A programmable smoke delivery device for PET imaging with cigarettes containing 11C-nicotine.
PET imaging with 11C-nicotine-loaded cigarettes is a valuable tool to directly assess fast nicotine kinetics and its neuropharmacological role in tobacco dependence. To eliminate variations among puffs inhaled by subjects, this work aimed to develop a programmable smoke delivery device (SDD) to produce highly reproducible and adjustable puffs of cigarette smoke for PET experiments. The SDD was built around a programmable syringe pump as a smoking machine to draw a puff of smoke from a 11C-nicotine-loaded cigarette and make it available for a subject to take the smoke into the mouth and then inhale it during PET data acquisition. Brain nicotine time activity curves and total body absorbed 11C-nicotine doses (TAD) were measured in smokers who inhaled a single puff of smoke via the SDD from a 11C-nicotine-loaded cigarette. Nearly identical brain nicotine kinetics were observed between participants who inhaled a puff of smoke through the SDD and those who inhaled directly from a cigarette. This new device minimizes puff variations that exist with earlier smoke delivery apparatuses which could introduce confounding factors. The SDD is effective in delivering 11C-nicotine from the study cigarettes. Despite a 2-s increase in aging of smoke delivered through the SDD versus smoke taken directly from a cigarette, the difference in brain nicotine kinetics after 11C-nicotine delivery with and without use of the SDD is negligible. This refined device may be useful for future research on the deposition and pharmacokinetics of nicotine inhaled with tobacco smoke.


MicroRNAs as Indicators of Malignancy in Pancreatic Ductal Adenocarcinoma (PDAC) and Cystic Pancreatic Lesions.
The dysregulation of microRNAs has recently been associated with cancer development and progression in pancreatic ductal adenocarcinoma (PDAC) and cystic pancreatic lesions. In solid pancreatic tumor tissue, the dysregulation of miR-146, miR-196a/b, miR-198, miR-217, miR-409, and miR-490, as well as miR-1290 has been investigated in tumor biopsies of patients with PDAC and was reported to predict cancer presence. However, the value of the predictive biomarkers may further be increased during clinical conditions suggesting cancer development such as hyperinsulinemia or onset of diabetes. In this specific context, the dysregulation of miR-486 and miR-196 in tumors has been observed in the tumor tissue of PDAC patients with newly diagnosed diabetes mellitus. Moreover, miR-1256 is dysregulated in pancreatic cancer, possibly due to the interaction with long non-coding RNA molecules that seem to affect cell-cycle control and diabetes manifestation in PDAC patients, and, thus, these three markers may be of special or "sentinel value". In blood samples, Next-generation sequencing (NGS) has also identified a set of microRNAs (miR-20a, miR-31-5p, miR-24, miR-25, miR-99a, miR-185, and miR-191) that seem to differentiate patients with pancreatic cancer remarkably from healthy controls, but limited data exist in this context regarding the prediction of cancer presences and outcomes. In contrast to solid pancreatic tumors, in cystic pancreatic cancer lesions, as well as premalignant lesions (such as intraductal papillary neoplasia (IPMN) or mucinous-cystic adenomatous cysts (MCAC)), the dysregulation of a completely different expression panel of miR-31-5p, miR-483-5p, miR-99a-5p, and miR-375 has been found to be of high clinical value in differentiating benign from malignant lesions. Interestingly, signal transduction pathways associated with miR-dysregulation seem to be entirely different in patients with pancreatic cysts when compared to PDAC. Overall, the determination of these different dysregulation "panels" in solid tumors, pancreatic cysts, obtained via fine-needle aspirate biopsies and/or in blood samples at the onset or during the treatment of pancreatic diseases, seems to be a reasonable candidate approach for predicting cancer presence, cancer development, and even therapy responses.


The role of prebiotics and synbiotics in critically ill patients.
To examine current knowledge regarding the role of prebiotics in critical illness when administered singly or in combinations with probiotics (synbiotics). Recent experimental and clinical studies support the fact that bioecological intestinal control with early enteral nutrition enriched with synbiotics may reduce systemic inflammation, improve the immunological status of the intestinal mucosa and help prevent infections in critically ill patients. Three prebiotics, oligofructose, galactooligosaccharides and lactulose are able to modify the balance of intestinal microbiota. It appears that treatment with synbiotics during critical illness should restore the balance of microbial communities in a beneficial way with positive effects on intestinal permeability and bacterial translocation. Only data from small trials are currently available to support use of prebiotics and synbiotics in the treatment of different clinical scenarios. However, in some critical conditions, this supplementation has so far not been effective. Numerous questions about the molecular mechanisms of action or clinical indications of prebiotics remain unanswered. Large, randomized, multicentre trials are necessary to precisely define the role of prebiotics as therapeutic agents in critical illness. These trials must identify clinically significant improvements in relevant clinical endpoints before any large-scale usage is advocated for critical illness.


