was assessed by a combination of vital dye studies and the growth of tumor cells inoculated into the liver and subcutaneous tissue of male, Sprague-Dawley rats. Trypan blue studies indicated that less than 1% of the cells frozen to -35 degrees C were considered viable, yet significant tumor take rates were noted, suggesting that for some cells the cryoinjury is reversible. As expected tumor take rates were reduced by lowering the temperature but were independent of the holding time. The volume doubling time and final tumor volume of the subcutaneous tumors was similar to that of controls, indicating that the growth potential of the cells which survive freezing is normal. The minimum lethal temperature was dependent upon the site of inoculation, subcutaneous tumors developing from cells frozen to -35 degrees C, whereas liver tumors did not develop from cells frozen beyond -25 degrees C, this may have important clinical implications.


Impact of apolipoprotein E ε4 and HIV on cognition and brain atrophy: antagonistic pleiotropy and premature brain aging.
The apolipoprotein E (APOE) ε4 allele may accelerate the progression of HIV disease, and increase the risk for developing HIV-associated neurocognitive disorder (HAND). Whether APOEε4 allele(s) and age may influence brain atrophy in HIV patients is unknown and was evaluated. Automated morphometry on magnetic resonance images, using FreeSurfer analyses, neuropsychological testing and APOE genotyping were performed in 139 subjects [70 seronegative controls (SN); 69 clinically-stable HIV subjects]. Compared to SN, HIV subjects had smaller volumes throughout the brain regardless of their HAND status. Compared to APOEε4- subjects, SN controls with APOEε4 had better memory and larger global brain volumes (cerebral white matter and cortex) while HIV subjects with the APOEε4 allele(s) had poorer cognition (verbal fluency, learning, executive function and memory) and smaller cerebral and cerebellar white matter and subcortical structures. Further stratification of age showed that younger (<50 years) APOEε4+SN subjects had larger putamen and cerebral white matter, while younger APOEε4+HIV subjects had poorer performance on verbal fluency and smaller brain volumes [3-way (HIV-status×APOEε4×Age) interaction-p-values=0.005 to 0.03]. These findings suggest that APOEε4 allele(s) may show antagonistic pleiotropy on cognition and brain atrophy in SN controls, but may lead to premature aging with neurodegeneration in younger HIV patients prior to the development of HAND. Potential mechanisms for such interactions may include stronger neuro-inflammation or greater amyloid deposition in younger HIV subjects with APOEε4 allele(s). Early screening for the APOEε4 allele and brain atrophy with morphometry may guide neuroprotective intervention of cognitively normal HIV subjects prior to the development of HAND. Longitudinal follow-up studies and larger sample sizes are needed to validate these cross-sectional results.


Food purchase and eating behavior during the COVID-19 pandemic: A cross-sectional survey of Russian adults.
The Russian government took strong containment measures to prevent the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with rigid hygiene protocols and restrictions on daily living, such as social distancing and closing businesses and schools. While these measures were crucial to stop the diffusion of SARS-CoV-2, numerous voices highlighted their disorderly psychological, social, and economic impacts on food consumption behavior and lifestyle. Therefore, this paper aims to understand how consumers' food-related habits in Russia have shifted due to the COVID-19 pandemic and potential problems and opportunities this might bring for the Russian food system. The study is based on an online cross-sectional survey using a structured questionnaire administered in Russian through the Survey Monkey platform. A total of 1297 valid answers was collected. The results reveal that diet and food shopping, preparation, and use have been widely affected. Indeed, the survey results suggested (i) a change in the modality of acquiring food, consumers reduced the number of shopping trips and buying more on each trip to minimize store visits; (ii) a surge of stockpiling of non-perishable food items; (iii) a shift toward healthier diets; (iv) an increase in culinary capabilities; (v) a decrease of food waste. The results are expected to inform current emergency plans as well as long-term food-related strategies in Russia.


Phasic dopamine release drives rapid activation of striatal D2-receptors.
Striatal dopamine transmission underlies numerous goal-directed behaviors. Medium spiny neurons (MSNs) are a major target of dopamine in the striatum. However, as dopamine does not directly evoke a synaptic event in MSNs, the time course of dopamine signaling in these cells remains unclear. To examine how dopamine release activates D2-receptors on MSNs, G protein activated inwardly rectifying potassium (GIRK2; Kir 3.2) channels were virally overexpressed in the striatum, and the resulting outward currents were used as a sensor of D2-receptor activation. Electrical and optogenetic stimulation of dopamine terminals evoked robust D2-receptor inhibitory postsynaptic currents (IPSCs) in GIRK2-expressing MSNs that occurred in under a second. Evoked D2-IPSCs could be driven by repetitive stimulation and were not occluded by background dopamine tone. Together, the results indicate that D2-receptors on MSNs exhibit functional low affinity and suggest that striatal D2-receptors can encode both tonic and phasic dopamine signals.


Major Genetic Drivers of Statin Treatment Response in African Populations and Pharmacogenetics of Dyslipidemia Through a One Health Lens.
A One Health lens is increasingly significant to address the intertwined challenges in planetary health concerned with the health of humans, nonhuman animals, plants, and ecosystems. A One Health approach can benefit the public health systems in Africa that are overburdened by noncommunicable, infectious, and environmental diseases. Notably, the COVID-19 pandemic revealed the previously overlooked two-fold importance of pharmacogenetics (PGx), for individually tailored treatment of noncommunicable diseases and environmental pathogens. For example, dyslipidemia, a common cardiometabolic risk factor, has been identified as an independent COVID-19 severity risk factor. Observational data suggest that patients with COVID-19 infection receiving lipid-lowering therapy may have better outcomes. However, among African patients, the response to these drugs varies from patient to patient, pointing to the possible contribution of genetic variation in important pharmacogenes. The PGx of lipid-lowering therapies may underlie differences in treatment responses observed among dyslipidemia patients as well as patients comorbid with COVID-19 and dyslipidemia. Genetic variations in APOE, ABCB1, CETP, CYP2C9, CYP3A4, CYP3A5, HMGCR, LDLR, NPC1L1, and SLCO1B1 genes affect the pharmacogenomics of statins, and they have individually been linked to differential responses to dyslipidemia and COVID-19 treatment. African populations are underrepresented in PGx research. This leads to poor accounting of additional diverse genetic variants that could be important in understanding interindividual and between-population variations in therapeutic responses to dyslipidemia and COVID-19. This expert review examines and synthesizes the salient and priority PGx variations, as seen through a One Health lens in Africa, to improve and inform personalized medicine in both dyslipidemia and COVID-19.


Department of Neurology, Northwestern University Medical School, Chicago, Illinois.
A case of non-progressive congenital myopathy is described in which there was absence of muscles and scapulo-peroneal distribution of weakness. The muscle biopsy showed preferential atrophy of Type I fibers and subsarcolemal bodies. These bodies were composed of an acidic protein with sulphahydryl groups which showed acid stable adenosine triphosphatase activity. The possibility of a maturational arrest as a cause is presented.


Metformin inhibited Nod-like receptor protein 3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE-/- mice.
The present study aimed to investigate the effect of metformin on diabetes-accelerated atherosclerosis and whether Nod-like receptor protein 3 (NLRP3) inflammasome is a target for metformin. ApoE-/- male mice were divided randomly into control, streptozocin-induced diabetes mellitus and metformin groups. Metabolic parameters, atherosclerotic lesion, activation of NLRP3 inflammasomes and related signaling pathways were detected. THP-1-differentiated macrophages were used in in vitro experiments. Compared with control mice, increased plasma lipids and proinflammatory interleukin-1β, aggravated macrophage infiltration into the atherosclerotic lesion, and accelerated development of atherosclerosis were observed in diabetic mice, which were associated with the activation of NLRP3 inflammasomes and dysregulation of thioredoxin-1 and thioredoxin-interacting protein. Treatment with metformin alleviated diabetes-induced metabolic disorders and atherosclerosis, as well as NLRP3 inflammasomes activation and dysregulation of thioredoxin-1/thioredoxin-interacting protein. In vitro experiments showed that high glucose induced the accumulation of reactive oxygen species and activated NLRP3 inflammasomes, which was significantly suppressed by treatment with metformin or antioxidant N-acetyl-L-cysteine. Moreover, Compound C, an inhibitor of adenosine 5'-monophosphate-activated protein kinase (AMPK), blocked the anti-inflammatory effect of metformin, indicating that metformin inhibited high glucose-induced NLRP3 inflammasomes activation through AMPK activation. Moreover, high glucose decreased thioredoxin-1 expression and increased thioredoxin-interacting protein expression, which was also reversed by metformin. Metformin inhibited NLRP3 inflammasomes activation and suppressed diabetes-accelerated atherosclerosis in apoE-/- mice, which at least partially through activation of AMPK and regulation of thioredoxin-1/thioredoxin-interacting protein.