Transient Brewster angle reflectometry of spiropyran monolayers.
Brewster angle reflectometry has been developed as a tool for determining the absorbance and refractive index changes in molecular monolayers containing spiropyran. The method is sensitive to changes in both the real and imaginary parts of the refractive index in the monolayers. It was used to monitor the conversion of spiropyran to merocyanine and the reversal of this reaction when the molecules were immobilised on quartz using silane coupling. An analytical solution of Fresnel formula allowed the transient reflectometry data to be converted into transient absorption information. Absorbances of transients as low as approximately 10(-6) were possible using the current apparatus with a single laser pulse transient measurement. It was found that spiropyran photoconverted to merocyanine with an efficiency of approximately 0.1. The photochemical reversion of converted merocyanine to spiropyran occurred with efficiencies of 0.03-0.2 and this was probably site dependent. It was found that the thermal conversion from merocyanine to spiropyran was slow and even after 10 min there was no significant thermal reversion. This measurement was possible because the real part of the refractive index of the monolayer could be monitored with time using an off-resonance probe at a wavelength where the merocyanine did not absorb light meaning that the probe did not photobleach the sample. Thus our method also provides a non-intrusive method for probing changes in molecules in thin films.


Delayed Consequences of Acute Kidney Injury.
Acute kidney injury (AKI) is an increasingly common complication of hospitalization and acute illness. Experimental data indicate that AKI may cause permanent kidney damage through tubulointerstitial fibrosis and progressive nephron loss, while also lowering the threshold for subsequent injury. Furthermore, preclinical data suggest that AKI may also cause distant organ dysfunction. The extension of these findings to human studies suggests long-term consequences of AKI including, but not limited to recurrent AKI, progressive kidney disease, elevated blood pressure, cardiovascular events, and mortality. As the number of AKI survivors increases, the need to better understand the mechanisms driving these processes becomes paramount. Optimizing care for AKI survivors will require understanding the short- and long-term risks associated with AKI, identifying patients at highest risk for poor outcomes, and testing interventions that target modifiable risk factors. In this review, we examine the literature describing the association between AKI and long-term outcomes and highlight opportunities for further research and potential intervention.


Incidence of intraoperative hypothermia. Adopting protocol for its prevention.
To determine the incidence of hypothermia during surgical procedures when adequate methods of preserving normothermia are applied. A prospective study in which patients ASA I-IV presented for surgery at the Armed Forces Hospital, Wadi Al-Dawasir, Kingdom of Saudi Arabia during the period from July 2000 until February 2003, in whom body core temperature was between 35-37 degree, were included. Ambient temperature of the operating room was thermostatically adjusted to record 26 degree and 24 degree if patients were less than 10 year-old or above. Depending on type of surgery; the patients were provided with space blankets and were lying on warm mattresses. Fluid or blood warmers and forced-air surface warming were used when needed. There were 3886 surgical patients operated upon during the period of the study. Their average age was 34.5 years (range 15 days to 104 years). Sixty patients (1.54%) developed intraoperative hypothermia (core temperature <35 C) and were admitted to the intensive care unit for monitoring and gradual rewarming. There was no mortality amongst them. Out of those 60 patients, 17 (28.3%) expressed dissatisfaction on this part of the service, but the overall patient's satisfaction scored 99.6%. Aggressive measures must be adopted to preserve normothermia as prevention of intraoperative hypothermia improves patient's outcome. All patients should have their core body temperature monitored during surgery. However, application of available methods of keeping normothermia reduces the incidence of intraoperative hypothermia but does not abolish it completely. Hypothermic patients should be closely monitored during gradual rewarming, preferably in the intensive care setting. A protocol for prevention of intraoperative hypothermia must be adopted by all operating theaters.


Bone malalignment in acute injuries of the wrist.
The purpose of this study was to analyze radiographic signs of carpal bone instability in patients with an acutely injured wrist. There were 80 patients (52 women and 28 men) with a fall on the outstretched hand. Fifty patients had a fracture of the distal radius, and eight had a scaphoid fracture. The patients with a bone fracture showed a larger scapholunate angle than those without a fracture (P less than 0.001, t-test). However, only four of them showed true carpal bone instability: two patients with a scaphoid fracture and one with a radius fracture had dorsiflexion instability of the wrist and one patient with a radius fracture had dorsal subluxation of the wrist. In addition, one patient without any bone fracture had scapholunate dissociation, one form of carpal bone instability. Although carpal bone instability is not frequent in an acutely injured wrist, its signs should be remembered in the radiographic analysis of the traumatic wrist to prevent subsequent articular disorders.


[Basal cell carcinoma associated with a squamous cell papilloma at the inner part of the eyelid].
There are numerous variants of cutaneous tumors involving the eyelids. Tumors of a different nature may at times be observed simultaneously in the same area of the eyelid. A clinicopathologic case of a 36-year-old male patient with 2 different cutaneous tumors at the nasal part of the left eyelid is reported. One was a nodular tumor on the inner canthus with a pearly appearance; the other had a papillomatous pattern. After surgical removal, the histopathological study of the tumors disclosed a typical basal cell carcinoma and a squamous cell papilloma. Both tumors can be commonly observed on the eyelids and surgical excision cured the patient.


A bottom-up view of toddler word learning.
A head camera was used to examine the visual correlates of object name learning by toddlers as they played with novel objects and as the parent spontaneously named those objects. The toddlers' learning of the object names was tested after play, and the visual properties of the head camera images during naming events associated with learned and unlearned object names were analyzed. Naming events associated with learning had a clear visual signature, one in which the visual information itself was clean and visual competition among objects was minimized. Moreover, for learned object names, the visual advantage of the named target over competitors was sustained, both before and after the heard name. The findings are discussed in terms of the visual and cognitive processes that may depend on clean sensory input for learning and also on the sensory-motor, cognitive, and social processes that may create these optimal visual moments for learning.


[Clipping comparable to coiling in intracranial aneurysm].
The 10-year follow-up results of the International Subarachnoid Aneurysm Trial essentially show the same results as the 5-year follow-up: no significant differences between endovascular coiling and neurosurgical clipping of ruptured intracranial aneurysms in terms of functional outcome (primary endpoint). The authors' statement that cumulative mortality rates still favour coiling did not hold up after modified intention-to-treat analysis had been performed. Moreover, the authors themselves show that survival between these treatment options is not significantly different. In the long term, coiling and clipping should therefore both be regarded viable treatment options.


Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines.
Histone acetyltransferases (HATs) are important enzymes that transfer acetyl groups onto histones and thereby regulate both gene expression and chromosomal structures. Previous work has shown that the activation of sirtuins, which are histone deacetylases, can extend lifespan. This suggests that inhibiting HATs may have a similar beneficial effect. In the present study, we utilized a range of HAT inhibitors or heterozygous Gcn5 and Ngg1 mutants to demonstrate marked yeast life extension. In human cell lines, HAT inhibitors and selective RNAi-mediated Gcn5 or Ngg1 knockdown reduced the levels of aging markers and promoted proliferation in senescent cells. Furthermore, this observed lifespan extension was associated with the acetylation of histone H3 rather than that of H4. Specifically, it was dependent upon H3K9Ac and H3K18Ac modifications. We also found that the ability of caloric restriction to prolong lifespan is Gcn5-, Ngg1-, H3K9-, and H3K18-dependent. Transcriptome analysis revealed that these changes were similar to those associated with heat shock and were inversely correlated with the gene expression profiles of aged yeast and aged worms. Through a bioinformatic analysis, we also found that HAT inhibition activated subtelomeric genes in human cell lines. Together, our results suggest that inhibiting the HAT Gcn5 may be an effective means of increasing longevity.