Endometrial gene expression in the window of implantation is altered in obese women especially in association with polycystic ovary syndrome.
To determine whether luteal phase endometrial transcriptome is altered in obese women during the window of implantation (WOI), considering the presence of infertility, fat distribution and association with polycystic ovary syndrome (PCOS). Prospective study. University-affiliated infertility clinic, between May 2007 and March 2009. One control group of women with normal weight (n=4), and four study groups of obese women (n=6 each one) according to the association with infertility, PCOS, and ovarian stimulation. The endometrium was biopsied 7 days after LH surge or hCG administration in 28 women. Endometrial gene expression during the WOI. One hundred and fifty-one genes were dysregulated in obese groups compared with controls. This dysregulation was more pronounced when infertility was associated. The biologic processes of these genes belonged mainly to development and regulation of different biological functions such as transcription and biosynthesis. The molecular functions overrepresented were transcription and peptide receptor activity. The endometrium of obese women with PCOS showed dysregulated genes related to biologic processes such as development, morphogenesis, and the immune system, as well as different molecular functions such as protein binding, binding, growth factor activity, and carboxylic acid transmembrane transporter activity. Some of these genes have been previously related to implantation and unexplained infertility. Obese women present a different endometrial gene expression than controls during the WOI, which is more pronounced when infertility or polycystic ovary syndrome are associated.


Methyl 3,4-bis-(cyclo-propyl-meth-oxy)benzoate.
The title compound, C(16)H(20)O(4), was obtained unintentionally as the byproduct of an attempted synthesis of methyl 3-(cyclo-propyl-meth-oxy)-4-hy-droxy-benzoate. In the crystal, the mol-ecules are linked by inter-molecular C-H⋯O inter-actions.


Subcutaneous implantable cardioverter-defibrillator: Initial experience.
Implantable cardioverter-defibrillators (ICDs) are important tools in the prevention of sudden death, but implantation requires transvenous access, which is associated with complications. Subcutaneous implantable cardioverter-defibrillators (S-ICDs) may prevent some of these complications. To evaluate the therapeutics and complications associated with S-ICD systems. S-ICD implantation was planned in 23 patients, for whom the indications were vascular access problems, increased risk of infection or young patients with long predicted follow-up. The population consisted of four patients with ischemic heart disease, three of them on hemodialysis (two with subclavian vein thrombosis), five with left ventricular noncompaction, four with Brugada syndrome, three with arrhythmogenic right ventricular cardiomyopathy, one with transposition of the great vessels, two with dilated cardiomyopathy and four with hypertrophic cardiomyopathy. S-ICDs were implanted in 21 patients, two having failed to fulfil the initial screening criteria. Mean implantation time was 77 minutes, with no complications. Defibrillation tests were performed, and in one patient the generator had to be repositioned to obtain an acceptable threshold. In a mean follow-up of 14 months, 10 patients had S-ICD shocks, which were appropriate in half of them; one developed infection, one needed early replacement due to loss of telemetry and one patient died of noncardiac cause. S-ICD implantation can be performed by cardiologists with a high success rate. Initial experience appears favorable, but further studies are needed with longer follow-up times to assess the safety and efficacy of this strategy compared to conventional devices.


The importance of social zeitgeber in paediatric type 1 narcolepsy: What we can learn from the COVID-19 restrictions adopted in Italy?
The lockdown due to the new coronavirus pandemic (COVID-19) has led to unparalleled changes in several aspects of human behaviour. During the lockdown, the general population delayed sleep timing and spent more time in bed; however, little is known on the effects of COVID-19 restriction on children and adolescents suffering type 1 narcolepsy. In the last months of 2019, we performed follow-up actigraphy in 18 type 1 narcolepsy children and adolescents under stable pharmacological treatment with sodium oxybate. We contacted these patients for a follow-up actigraphy during the first Italian lockdown. Actigraphs and the Epworth Sleepiness Scale for children and adolescents (ESS-CHAD) have been sent to participants' homes. Differences in motor activity were analysed through functional linear modelling. During lockdown, type 1 narcolepsy children and adolescents went to bed and woke up later, slept more during the daytime and napped more frequently. No difference emerged in time in bed, estimated total sleep time and nocturnal sleep quality. Similarly, no difference emerged in ESS-CHAD and body mass index. The time-series analysis of motor activity documented reduced activity during the early morning and in the evening during the lockdown period compared with pre-lockdown. Our study objectively showed that type 1 narcolepsy children and adolescents delayed the sleep phase and slept more during the daytime during the lockdown. The analysis of type 1 narcolepsy children and adolescents' behaviour during the lockdown has provided new information that could pave the way to a personalized school programme.


Asymptomatic uterine incarceration at term: a rare complication of pregnancy.
Uterine retroversion before 12 to 14 weeks' gestation occurs in approximately 15% of pregnancies and is usually considered an innocuous finding. When the uterus remains retroverted as the pregnancy advances, the growing uterine corpus becomes impacted in the hollow of the pelvic cavity and uterine incarceration may develop. Incarcerated retroverted uterus at term is an extremely rare and serious complication of pregnancy. A 30-year-old primigravida with asymptomatic uterine incarceration at term underwent a challenging Caesarean section because of the distortion of her anatomy. Recognition of a gravid uterus that is retroverted and incarcerated at term or near-term is critical because Caesarean section is necessary for delivery and that is likely to be challenging.


Control of aromatase activity in breast tumours: the role of the immune system.
Cytokines such as interleukin-6 (IL-6) and tumour necrosis factor alpha (TNF alpha), have been identified as important regulators of aromatase activity in fibroblasts derived from normal and malignant breast tissues, and may play an important role in controlling aromatase activity in breast tumours. The major source of such cytokines within breast tumours remains to be established but macrophages and lymphocytes, which can infiltrate tumours, have been identified as a potential source of aromatase stimulatory cytokines. To obtain further insight into the possible role played by the immune system in cancer development, and in particular its ability to regulate aromatase activity via cytokine production, we have obtained peripheral blood monocytes and lymphocytes from an immunosuppressed kidney transplant recipient, receiving cyclosporin A therapy, and a woman with breast cancer. Monocytes and lymphocytes were stimulated with lipopolysaccharide (LPS), and the conditioned medium (CM) collected from these cells was tested for its ability to stimulate aromatase activity in fibroblasts derived from normal breast tissue from a woman undergoing lumpectomy for the removal of a breast tumour. The white blood cell count was lower for the immunosuppressed patient, mainly because of the reduction in the number of monocytes and lymphocytes. The ability of CM from the monocytes and lymphocytes of the immunosuppressed patient to stimulate aromatase activity was significantly reduced (68% and 82% for monocytes and lymphocytes, respectively) compared with that of CM from the cells of the woman with breast cancer. It is possible, therefore, that immunosuppression, which has been found to be associated with a reduction in the incidence of de novo breast cancer in kidney transplant recipients, may exert its effect by inhibiting cytokine production by the cells of the immune system and thus oestrogen synthesis. In contrast to the stimulatory effects that TNF alpha has on aromatase activity in breast fibroblasts, in MCF-7 breast cancer cells, which possess low aromatase activity, it reduced activity. However, the extent of inhibition of aromatase activity in these epithelial cells was much lower than the marked stimulation which it can induce in breast fibroblasts.


Survival in neuroendocrine neoplasms; A report from a large Norwegian population-based study.
Neuroendocrine neoplasms (NENs) are heterogeneous tumors originating from neuroendocrine cells. Their malignant potential varies from indolence to high-grade malignancy (carcinomas). We studied the survival of all NENs in Norway according to malignant potential and different primary sites. We identified all NEN cases diagnosed in 1993 to 2015 and reported to the national population-based Cancer Registry of Norway. We included 62 morphological types. According to morphological characteristics and known disease behavior, we stratified the tumors into two different groups: low/intermediate aggressiveness and high aggressiveness. A total of 17,128 NENs were analyzed. Median age was 67 years and 47.6% were females. The most common primary sites were in the lungs and the gastroenteropancreatic (GEP) system. The 5-year relative survival in patients with low/intermediate aggressive NENs was 64.8% (95% CI, 63.3-66.2) and high aggressive NENs 8.4% (95% CI, 7.8-9.1). Females had higher survival rates than males (p <0.001). The relative 5-year survival rate in patients younger than 50 years was 89.1% (95% CI, 87.4-90.7) vs 41.0% (95% CI, 34.9-46.9) in patients ≥80 years. In multivariable analysis gender, age at diagnosis, time of diagnosis, stage and primary sites were all predictors of outcome both in patients with low/intermediate tumors and high aggressive tumors. Survival improved significantly over time, regardless of sex, age and tumor stage.


Is adjuvant chemotherapy necessary in pT1N1 gastric cancer?
Due to a lack of consensus on adjuvant treatments for pT1N1 gastric cancer, surgeons face a dilemma when deciding treatments for patients with pT1N1 gastric cancer after gastrectomy. The objective of this study was to determine survival benefits of adjuvant chemotherapy and risk factors for tumor recurrence in gastric cancer patients with pT1N1. Between 1996 and 2010, 510 patients who underwent curative resection for pT1N1 gastric cancer at three institutes were divided into two groups: adjuvant chemotherapy group (N = 150) and surgery-only group (N = 360). Disease-free survival rates and risk factors for tumor recurrence were analyzed. During the median follow-up of 78 months, 7.5% of patients experienced tumor recurrence (7.3% in adjuvant chemotherapy group and 7.5% in surgery-only group). The 5-year disease-free survival rate was 91.8% in the adjuvant chemotherapy group and 94.6% in the surgery-only group without significant difference between the two. In univariate analysis, older age (>65 years), male gender, body mass index <25 kg/m2, elevated gross type, and differentiated histology were associated with tumor recurrence. Multivariate analysis showed that advanced age and male gender were independent risk factors for tumor recurrence. In addition, adjuvant chemotherapy showed no benefitial effect on tumor recurrence in pT1N1 gastric cancer. Adjuvant chemotherapy did not show any oncologically benefitial effect on tumor recurrence, it might be unnecessary for pT1N1 gastric cancer after curative surgery.


Phosphatase activity of placental extracts and pregnant mare's plasma.
Equine placental extracts show phosphatase activity with a pH optimum between 4.5 and 6. The enzyme shows heat stability to 45 degrees C and electrophoresis on cellulose acetate demonstrates the presence of two bands of activity. Histochemistry confirms the presence of phosphatase activity in the placental villi. Assay of plasma samples from pregnant mares showed no increase in phosphatase activity through pregnancy under conditions of test.


Roles of sequential ubiquitination of PCNA in DNA-damage tolerance.
Living organisms not only repair DNA damage induced by environmental agents and endogenous cellular metabolites, but have also developed mechanisms to survive in the presence of otherwise lethal lesions. DNA-damage tolerance (DDT) is considered such a mechanism that resumes DNA synthesis in the presence of replication-blocking lesions. Recent studies revealed that DDT in budding yeast is achieved through sequential ubiquitination of DNA polymerase processivity factor, proliferating cell nuclear antigen (PCNA). It is generally believed that monoubiquitinated PCNA promotes translesion DNA synthesis, whereas polyubiquitinated PCNA mediates an error-free mode of lesion bypass. This review will discuss how ubiquitinated PCNA modulates different means of lesion bypass.


Self-reported prognostic factors in adults reporting neck or low back pain: An umbrella review.
Numerous systematic reviews have attempted to synthesize evidence on prognostic factors for predicting future outcomes such as pain, disability and return-to-work/work absence in neck and low back pain populations. An umbrella review of systematic reviews was conducted to summarize the magnitude and quality of the evidence for each prognostic factor investigated. Searches were limited to the last 10 years (2008-11th April 2018, updated 28th September 2020). A two-stage approach was undertaken: in stage one, data on prognostic factors was extracted from systematic reviews identified from the systematic search that met the inclusion criteria. Where a prognostic factor was investigated in ≥1 systematic review and where 50% or more of those reviews found an association between the prognostic factor and one of the outcomes of interest, it was taken forward to stage two. In stage two, additional information extracted included the strength of association found, consistency of effects and risk of bias. The GRADE approach was used to grade confidence in the evidence. Stage one identified 41 reviews (90 prognostic factors), with 35 reviews (25 prognostic factors) taken forward to stage two. Seven prognostic factors (disability/activity limitation, mental health; pain intensity; pain severity; coping; expectation of outcome/recovery and fear-avoidance) were judged as having moderate confidence for robust findings. Although there was conflicting evidence for the strength of association with outcome, these factors may be used for identifying vulnerable subgroups or people able to self-manage. Further research can investigate the impact of using such prognostic information on treatment/referral decisions and patient outcomes.


Lipid profiling reveals the presence of unique lipid mediators in human milk from healthy and mastitic subjects.
Milk lipids are an important energy source for infants, but the composition of milk lipids has not yet been clarified in detail. In this study, we analyzed free fatty acids and their metabolites in milk from humans and cows. In comparison to cow milk, human milk showed a higher content of free fatty acids including polyunsaturated fatty acids, especially ω-3 fatty acids and their metabolites. Polyunsaturated fatty acids were enriched at an early period of lactation, while saturated fatty acids did not change significantly over the period. Moreover, human milk contained high levels of ω-3 fatty acid metabolites, particularly 18-hydroxyeicosapentaenoic acid, an eicosapentaenoic acid-derived metabolite with anti-inflammatory activity. In comparison with human normal milk, thromboxane B2 and protectin D1 levels were significantly elevated in milk from individuals with mastitis, suggesting that these lipid mediators could be potential biomarkers of obstructive mastitis. Overall, the unique lipid profile of human milk supports the efficacy of breast-feeding for supply of more nutritional and bioactive lipids in comparison to artificial or cow milk to infants, in whom digestive and absorptive functions are still immature.


Persistence of antibody response to pneumococcal capsular polysaccharides in vaccinated long term-care residents in Brazil.
To evaluate the immunogenicity of 23-valent pneumococcal polysaccharide vaccine in 52 nursing homes residents aged > or = 60 years, IgG antibodies to serotypes 1, 5, 6B, and 8 were measured by ELISA and compared before, and 1 and 12 months following vaccination. A significant immunological response for all serotypes was observed at 1 month after vaccination. The mean increase in antibody concentration was highly variable and ranged from 1.6 to 2.7. After 1 year, the mean concentrations remained significantly higher than prior to vaccination for serotypes 1, 6B, and 8, although there was a decrease in all mean IgG concentrations. Antibody levels were higher in men than in women, before and after immunisation. Post-vaccination values tended to be lower among subjects aged >75 years. Reduction in IgG concentrations by 33% 1 year after vaccination suggests that revaccination of institutionalised elderly people may be needed.


[Perioperative pain therapy].
Scientific studies have proven without doubt that an optimized perioperative pain therapy will improve patient comfort, reduce postoperative complications, enhance postoperative recovery and shorten the length of postoperative hospital stay. It is necessary to incorporate the acute pain therapy into a perioperative multimodal and interdisciplinary therapeutic concept. Local or regional anesthesia will provide the best analgesic effect after surgery and should be considered in all patients. Optimal treatment of patients with peripheral nerve blocks, spinal or epidural analgesia should be treated by a specialized acute pain service. However, only 15-20% of all surgical cases will be taken care of by such a pain service. Therefore, most surgical patients will only receive adequate analgesia if surgeons are familiar with the principles of postoperative pain therapy. Regular assessment of pain perception is the cornerstone of optimized pain therapy. Furthermore, pain assessment will allow the administration and to some extent dosage of analgesic therapy to be delegated to nursing personnel.