Berberine Prevents Disease Progression of Nonalcoholic Steatohepatitis through Modulating Multiple Pathways.
The disease progression of nonalcoholic fatty liver disease (NAFLD) from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is driven by multiple factors. Berberine (BBR) is an ancient Chinese medicine and has various beneficial effects on metabolic diseases, including NAFLD/NASH. However, the underlying mechanisms remain incompletely understood due to the limitation of the NASH animal models used. Methods: A high-fat and high-fructose diet-induced mouse model of NAFLD, the best available preclinical NASH mouse model, was used. RNAseq, histological, and metabolic pathway analyses were used to identify the potential signaling pathways modulated by BBR. LC-MS was used to measure bile acid levels in the serum and liver. The real-time RT-PCR and Western blot analysis were used to validate the RNAseq data. Results: BBR not only significantly reduced hepatic lipid accumulation by modulating fatty acid synthesis and metabolism but also restored the bile acid homeostasis by targeting multiple pathways. In addition, BBR markedly inhibited inflammation by reducing immune cell infiltration and inhibition of neutrophil activation and inflammatory gene expression. Furthermore, BBR was able to inhibit hepatic fibrosis by modulating the expression of multiple genes involved in hepatic stellate cell activation and cholangiocyte proliferation. Consistent with our previous findings, BBR's beneficial effects are linked with the downregulation of microRNA34a and long noncoding RNA H19, which are two important players in promoting NASH progression and liver fibrosis. Conclusion: BBR is a promising therapeutic agent for NASH by targeting multiple pathways. These results provide a strong foundation for a future clinical investigation.


Nanotechnology in food processing sector-An assessment of emerging trends.
Use of nanoscience based technology in the food industry is fast emerging as new area for research and development. Several research groups including private companies in the industry have initiated research programmes for exploring the wide scope of nanotechnology into the value chain of food processing and manufacturing. This paper discusses the current focus of research in this area and assesses its potential impacts. Using the developed relational database framework with R&D indicators like literature and patent documents for assessment of the potential of nanotechnology in food sector, a model to organize and map nanoresearch areas to the food processing sector was developed. The study indicates that the about five basic categories of nanotechnology applications and functionalities currently in the development of food sector, include food processing, packaging, nutraceuticals delivery, food safety and functional foods.


Economic evaluation of progeny-testing and genomic selection schemes for small-sized nucleus dairy cattle breeding programs in developing countries.
In developing countries minimal and erratic performance and pedigree recording impede implementation of large-sized breeding programs. Small-sized nucleus programs offer an alternative but rely on their economic performance for their viability. We investigated the economic performance of 2 alternative small-sized dairy nucleus programs [i.e., progeny testing (PT) and genomic selection (GS)] over a 20-yr investment period. The nucleus was made up of 453 male and 360 female animals distributed in 8 non-overlapping age classes. Each year 10 active sires and 100 elite dams were selected. Populations of commercial recorded cows (CRC) of sizes 12,592 and 25,184 were used to produce test daughters in PT or to create a reference population in GS, respectively. Economic performance was defined as gross margins, calculated as discounted revenues minus discounted costs following a single generation of selection. Revenues were calculated as cumulative discounted expressions (CDE, kg) × 0.32 (€/kg of milk) × 100,000 (size commercial population). Genetic superiorities, deterministically simulated using pseudo-BLUP index and CDE, were determined using gene flow. Costs were for one generation of selection. Results show that GS schemes had higher cumulated genetic gain in the commercial cow population and higher gross margins compared with PT schemes. Gross margins were between 3.2- and 5.2-fold higher for GS, depending on size of the CRC population. The increase in gross margin was mostly due to a decreased generation interval and lower running costs in GS schemes. In PT schemes many bulls are culled before selection. We therefore also compared 2 schemes in which semen was stored instead of keeping live bulls. As expected, semen storage resulted in an increase in gross margins in PT schemes, but gross margins remained lower than those of GS schemes. We conclude that implementation of small-sized GS breeding schemes can be economically viable for developing countries.


Integrating scRNA-seq and bulk RNA-seq to characterize infiltrating cells in the colorectal cancer tumor microenvironment and construct molecular risk models.
Colorectal cancer (CRC) is a malignancy that is both highly lethal and heterogeneous. Although the correlation between intra-tumoral genetic and functional heterogeneity and cancer clinical prognosis is well-established, the underlying mechanism in CRC remains inadequately understood. Utilizing scRNA-seq data from GEO database, we re-isolated distinct subsets of cells, constructed a CRC tumor-related cell differentiation trajectory, and conducted cell-cell communication analysis to investigate potential interactions across cell clusters. A prognostic model was built by integrating scRNA-seq results with TCGA bulk RNA-seq data through univariate, LASSO, and multivariate Cox regression analyses. Eleven distinct cell types were identified, with Epithelial cells, Fibroblasts, and Mast cells exhibiting significant differences between CRC and healthy controls. T cells were observed to engage in extensive interactions with other cell types. Utilizing the 741 signature genes, prognostic risk score model was constructed. Patients with high-risk scores exhibited a significant correlation with unfavorable survival outcomes, high-stage tumors, metastasis, and low responsiveness to chemotherapy. The model demonstrated a strong predictive performance across five validation cohorts. Our investigation involved an analysis of the cellular composition and interactions of infiltrates within the microenvironment, and we developed a prognostic model. This model provides valuable insights into the prognosis and therapeutic evaluation of CRC.