Broadly active zinc finger protein-guided transcriptional activation of HIV-1.
Human immunodeficiency virus type 1 (HIV-1) causes a persistent viral infection resulting in the demise of immune regulatory cells. Clearance of HIV-1 infection results in integration of proviral DNA into the genome of host cells, which provides a means for evasion and long-term persistence. A therapeutic compound that specifically targets and sustainably activates a latent HIV-1 provirus could be transformative and is the goal for the "shock-and-kill" approach to a functional cure for HIV-1. Substantial progress has been made toward the development of recombinant proteins that target specific genomic loci for gene activation, repression, or inactivation by directed mutations. However, most of these modalities are too large or too complex for efficient therapeutic application. We describe here the development and testing of a novel recombinant zinc finger protein transactivator, ZFP-362-VPR, which specifically and potently enhances proviral HIV-1 transcription both in established latency models and activity across different viral clades. Additionally, ZFP-362-VPR-activated HIV-1 reporter gene expression in a well-established primary human CD4+ T cell latency model and off-target pathways were determined by transcriptome analyses. This study provides clear proof of concept for the application of a novel, therapeutically relevant, protein transactivator to purge cellular reservoirs of HIV-1.


Prescription analgesic use among young adults: adherence to physician instructions and diversion.
To understand the extent to which medication adherence was related to diversion of prescription analgesics. Cross-sectional analyses of data from the College Life Study, a prospective study of young adults. Participants were originally sampled as incoming first-time first-year college students from one large public university in the Mid-Atlantic United States. One hundred ninety-two young adults aged 21-26 who were prescribed an analgesic to treat acute pain in the past year. Diversion of prescription analgesics. The study tested two competing hypotheses: 1) individuals who skip doses (under-users) are at greatest risk for diversion because they have leftover medication; and 2) individuals who over-use their prescriptions (over-users) are at greatest risk for diversion, perhaps because of a general propensity to engage in deviant behavior. Fifty-eight percent followed physician's instructions regarding their prescription analgesic medication; 27% under-used their prescribed medication and 16% over-used their prescribed medication. Twenty-seven percent of the total sample diverted their medication, with over-users being the most likely to divert (63%). Holding constant demographic characteristics and perceived harmfulness of nonmedical use, over-users were almost five times as likely as adherent users to divert analgesic medications (P < 0.05). Further research is needed to better understand the relationship between adherence and diversion. If these findings are replicated, physicians who are involved in pain management for acute conditions among young adults should take steps to monitor adherence and reduce diversion of prescription analgesics.


A new rapid method to measure human platelet cholesterol: a pilot study.
Platelet cholesterol (PC) could be used to assess "tissue" cholesterol of patients with vascular disease. However, the methods available so far to measure PC involve a complex extraction process. We developed a rapid method to measure PC and assessed its correlation with serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C ratio, triglycerides (TG), and non-HDL-C. We assessed repeatability (20 times, 3 participants) and reproducibility (8 times, 2 participants). A group of 47 healthy participants was studied. Blood was collected to analyze serum TC, LDL-C, HDL-C, and TG. Citrated blood was used to prepare a platelet pellet. A "clear soup" was produced (by disrupting this pellet using freeze-thaw and sonication cycles) and used to measure PC. Repeatability of PC showed a coefficient of variation (CV) of 4.8%. The reproducibility of PC over a period of 2 months was CV 7.5% and 8.1% (8 measurements for 2 participants). The PC of participants with serum LDL-C >2.6 mmol/L (treatment goal recommended by the National Cholesterol Education Program Adult Treatment Panel III) was 377 ± 120 μmol/10(12) platelets (n = 25). There was a significant correlation (Spearman, correlation coefficient) of PC (n = 25) with serum LDL-C (r(s) = 0.45, P = .02), LDL-C/HDL-C (r(s) = 0.45, P = .02), TG (r(s) = 0.43, P = .03), and non-HDL-C (r(s) = 0.53, P = .007). This technique of measuring PC has the advantage of being reproducible, fast, and simpler than previous methods. Thus, it may be useful for multiple sampling when investigating changes in PC in hypercholesterolemic patients. More extensive evaluation is necessary.


Exercise Core Temperature Response with a Simulated Burn Injury: Effect of Body Size.
Although the severity of a burn injury is often associated with the percentage of total body surface area burned (%TBSA), the thermoregulatory consequences of a given %TBSA injury do not account for the interactive effects of body morphology and metabolic heat production (Hprod). Using a simulated burn injury model to mimic the detrimental effect of a 40% TBSA injury on whole-body evaporative heat dissipation, core temperature response to exercise in physiologically uncompensable conditions between morphologically disparate groups were examined at (i) an absolute Hprod (W), and (ii) a mass-specific Hprod (W·kg). Healthy, young, nonburned individuals of small (SM, n = 11) or large (LG, n = 11) body size cycled for 60 min at 500 W or 5.3 W·kg of Hprod in 39°C and 20% relative humidity conditions. A 40% burn injury was simulated by affixing a highly absorbent, vapor-impermeable material across the torso (20% TBSA), arms (10% TBSA), and legs (10% TBSA) to impede evaporative heat loss in those regions. Although the elevation in core temperature was greater in SM compared with LG at an Hprod of 500 W (SM, 1.69°C ± 0.26°C; LG, 1.05°C ± 0.26°C; P < 0.01), elevations in core temperature were not different at an Hprod of 5.3 W·kg between groups (SM, 0.99°C ± 0.32°C; LG, 1.05°C ± 0.26°C; P = 0.66). These data suggest that among individuals with a 40% TBSA burn injury, a smaller body size leads to exacerbated elevations in core temperature during physical activities eliciting the same absolute Hprod (non-weight-bearing tasks) but not activities eliciting the same mass-specific Hprod (weight-bearing tasks).


Factors defining the stability of poly(lactide-co-glycolide) spheres for the sustained release of a cysteine protease inhibitor.
Colloidal stability and the regularity of the release kinetics benefit from the high circularity and the narrow size dispersion of polymeric particles as drug delivery carriers. A method for obtaining such particles composed of poly(lactide-co-glycolide) (PLGA), averaging at 1.0 ± 0.3 µm in size, is reported here, along with the analysis of the effects of different synthesis parameters on their morphological characteristics. As in agreement with the classical nucleation theory, the particle size and the degree of cohesion were inversely proportional to supersaturation. Consequently, the optimal conditions for the precipitation of small and narrowly dispersed particles involved an abrupt elevation of supersaturation. Owing to the high colloidal stability of the particles, centrifugation exhibited a counterintuitive effect on them, refining their morphological features and promoting their individuation. Polyvinyl alcohol (PVA) was used as a steric repulsion additive and its effect on the stability of PLGA spheres was concentration-dependent, with the particles aggregating, partially coalescing and losing their distinct features both with no PVA in the system and at PVA concentrations higher than the optimal. At its narrowest, the particle size distribution was bimodal, exhibiting the average circularity of 0.997 ± 0.003 and the average roundness of 0.913 ± 0.054. PLGA spheres were loaded with an inhibitor of EhCP4, a cysteine protease from E. histolytica, a parasite causing amoebic dysentery in the tropical and developing world. The burst release of the drug at early time points was followed by a zero-order release period, yielding a biphasic profile that can be of benefit in the delivery of anti-infective agents. The release profile fitted poorly with the Hixson-Crowell kinetic model and excellently with the Higuchi and the Korsmeyer-Peppas ones, indicating that the release is conditioned by diffusion rather than by the degradation of the polymer. The release and the erosion proceeded independently from one another, suggesting that the pore formation, water penetration and swelling are the primary driving forces for the release of the drug.


Jesridonin in combination with paclitaxel demonstrates synergistic anti-tumor activity in human esophageal carcinoma cells.
The novel compound jesridonin, has extensive anti-tumor activity. In this study, we aim to investigate the cytotoxic effects of jesridonin in combination with paclitaxel. Our results showed that jesridonin in combination with paclitaxel had synergistic cytotoxic effects on human esophageal carcinoma both in vitro and in vivo. Hoechst 33258 staining and the Annexin-V FITC assay demonstrated that paclitaxel synergized with jesridonin in a stronger induction of apoptosis than treatment with paclitaxel or jesridonin alone. Western blotting results revealed that the synergistic apoptosis-induction effects of paclitaxel and jesridonin were mediated by the mitochondrial pathway. This may provide a novel strategy to overcome drug resistance for esophageal cancer therapy.