Electroacupuncture in rats infected with Strongyloides venezuelensis: effects on gastrointestinal transit and parasitological measurements.
To investigate the effects of electroacupuncture (EA) at ST36 and CV12 on gastrointestinal transit and parasitological measurements during Strongyloides venezuelensis infection in rats. Rats were infected with S. venezuelensis and allocated to one of three groups that were infected and remained untreated (SV group, n=8), infected and treated with EA at CV12 (SV+CV12 group, n=8) or infected and treated with EA at ST36 (SV+ST36 group, n=8). EA was performed every 3 days over a 21-day period, at 4 mA intensity and 15 Hz frequency for 20 min. At 2 and 20 days post-infection (dpi), body weight, food and water intake, and faecal characteristics were monitored over a 24-hour period. Gastric emptying, caecal arrival time, small intestinal transit and eggs per gram (EPG) of faeces were calculated at 3, 9, 15 and 21 dpi. At 21 dpi, intestinal worm recovery was counted. EA at ST36 and CV12 slowed gastric emptying over the course of infection time. An accelerated intestinal transit was observed in the ST36 group, and after CV12 treatment the same effect was observed at 9 and 15 dpi. At 9 dpi, EPG was increased in the CV12 group. ST36 treatment decreased EPG at 9 and 15 dpi. At 21 dpi, both the ST36 and CV12 groups had increased EPG and worm numbers. No changes were observed in the other parameters analysed. EA at ST36 and CV12 provoked changes in gastrointestinal transit that may be beneficial to the host during S. venezuelensis infection; however, based on the number of worms and EPG at 21 dpi, the indication for EA in the treatment of strongyloidiasis needs to be carefully assessed.


Influence of second coordination sphere hydroxyl groups on the reactivity of copper(I) complexes.
We report the enhanced reactivity of hydroxyl substituted CuN(3)(+) derivatives, where N(3) = tris(picolinyl)methane (tripic) and related derivatives, upon deprotonation of the O-H functionality. The work capitalizes on new methodology for incorporating hydroxyl groups into the second coordination sphere of copper centers. The key synthetic methodology relies on Pd-catalyzed coupling reactions of dilithiated 6-methyl-2-pyridone with bromopyridyl derivatives. These building blocks allow the preparation of tridentate N(3) ligands with OH and OMe substituents flanking the fourth coordination site of a tetrahedral complex. Coupling of these tridendate ligands gives the corresponding hydroxy- and methoxy-functionalized bistripodal ligands. [Cu[bis(2-methylpyrid-6-yl)(2-hydroxypyrid-6-yl)methane](NCMe)](+) ([Cu(2H)(NCMe)](+)) oxidizes readily in air to afford the mixed valence Cu(1.5) dimer ([Cu(2)(2)(2)](+)). Formation of [Cu(2)(2)(2)](+) is accelerated in the presence of base and can be reversed with a combination of decamethylferrocene and acid. The reactivity of [Cu(2H)(NCMe)](+) with dioxygen requires deprotonation of the hydroxyl substituent: neither [Cu(tripic)(NCMe)](+) nor the methoxy-derivatives displayed comparable reactivity. A related mixed valence dimer formed upon oxidation of the dicopper(I) complex of a tetrahydroxy bis(tridentate) ligand, [Cu(2)(6H(4))(NCMe)(2)](2+). The dicopper(I) complex of the analogous tetramethoxy N(6)-ligand, [Cu(2)(5)(NCMe)(2)](2+), instead reversibly binds O(2). Deprotonation of [Cu(2H)(CO)](+) and [Cu(2H)(NCMe)](+) afforded the neutral derivatives Cu(2)(CO) and Cu(2)(2)(2), respectively. The dicopper(I) derivative Cu(2)(2)(2) can be reoxidized, reprotonated, and carbonylated. The silver(I) complex, [Ag(2H)(NCMe)]BF(4), forms an analogous neutral dimer (Ag(2)(2)(2)) upon deprotonation of the hydroxyl group. The structures of ligand 2H, [Cu(2)(5)(NCMe)(2)](+), [Cu(2)(2)(2)](+), [Cu(2)(6H(2))](+), [Ag(2H)(NCMe)]BF(4), and Ag(2)(2)(2) were confirmed by single crystal X-ray diffraction.


[Nitric oxide metabolites and their significance in pathogenesis of bronchial asthma].
To study the possible potential of nitric oxide (NO) in the processes of atopic inflammation, the authors evaluated the intensity of nitrosyling and oxidative stresses in the bronchoalvelar lavage fluid and expired air condensate of patients with bronchial asthma (BA). Chronic inflammation was shown to result in an increase in the processes of nitration and oxidation in worsening BA and to reliably correlate with airway NO-producing functions, by explaining the pathological effects of NO due to the formation of 3-nitrotyrosine and malonic dialdehyde with the existing imbalance in NO metabolism, by intensifying nitrosylating stress. In the authors' opinion, nitrosothiols that are required as a NO donor may be rapidly destroyed or virtually do not form so the peroxynitrite-nitrosothiol ratio may predetermine the final effects of NO.


Cow-level factors associated with nitrogen utilization in grazing dairy cows using a cross-sectional analysis of a large database.
Reducing nitrogen pollution while maintaining milk production is a major challenge of dairy production. One of the keys to delivering on this challenge is to improve the efficiency of how dairy cows utilize nitrogen. Thus, estimating the nitrogen utilization of lactating grazing dairy cows and exploring the association between animal factors and productivity with nitrogen utilization are the first steps to understanding the nitrogen utilization complex in dairy cows. Nitrogen utilization metrics were derived from milk and body weight records from 1,291 grazing dairy cows of multiple breeds and crossbreeds; all cows had sporadic information on nitrogen intake concurrent with information on nitrogen sinks (and other nitrogen sources such as body tissue mobilization). Several nitrogen utilization metrics were investigated, including nitrogen use efficiency (nitrogen output as products such as milk and/or meat divided by nitrogen intake) and nitrogen excreted (nitrogen intake less the nitrogen output as products such as milk and/or meat). In the present study, a primiparous Holstein-Friesian used, on average, 20.6% of the nitrogen it ate, excreting the surplus as feces and urine, representing 402 g N/day. Inter-cow variability existed, with a between cow standard deviation of 0.0094 for nitrogen use efficiency and 24 g N/ day for nitrogen excretion. As lactation progressed, nitrogen use efficiency declined while nitrogen excretion increased. Nevertheless, nitrogen use efficiency improved (i.e., decreased) from first to second parity, even though it did not improve from second to third parity or greater. Furthermore, nitrogen excretion continued to increase from first to third parity or greater. Nitrogen use efficiency and nitrogen excretion were negatively correlated (-0.56 to -0.40), signifying that dairy cows who partition more of the ingested nitrogen into products such as milk and/or meat, on average, also excrete less nitrogen. Milk urea nitrogen was, at best, weakly correlated with nitrogen use efficiency and nitrogen excretion; the correlation were between -0.01 and 0.06. In conclusion, several cow-level factors like parity, stage of lactation, and breed were associated with the range of different nitrogen efficiency metrics investigated; moreover, even after accounting for such effects, 4.8% to 6.3% of the remaining variation in the nitrogen use efficiency and nitrogen balance metrics were attributable to inter-cow differences.


CigTrak: Smartwatch-Based Accurate Online Smoking Puff & Episode Detection with Gesture-Focused Windowing for CNN.
Wearable-based motion sensing solutions are capable of automatically detecting and tracking individual smoking puffs and/or episodes to aid the users in their journey of smoking cessation. But they are either obtrusive to use, perform with a low accuracy, or have questionable ability of running fully on a low-power device like a smartwatch, all affecting their widespread adoption. We propose 'CigTrak', a novel pipeline for an accurate smoking puff and episode detection using 6-DoF motion sensor on a smartwatch. A multi-stage method for puff detection is devised, comprising a novel kinematic analysis of puffing motion enabling temporal localization of puff. A Convolutional Neural Network (CNN)-backed model uses this candidate puff as an input instance by re-sampling it to required input size for the final decision. Clusters of detected puffs are further used to detect episodes. Data from 13 subjects was used for evaluating puff detection, and 9 subjects for evaluating episode detection. CigTrak achieved a high subject-independent performance for puff detection (F1-score 0.94) and free-living episode detection (F1-score 0.89), surpassing state of the art performance. CigTrak was also implemented fully online on two different smartwatches for testing a real-time puff detection.Clinical Relevance- Cigarette smoking affects physical & mental well-being of a person, and is the leading cause of preventable diseases, adversely affecting cardiac and respiratory systems. With many adults wanting to quit smoking [1], a reliable way of auto-journaling of smoking activities can greatly aid in cessation efforts through self-help, and reduce burden on healthcare industry. CigTrak, with its high accuracy in detecting smoking puffs and episodes, and capability of running fully on a smartwatch, can be readily used for this purpose.