Prevalence of SOS-mediated control of integron integrase expression as an adaptive trait of chromosomal and mobile integrons.
Integrons are found in hundreds of environmental bacterial species, but are mainly known as the agents responsible for the capture and spread of antibiotic-resistance determinants between Gram-negative pathogens. The SOS response is a regulatory network under control of the repressor protein LexA targeted at addressing DNA damage, thus promoting genetic variation in times of stress. We recently reported a direct link between the SOS response and the expression of integron integrases in Vibrio cholerae and a plasmid-borne class 1 mobile integron. SOS regulation enhances cassette swapping and capture in stressful conditions, while freezing the integron in steady environments. We conducted a systematic study of available integron integrase promoter sequences to analyze the extent of this relationship across the Bacteria domain. Our results showed that LexA controls the expression of a large fraction of integron integrases by binding to Escherichia coli-like LexA binding sites. In addition, the results provide experimental validation of LexA control of the integrase gene for another Vibrio chromosomal integron and for a multiresistance plasmid harboring two integrons. There was a significant correlation between lack of LexA control and predicted inactivation of integrase genes, even though experimental evidence also indicates that LexA regulation may be lost to enhance expression of integron cassettes. Ancestral-state reconstruction on an integron integrase phylogeny led us to conclude that the ancestral integron was already regulated by LexA. The data also indicated that SOS regulation has been actively preserved in mobile integrons and large chromosomal integrons, suggesting that unregulated integrase activity is selected against. Nonetheless, additional adaptations have probably arisen to cope with unregulated integrase activity. Identifying them may be fundamental in deciphering the uneven distribution of integrons in the Bacteria domain.


Prevailing mood, mood changes and dreams in bipolar disorder.
In this preliminary and exploratory study, we collected the dream reports and mood ratings of 6 outpatients with bipolar disorder over a 6-month period to compare the relationship between dream themes and mood states. We found that neutral mood states were associated with mundane, routine or uneventful dreams while manic states featured bizarre and improbable dream themes. Neither depressed nor mixed states showed a consistent trend in dream themes. By categorizing the dreams that preceded mood shifts, we were able to identify a particular type of dream that seemed to precede a mood shift, particularly in the direction of mania. Shifts to mania were heralded by dreams of death and bodily injury. Forthcoming depression was more clearly associated with a decrease in overall number of dreams reported. The significance of dreaming in relation to mood is discussed in terms of these preliminary findings and our bipolar dream scale is offered for the convenience of subsequent investigators.


Inhibition of mitochondrial glycerol-3-phosphate dehydrogenase by α-tocopheryl succinate.
α-Tocopheryl succinate (TOS), a redox-silent analogue of vitamin E, suppresses cell growth in a number of clinical and experimental cancers, inhibits mitochondrial succinate dehydrogenase (SDH) and activates reactive oxygen species (ROS) generation. The aim of this study was to test whether TOS also inhibits glycerol-3-phosphate dehydrogenase (mGPDH), another flavoprotein-dependent enzyme of the mitochondrial respiratory chain because there are differences between electron transfer pathway from SDH and mGPDH to coenzyme Q pool. For our experiments brown adipose tissue mitochondria with high expression of mGPDH were used. Our data showed that inhibition of glycerol-3-phosphate (GP)-dependent oxygen consumption by TOS was more pronounced than the succinate (SUC)-dependent one (50% inhibition was reached at 10 μmol/l TOS vs. 80 μmol/l TOS, respectively). A comparison of the inhibitory effect of TOS on GP-oxidase, GP-cytochrome c oxidoreductase and GP-dehydrogenase activities showed that TOS directly interacts with the dehydrogenase. After TOS application the GP-dependent generation of ROS was highly depressed. It may thus be concluded that TOS-induced inhibition of mGPDH is more pronounced than TOS-induced inhibition of SDH and that the inhibitory effect of TOS for both substrates is exerted at different locations of the particular dehydrogenases. Our data indicate that the inhibition of mGPDH activity could also play a role in TOS-induced growth suppression in neoplastic cells.


Identification of Virulence Determinants During Host-Pathogen Interaction Using Tn-Seq Technology.
Transposon sequencing (Tn-seq) is a powerful genetic tool that enables the detection of essential genes within a given environment. The application of Tn-seq to Staphylococcus aureus has generated transposon libraries in numerous strains with inactivation of virtually every nonessential gene in the genome. This exciting technology coupled with increasingly available computational tools has been deployed in animal models of infection to identify essential S. aureus genes within specific host environments. In this chapter, we describe the application of Tn-seq to a murine model of osteomyelitis as a paradigm for using this powerful technology to elucidate mechanisms of bacterial pathogenesis.


A method for the analysis of 121 multi-class environmental chemicals in urine by high-performance liquid chromatography-tandem mass spectrometry.
Biomonitoring of human exposure to environmental chemicals has gained momentum in recent years. Biomonitoring methods often include analysis of a single class of chemicals with similar chemical properties. In this study, we describe a method that involves solid-phase extraction (SPE) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and capable of measuring 121 environmental chemicals comprising plasticizers (PMs; n = 45), environmental phenols (EPs; n = 45), and pesticides (n = 31) through a single extraction of urine. Urine samples were incubated with 20 µL of β-glucuronidase/arylsulfatase (4000 units/mL urine) (from Helix pomatia) buffered at pH 5.5 for 2 h at 37 °C for optimal deconjugation conditions. We compared two extraction methods, namely liquid-liquid extraction and SPE, and the latter with ABS Elut NEXUS® cartridges was optimized to yield best extraction efficiencies. For increased resolution and chromatographic separation, two methods involving Ultra AQ C18® and Betasil™ C18® columns were used. The MS/MS analyses were performed under both negative and positive ionization modes. The optimized method yielded excellent intra- and inter-day variabilities (relative standard deviation: 0.40-11%) and satisfactory recoveries (80-120%) for >95% of the analytes. The limits of detection were ≤ 0.1 ng/mL for 101 analytes and between 0.1 and 1.0 ng/mL for 18 analytes. The optimized SPE LC-MS/MS method was validated through the analysis of standard reference materials and proficiency test urine samples and further applied in the analysis of 21 real urine samples to demonstrate simultaneous determination of 121 environmental chemicals in urine samples.


In vitro assay for protease activity of proprotein convertase subtilisin kexins (PCSKs): an overall review of existing and new methodologies.
The mammalian proprotein convertase subtilisin kexins (PCSKs) previously called proprotein or prohormone convertases (PCs) are a family of Ca(+2)-dependent endoproteases in the subtilisin family. These proteolytic enzymes exert their many crucial physiological and biological functions in vivo via their ability to cleave larger inactive precursor proteins into their biologically active mature forms. This event takes place in a highly efficient and selective manner. Such actions of PCSKs either alone or in combination to cleave specific protein bonds are the hallmark events that not only define the normal functions and metabolism of the body but also may lead to a variety of diseases or disorders with associated conditions. These include among others, diabetes, obesity, cancer, cardiovascular diseases, reproduction abnormalities as well as viral bacterial infections. These conditions were the direct consequences of an enhanced level of enzymatic activity of one or more PCSKs except only PCSK9, whose protease activity in relation to its physiological substrate has yet to be characterized. Owing to this finding, a large number of research studies have been exclusively devoted to develop rapid, efficient and reliable in vitro methods for examining the protease activity of these enzymes. Several assays have been developed to monitor PCSK activity and these are widely used in chemical, biochemical, cellular and animal studies. This review will cover various methodologies and protocols that are currently available in the literature for PCSK activity assays. These include liquid phase methods using fluorogenic, chromogenic and intramolecularly quenched fluorescent substrates as well as a newly developed novel solid phase fluorescence method. This review will also highlight the usefulness of these methodologies and finally a comparative analysis has been made to examine their merits and demerits with some key examples.