Effect of adsorbed protein on hydroxyapatite zeta potential and Streptococcus mutans adherence.
The adherence of Streptococcus mutans PK1 to hydroxyapatite disks pretreated with various acidic and basic proteins in imidazole buffer was studied. Adsorption of a basic protein onto an hydroxyapatite disk enhanced or had no effect on bacterial adherence, whereas adsorption of an acidic protein reduced adherence. The effect of adsorbed protein on bacterial adherence was of both short and long range. The long-range effect of the acidic proteins in reducing the number of bacteria adhering to hydroxyapatite was related to protein adsorption causing an increase in surface net negative charge, as shown by zeta potential measurement. Basic protein produced a net positive surface charge which facilitated adherence. Within the acidic protein group, the acidic residue percentage of the adsorbed protein was negatively correlated with the number of bacteria adhering, whereas the nonpolar residue percentage was positively correlated with bacterial adherence. Within the basic protein group, the basic residue percentage was correlated with the number of cells adhering. These results indicate the involvement of short-range hydrophobic and ionic interactions in bacterial adherence to protein-coated hydroxyapatite.


Cancer and the endogenous "pineal clock": a means of early diagnosis and successful treatment as well as prevention of cancers.
The majority of chronic diseases, most notably those accompanying aging, result from progressive deterioration of central neuroimmunoendocrine control, often referred to as immunological surveillance. This is as true of cancer as it is of the development of cardiovascular, autoimmune, and neurodegenerative disease, in all of these immunological surveillance break downs, leading to an unraveling of the neuroimmunoendocrine process that inhibits proliferation of preneoplastic and neoplastic cells already existing in the body. The onset of cancer is anticipated by changes in the hormonalimmune coordination resulting in chronic quantitative alterations in the synthesis and release of hormones and the loss of the natural synchronicity of that release, which occurs according to circadian rhythms in the healthy organism, principally under the control of the pineal network. Periodic circadian hormonal release is the source of immune system regulation, thus altering hormone rhythms impairs the immune system's ability to maintain control over emerging tumor cells, not necessarily to eliminate them, but to inhibit proliferation. Malignancy, then, is the result of suppression of or interference with the regular release of hormones that maintain strict regulation of the thymo-lymphatic immune system's maturation and activity. This understanding means that we can act to prevent cancer by means of efficiently monitoring and maintenance of physiological hormonal values. For the cyclic synthesis of malignancies that are metastasized, a means of xenogeneic bone marrow transplantation is proposed as an alternative therapeutic approach.


Chiropractic treatment of lateral epicondylitis: a case report utilizing active release techniques.
The purpose of this report is to describe the chiropractic management of a case of lateral epicondylitis with active release techniques (ART). A 48-year-old white man presented to a chiropractic clinic with a complaint of left lateral elbow pain that began 2 years previous with insidious onset. The patient reported an inability to play 18 consecutive holes of golf due to the pain. Treatment consisted of 5 sessions of ART (a soft tissue technique that is applied to muscles, fascia, tendons, ligaments, and nerves) applied to the left elbow soft tissue over a duration of 3 weeks. The patient reported an absence of pain and ability to consistently play 18 consecutive holes of golf up to 3 times per week at 4 and 8 weeks post-treatment. This patient with lateral epicondylitis responded favorably to chiropractic treatment using the application of ART, as demonstrated by reduced pain and increased functional outcomes.