Proximal humeral fractures treated with an intramedullary cage and plate: clinical and radiographic outcomes at a minimum of 1 year postoperatively.
Proximal humeral fractures are common injuries. Although certain fracture types may benefit from surgery including open reduction-internal fixation (ORIF), the optimal method for fixation is unclear. Newer implant designs that improve healing by minimizing hardware failure and recurrent fracture displacement may optimize clinical outcomes. Over a 27-month period, 37 consecutive patients with proximal humeral fractures were treated by a single surgeon with a lateral humeral plate through which an intramedullary nitinol cage was inserted. Additional screws were placed through the tuberosities and cage as required. Fractures were classified by both the Neer classification and angulation or displacement in the coronal plane. At most recent follow-up, radiographic results, patient-reported outcome measurements, range of motion, complications, and reoperations were recorded. Thirty-one patients had a minimum of 1 year of clinical and radiographic follow-up. The average follow-up period was 91 weeks. By use of the Neer classification, there were 4 two-part, 21 three-part, and 6 four-part fractures. Twenty-one fractures were displaced in valgus and 10 in varus. Outcome measurements at most recent follow-up demonstrated an average American Shoulder and Elbow Surgeons score of 68; Single Assessment Numeric Evaluation score of 70; Quick Disabilities of the Arm, Shoulder and Hand score of 27; Veterans RAND-12 Physical Component Score of 37 and Mental Component Score of 51; Constant score of 55; Patient-Reported Outcomes Measurement Information System score of 29; and Oxford Shoulder Score of 23. Average active range of motion showed forward elevation of 134°, abduction of 91°, external rotation with the arm at the side of 30° (range, -10° to 60°), and internal rotation with the arm at the side to L1 (range, T6-S4). There were 11 complications (35%), including 2 cases of axillary nerve neurapraxia that resolved and 4 cases of avascular necrosis (13%). Unplanned reoperations were performed in 6 patients (19%). One patient underwent revision for loose hardware removal, 1 patient underwent revision ORIF after a fall, and 4 patients required component removal and revision to shoulder arthroplasty. No screw cutout or varus head collapse occurred. The management of proximal humeral fractures remains challenging. Our results demonstrate similar fracture healing, clinical improvement, and complication rates compared with conventional ORIF with screws and a side plate. At 1 year of follow-up, there were low rates of recurrent fracture displacement and screw cutout. There was a higher-than-expected rate of avascular necrosis as compared with other studies using a similar fixation construct. Larger studies and longer follow-up may demonstrate decreased rates of revision surgery and superior outcomes. Additional studies may determine whether this fixation method is superior to others for proximal humeral fractures.


BATFormer: Towards Boundary-Aware Lightweight Transformer for Efficient Medical Image Segmentation.
Transformers, born to remedy the inadequate receptive fields of CNNs, have drawn explosive attention recently. However, the daunting computational complexity of global representation learning, together with rigid window partitioning, hinders their deployment in medical image segmentation. This work aims to address the above two issues in transformers for better medical image segmentation. We propose a boundary-aware lightweight transformer (BATFormer) that can build cross-scale global interaction with lower computational complexity and generate windows flexibly under the guidance of entropy. Specifically, to fully explore the benefits of transformers in long-range dependency establishment, a cross-scale global transformer (CGT) module is introduced to jointly utilize multiple small-scale feature maps for richer global features with lower computational complexity. Given the importance of shape modeling in medical image segmentation, a boundary-aware local transformer (BLT) module is constructed. Different from rigid window partitioning in vanilla transformers which would produce boundary distortion, BLT adopts an adaptive window partitioning scheme under the guidance of entropy for both computational complexity reduction and shape preservation. BATFormer achieves the best performance in Dice of 92.84 %, 91.97 %, 90.26 %, and 96.30 % for the average, right ventricle, myocardium, and left ventricle respectively on the ACDC dataset and the best performance in Dice, IoU, and ACC of 90.76 %, 84.64 %, and 96.76 % respectively on the ISIC 2018 dataset. More importantly, BATFormer requires the least amount of model parameters and the lowest computational complexity compared to the state-of-the-art approaches. Our results demonstrate the necessity of developing customized transformers for efficient and better medical image segmentation. We believe the design of BATFormer is inspiring and extendable to other applications/frameworks.


Amides of piperidine, morpholine and piperazine substituted 1-phenylethylamines: inhibitors of acylCoA:cholesterol acyltransferase (ACAT) activity in vitro and in vivo.
Amides of some substituted 1,2-diarylethylamines have been shown to exhibit potent acylCoA:cholesterol acyltransferase (ACAT, EC 188.8.131.52) inhibitory activity in vitro in microsomal ACAT assays but show poor in vivo activity in a cholesterol-fed hamster model. In an effort to design ACAT inhibitors that are potent in both our in vitro and in vivo assays a series of amides of piperidine, morpholine and piperazine substituted 1-phenylethylamines were synthesized. Compounds of this series were found to be very potent inhibitors of ACAT in a microsomal ACAT assay and also exhibited potent activity in a cholesterol-fed hamster model.


Primary epithelial cell models for cystic fibrosis research.
When primary human airway epithelial (hAE) cells are grown in vitro on porous supports at an air-liquid interface (ALI), they recapitulate in vivo morphology and key physiologic processes. These cultures are useful for studying respiratory tract biology and diseases and for testing new cystic fibrosis (CF) therapies. This chapter gives protocols enabling creation of well-differentiated primary CF and non-CF airway epithelial cell cultures with non-proprietary reagents. We also discuss the production of retroviral and lentiviral vectors, the derivation of hAE cell lines, reporter gene assays, and the evolving science of gene overexpression and knockdown in ALI hAE cultures.


Convergence of excitatory inputs from the chorda tympani, glossopharyngeal, and vagus nerves onto inferior salivatory nucleus neurons in the cat.
Inferior salivatory nucleus (ISN) neurons were identified by their antidromic spike responses to tympanic nerve stimulation, and their responses to stimulation of the ipsilateral chorda tympani, glossopharyngeal, and vagus nerves were investigated in urethane-chloralose-anesthetized cats. Of the 53 ISN neurons identified, stimulation of at least one of these nerves evoked spike responses in 35 (66%), and 25 (47%) were excited by inputs from more than two stimulated nerves. The mean latencies of the reflex responses evoked by stimulation of the chorda tympani, glossopharyngeal, and vagus nerves were 10.4, 13.7, and 18.9 ms, respectively.


Experimental (FT-IR, FT-Raman, 1H NMR) and theoretical study of magnesium, calcium, strontium, and barium picolinates.
The experimental IR, Raman, and 1H NMR spectra of picolinic acid, as well as magnesium, calcium, strontium, and barium picolinates were registered, assigned and studied. Characteristic changes in the spectra of metal picolinates in comparison with the spectrum of ligand were observed, which lead to the conclusion that perturbation of the aromatic system of picolinates increases along with the series Mg-->Ca-->Sr-->Ba. Theoretical structures of beryllium and magnesium picolinates, as well as theoretical IR spectrum of magnesium picolinate were calculated in B3PW91/6-311++G(d, p) level. On the basis of calculated bond lengths in pyridine ring geometric, aromaticity indexes HOMA were calculated. The idea of these indexes is based on the fact that the essential factor in aromatic stabilization is the pi delocalization manifested in: planar geometry, equalization of the bond lengths and angles, and symmetry. The decidedly lower value of HOMA for magnesium picolinate (i.e. 0.545; 0.539) than that for beryllium picolinate (i.e. 0.998; 0.998) indicate higher aromatic properties of Be picolinate than of Mg picolinate. The comparison of theoretical and literature experimental structures of magnesium picolinate was done. The experimental structure contains two water molecules, so the calculations for hydrated magnesium picolinate were carried on, and the influence of coordinated water molecule on the structure of picolinates was discussed. The HOMAs for hydrated experimental and calculated Mg picolinate amount to 0.870; 0.743, and 0.900; 0.890, respectively, whereas for anhydrous structure, it is as described above, i.e. 0.545; 0.539. Thus, the calculations clearly showed that water molecules coordinated to the central atom weakens the effect of metal on the electronic system of ligand.


Comparison of the effects of commercial whey protein and native whey protein on muscle strength and muscle protein synthesis in rats.
Commercial whey protein (CWP) is generally produced in the cheese making process with heat treatment. Recently, native whey protein (NWP) can be obtained through microfiltration without heat treatment. The difference in physicochemical properties of CWP and NWP was confirmed in previous studies; however, in vivo research on the effect on muscle strength and protein synthesis is still lacking. In this study, rats were orally administered 1.56 g protein/kg body weight of lyophilized beverages containing CWP and NWP for 8 weeks. The biological value and net protein utilization in the NWP were significantly higher than in the CWP. Moreover, NWP increased muscle mass and grip strength compared to CWP. NWP also increased the phosphorylation of the mammalian target of rapamycin and ribosomal protein S6 kinase, pivotal proteins for muscle protein synthesis. These results suggest that NWP enhance muscle strength and protein synthesis more effectively than CWP.


Hyperostosis corticalis generalisata: surgical management and long-term follow-up of one patient.
A 24-year-old woman presented for treatment of her distorted facial appearance. She showed marked widening of the face and skull, which had first become noticeable in childhood. Significant thickening of the cortical bone was seen radiographically throughout the skeleton. Routine laboratory and endocrinological tests showed normal results. These findings, together with a family history of bone disorder, led to the diagnosis of hyperostosis corticalis generalisata. The lower border of the mandible was resected, resulting in improved facial appearance. During the 8-year follow-up, no changes were seen with regard to the mandible.


Carbon and phosphorus co-doped carbon nitride hollow tube for improved photocatalytic hydrogen evolution.
Graphitic carbon nitride, regarded as a charming conjugated polymer, has been a visible light photocatalyst. Bulk carbon nitride endures the limited light absorption ability, few surface active sites and slow separation of photoinduced charge carriers, leading to the poor catalytic activity. Herein, a new carbon (C) and phosphorus (P) co-doped carbon nitride hollow tube with adjustable optical property (CPCN) was developed by applying melamine and polyacrylic amide as the precursors and phosphoric acid as the P source via a hydrothermal-thermal copolymerization way. The effects of polyacrylic amide content on the morphology and photocatalytic performance were intensively investigated. The special hollow tube favors the improvement of active sites and visible light harvesting ability. Meantime, C and P co-doping results in the narrow band gap and rapid charge transfer, thus enabling an enhanced catalytic activity under visible light irradiation. Particularly, CPCN-50 exhibits a remarkable H2 generation rate of 4485.7 μmol h-1 g-1 under λ > 400 nm, which is higher than pure carbon nitride CN (902.3 μmol h-1 g-1), C doped sample CCN-50 (3741.1 μmol h-1 g-1) and P doped sample CNP (2280.0 μmol h-1 g-1). It implies that C, P co-doping exhibits a synergistic effect on boosting photoinduced charge transfer and hindering the recombination. Moreover, CPCN-50 illustrates a higher H2 generation rate (3024.5 μmol h-1 g-1) than CN (400.8 μmol h-1 g-1) under λ > 420 nm irradiation. This way developed in this work might exhibit utility for synthesizing highly effective photocatalysts for the CO2 reduction, H2 evolution and so on.


Direct electrical stimulation impacts on neuromuscular junction morphology on both stimulated and unstimulated contralateral soleus.
There is increasing evidence of crosstalk between organs. The neuromuscular junction (NMJ) is a peripheral chemical synapse whose function and morphology are sensitive to acetylcholine (ACh) release and muscle depolarization. In an attempt to improve our understanding of NMJ plasticity and muscle crosstalk, the effects of unilateral direct electrical stimulation of a hindlimb muscle on the NMJ were investigated in rats exposed long-term post-synaptic neuromuscular blockade. Sprague Dawley rats were subjected to post-synaptic blockade of neuromuscular transmission by systemic administration of α-cobrotoxin and mechanically ventilated for up to 8 days and compared with untreated sham operated controls and animals exposed to unilateral chronic electrical stimulation 12 h/day for 5 or 8 days. NMJs produced axonal and glial sprouts (growth of processes that extend beyond the confines of the synapse defined by high-density aggregates of acetylcholine receptors [AChRs]) in response to post-synaptic neuromuscular blockade, but less than reported after peripheral denervation or pre-synaptic blockade. Direct electrical soleus muscle stimulation reduced the terminal Schwann cell (tSC) and axonal sprouting in both stimulated and non-stimulated contralateral soleus. Eight days chronic stimulation reduced (P < 0.001) the number of tSC sprouts on stimulated and non-stimulated soleus from 6.7 ± 0.5 and 6.9 ± 0.5 sprouts per NMJ, respectively, compared with 10.3 ± 0.9 tSC per NMJ (P < 0.001) in non-stimulated soleus from rats immobilized for 8 days. A similar reduction of axonal sprouts (P < 0.001) was observed in stimulated and non-stimulated contralateral soleus in response to chronic electrical stimulation. RNAseq-based gene expression analyses confirmed a restoring effect on both stimulated and unstimulated contralateral muscle. The cross-over effect was paralleled by increased cytokine/chemokine levels in stimulated and contralateral unstimulated muscle as well as in plasma. Motor axon terminals and terminal Schwann cells at NMJs of rats subjected to post-synaptic neuromuscular blockade exhibited sprouting responses. These axonal and glial responses were likely dampened by a muscle-derived myokines released in an activity-dependent manner with both local and systemic effects.


Targeted delivery of triptolide by dendritic cell-derived exosomes for colitis and rheumatoid arthritis therapy in murine models.
Triptolide (TP) elicits a beneficial effect in the treatment of autoimmune diseases, such as ulcerative colitis (UC) and rheumatoid arthritis (RA). However, its multiorgan toxicity needs to be resolved. Dendritic cells (DCs) are the primary target of TP, which induces immunosuppression, and DC-derived exosomes (DEX) can selectively enter DCs in vivo. Here, we encapsulated TP with DEX (DEXTP) to generate TP-targeted delivery to reduce toxicity. The effect of DEXTP was evaluated in murine colitis and RA models. Toxicity was examined by haematoxylin and eosin staining and serum biochemical marker detection. Affinity of DEXs for DCs was tracked by fluorescent labelling. The immune environment was evaluated and mimicked in vitro for further analysis of the mechanism. DEXTP effectively carried TP to DCs in vivo, and alleviated local inflammation and damage in colitis and RA mice with no obvious toxicity. Additionally, DEXTP reshaped the immune milieu by decreasing CD4+ T-cell levels and increasing regulatory T-cell levels in vivo. Furthermore, consistent T-cell differentiation was observed in vitro, and DC activation was inhibited by alterations in surface factors and secrete cytokines, and by induction of apoptosis or other form of death. Encapsulating TP with DEX is a new method that both reduces the toxicity of TP and induces immunosuppression in UC and RA mice. The underlying immune mechanism involves DEXTP targeting DCs in vivo, to inhibit DC activation and induce DC apoptosis, which further induces T-cell immunosuppression.


Toxicity After Stereotactic Body Radiation Therapy for Prostate Cancer in Patients With Inflammatory Bowel Disease: A Multi-institutional Matched Case-Control Series.
To evaluate the safety of stereotactic body radiation therapy (SBRT) for prostate cancer in men with inflammatory bowel disease (IBD). We queried a consortium database for patients with IBD receiving SBRT for prostate cancer between 2006 and 2012. Identified patients were matched with patients without a history of IBD in a 3:1 fashion based on dose, fractionation, use of androgen deprivation therapy, and age distribution. Logistic regression was used to evaluate the association between having IBD and experiencing acute and late gastrointestinal (GI) and genitourinary (GU) toxicities as scored on the Common Terminology Criteria for Adverse Events scale. Time to late toxicity was evaluated using proportional hazard Cox models. Our study was limited by absence of data on prostate size, baseline International Prostate Symptom Score, and rectal dose-volume histogram parameters. Thirty-nine patients with flare-free IBD at time of treatment (median follow-up 83.9 months) and 117 matched controls (median follow-up 88.7 months) were identified. A diagnosis of IBD was associated with increased odds of developing any late grade GI toxicity (odds ratio [OR] 6.11, P <.001) and GU toxicity (odds ratio 6.14, P < .001), but not odds of developing late grade ≥2 GI (P = .08) or GU toxicity (P = .069). Acute GI and GU toxicity, both overall and for grade ≥2 toxicities, were more frequent in men with IBD (P < .05). Time to late GI and GU toxicity of any grade was significantly shorter in patients with IBD (P < .001). Time to late grade ≥2 GU, but not grade ≥2 GI toxicity, was also shorter in patients with IBD (P = .044 for GU and P = .144 for GI). Patients with IBD who received SBRT for PCa had a higher likelihood of developing acute GI and GU toxicity, in addition to experiencing lower grade late toxicities that occurred earlier. However, patients with IBD did not have a higher likelihood for late grade ≥2 GI or GU toxicity after SBRT compared with the control cohort. Interpretation of this data are limited by the small sample size. Thus, men with IBD in remission should be properly counseled about these risks when considering SBRT.


A three-dimensional NMR experiment with improved sensitivity for carbonyl-carbonyl J correlation in proteins.
Recently, a quantitative J correlation technique has been presented that permits measurement of 3Jc'c' in proteins isotopically enriched with 13C [Hu, J.-S. and Bax, A. (1996) J. Am. Chem. Soc., 118, 8170-8171]. Here, we describe an analogous experiment that is less sensitive to transverse 13C' relaxation, which is the principal limiting factor in all 13C-13C long-range correlation experiments on macromolecules. The new scheme utilizes homonuclear Hartmann-Hahn cross polarization (TOCSY) instead of a COSY type transfer to accomplish magnetization transfer; a description of the relevant relaxation terms is presented. The experiment is demonstrated for ubiquitin and HIV-1 Nef. The results show excellent agreement between 3Jc'c' values measured for ubiquitin with the new scheme and those reported previously. The experiment is particularly useful for distinguishing backbone phi angles that are smaller than -120 degrees from those larger than -120 degrees.


Chemical mediators: the remarkable structure and host-selectivity of depsilairdin, a sesquiterpenic depsipeptide containing a new amino acid.
The chemical structure determination of depsilairdin, a highly selective phytotoxin produced by the plant pathogenic fungus Leptosphaeriamaculans/Phoma lingam, is described. The elucidation of the unusual chemical structure used a combination of NMR spectral data and X-ray crystallography. The absolute configuration was established using chemical degradation and synthesis of (3S,6R)-3,6-diisopropyl-2,5-morpholinedione and its (3R,6S) and (3R,6R) stereoisomers. Similar to the fungal pathogen, depsilairdin caused strong lesions only on brown mustard leaves but not on related species. [structure: see text]


Rational design of SAM analogues targeting SAM-II riboswitch aptamer.
Riboswitches are noncoding RNA elements embedded in 5'-untranslated region of many bacterial mRNAs regulating gene expression in response to essential metabolites. They are unique from other RNA targets because they have evolved to form specific structural receptors for the purpose of binding small molecular metabolites suggesting that structure-based rational drug design approach may be used in designing metabolite mimics targeting riboswitches. We have developed a fluorescence binding assay for SAM-II riboswitch aptamer and identified an S-adenosylmethionine (SAM) analogue that selectively binds to SAM-II riboswitch aptamer with comparable binding affinity to its native metabolite using structure-based design approach.


OH-initiated transformation and hydrolysis of aspirin in AOPs system: DFT and experimental studies.
Advanced oxidation processes (AOPs) are widely used in wastewater treatment of pharmaceutical and personal care products (PPCPs). In this work, the OH-initiated transformation as well as the hydrolysis of a typical PPCPs, aspirin, was investigated using density functional theory (DFT) calculations and laboratory experiments. For DFT calculations, the frontier electron densities and bond dissociation energies were analyzed. Profiles of the potential energy surface were constructed, and all the possible pathways were discussed. Additionally, rate constants for each pathway were calculated with transition state theory (TST) method. UV/H2O2 experiments of aspirin were performed and degradation intermediates were identified by UPLC-MS-MS analysis. Different findings from previous experimental works were reported that the H-abstraction pathways at methyl position were dominated and OH-addition pathways on benzene ring were also favored. Meantime, hydroxyl ASA was confirmed as the main stable intermediate. Moreover, it was the first time to use DFT method to investigate the hydrolysis mechanisms of organic ester compound.


Erdheim-Chester disease of the brain: cytological features and differential diagnosis of a challenging case.
Erdheim-Chester disease (ECD) is an uncommon, systemic xanthogranulomatous disorder, with distinct clinicopathological features, that is rarely expected preoperatively. We describe a case that presented in the brain of a 26-yr-old male patient and clinically mimicked the appearance of a neoplasm. The final diagnosis was a surprise. In retrospect, the diagnosis was suggested by the intraoperative "squash" preparations, which demonstrated a mixed cellular proliferation of lymphohistiocytic elements and large, multinucleated cells with vesicular nuclei, prominent nucleoli, and abundant cytoplasm. To the best of our knowledge, this is the first report detailing the cytopathological features of ECD.


Extended En Bloc Reoperation for Recurrent or Persistent Parathyroid Carcinoma: Analysis of 31 Cases in a Single Institute Experience.
Parathyroid carcinoma (PC) is a rare malignancy that is difficult to eradicate completely after recurrence. We assessed the efficiency of extended en bloc resection (EEBR) in the management of recurrent or persistent PC. In this observational cohort study, 31 patients who underwent reoperations for recurrent or persistent PC were enrolled after 2-9 surgeries by other medical teams. EEBRs, which provided the oncologic resection by removing all possible tumor-bearing scar tissues, were adopted in 25 patients. The other 6 with gross infiltration into the upper aerodigestive tract (UAT) underwent less radical procedures for unwillingness to sacrifice laryngeal function. The 5-year overall survival (OS) rate after EEBR was 59.6% compared with 16.7% after less radical procedures, with an improved median expected survival time of 90.0 months compared with 13.0 months after local excision. EEBR exhibited a favorable local control of relapses in 84.0% of patients after a median follow-up period of 27.0 months, 40.0% even achieved disease-free survival, although 56.0% had subsequent distant metastases (DMs) and suffered a worse 5-year OS of 36.7% in contrast with 100.0% in the absence of DM (p = 0.011). UAT invasion, rather than age, number of previous operations, or preoperative PTH levels, was the unique independent factor associated with both DM (HR = 5.466, p = 0.006) and mortality (HR = 7.606, p = 0.011). EEBRs provide better outcomes than other conventional surgical approaches and might offer a second chance of cure for patients with recurrent or persistent PC in the absence of DM.


Genetic linkage between Bf S0.7 (Bf S1) and HLA-Bw50.
Two hundred and one unrelated French Basque individuals were studied for HLA-A, B, C, DR and Bf polymorphisms. The results show that the Bf S0.7 (Bf S1) variant, which is known to be associated with HLA-Bw21, presents a highly significant linkage disequilibrium with a subtypic specificity, i.e., Bw50 (delta = 0.0123, delta S=100%, P less than 10(-8)). As neither Bf S0.7 variant nor Bw50 antigen is found in Mongoloid populations, it is suggested that in evolutionary terms, the Bf S0.7 mutation is a more recent event than the HLA-Bw21 split.


Trends in cigarette smoking among US adults with diabetes: findings from the Behavioral Risk Factor Surveillance System.
Smoking substantially increases morbidity and mortality rates in people with diabetes. Previous studies have shown that the prevalence of smoking among people with diabetes is similar to that among people without diabetes. We sought to examine temporal trends in the prevalence of smoking among people with diabetes since 1990. We analyzed data from the Behavioral Risk Factor Surveillance System for 1990-2001. The age-adjusted prevalence of smoking among adults with diabetes was 23.6% (men, 25.4%; women, 22.2%) in 1990 and 23.2% (men, 24.8%; women, 21.9%) in 2001. In comparison, the prevalence among participants without diabetes was 24.2% (men, 25.7%; women, 22.8%) in 1990 and 23.2% (men, 24.8%; women, 21.5%) in 2001. Thus, the prevalence of cigarette smoking was similar and remained stable from 1990 through 2001. Among participants with diabetes, significant decreases in the prevalence of smoking occurred among African Americans and those aged >/=65 years. New efforts and commitments to promote smoking cessation among people with diabetes are needed.