[Protective effect of rosmarinic acid on hypoxia/reoxygenation injury in cardiomyocytes].
To study the protective effect of rosmarinic acid (Ros A) on the primary cardiomyocyte hypoxia/reoxygenation (H/R) injury. Primary cardiomyocytes of rats were cultured in vitro to establish the H/R injury of cardiomyocytes and observe the changes in the cell viability and LDH leakage. The changes in ATP content and ROS in cardiomyocytes were measured by using chemiluminescence and fluorescent probe technique. The effects of rosmarinic acid on the apoptosis of cardiomyocytes, cleaved-caspase 3, Akt and p-Akt protein expression were further detected by flow cytometry and western blot analysis. According to the experimental results, Ros A at doses of 25, 50, 100 mg x L(-1) could inhibit the decrease in H/R-induced cell viability, LDH leakage and excessive ROS generation, and maintain the ATP level in cells. Ros A at doses of 50, 100 mg x L(-1) could remarkably inhibit the H/R-induced cardiomyocyte apoptosis and down-regulate the expression of cleaved caspase-3. Moreover, Ros A at doses of 100 mg x L(-1) could significantly up-regulate the expression of p-Akt. Ros A has the significant effect in resisting the cardiomyocyte H/R injury, improve cardiomyocyte energy metabolism and reduce cell apoptosis, which is related to the activation of Akt pathway.


[Gonadotropic function of the pituitary gland in patients with intersexualism and gonadal dysgenesis].
Radioimmunoassay was used to study the blood content of LH and FSH in 116 patients aged 1 to 36 years with abnormalities of sexual development (false male hermafroditism, false female hermafroditism, true hermafroditism and gonadal dysgenesis). With a view of control the content of gonadotropins was measured in 92 subjects (33 females and 59 males) of the same age. The data were evaluated in accordance with the age and genetic sex of patients. It was shown that in health, the concentration of LH and FSH reflected the process of puberty, permanently growing until 18 years, whereas in patients, the age-related time course was less consistent. Unidirectional changes in the hormonal level (towards its rise) were common to all the forms of abnormal sexual development. In all the examinees, the pattern of changes in gonadotropic activity reflected the features of the formation of the neuroendocrine mechanisms by which the sexual system is controlled in ontogenesis.


Comprehensive identification and annotation of cell type-specific and ubiquitous CTCF-binding sites in the human genome.
Chromatin insulators are DNA elements that regulate the level of gene expression either by preventing gene silencing through the maintenance of heterochromatin boundaries or by preventing gene activation by blocking interactions between enhancers and promoters. CCCTC-binding factor (CTCF), a ubiquitously expressed 11-zinc-finger DNA-binding protein, is the only protein implicated in the establishment of insulators in vertebrates. While CTCF has been implicated in diverse regulatory functions, CTCF has only been studied in a limited number of cell types across human genome. Thus, it is not clear whether the identified cell type-specific differences in CTCF-binding sites are functionally significant. Here, we identify and characterize cell type-specific and ubiquitous CTCF-binding sites in the human genome across 38 cell types designated by the Encyclopedia of DNA Elements (ENCODE) consortium. These cell type-specific and ubiquitous CTCF-binding sites show uniquely versatile transcriptional functions and characteristic chromatin features. In addition, we confirm the insulator barrier function of CTCF-binding and explore the novel function of CTCF in DNA replication. These results represent a critical step toward the comprehensive and systematic understanding of CTCF-dependent insulators and their versatile roles in the human genome.


Deletion of deoxyribonucleic acid binding domain of the vitamin D receptor abrogates genomic and nongenomic functions of vitamin D.
The vitamin D hormone 1,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the biologically active form of vitamin D, is essential for an intact mineral metabolism. Using gene targeting, we sought to generate vitamin D receptor (VDR) null mutant mice carrying the reporter gene lacZ driven by the endogenous VDR promoter. Here we show that our gene-targeted mutant mice express a VDR with an intact hormone binding domain, but lacking the first zinc finger necessary for DNA binding. Expression of the lacZ reporter gene was widely distributed during embryogenesis and postnatally. Strong lacZ expression was found in bones, cartilage, intestine, kidney, skin, brain, heart, and parathyroid glands. Homozygous mice are a phenocopy of mice totally lacking the VDR protein and showed growth retardation, rickets, secondary hyperparathyroidism, and alopecia. Feeding of a diet high in calcium, phosphorus, and lactose normalized blood calcium and serum PTH levels, but revealed a profound renal calcium leak in normocalcemic homozygous mutants. When mice were treated with pharmacological doses of vitamin D metabolites, responses in skin, bone, intestine, parathyroid glands, and kidney were absent in homozygous mice, indicating that the mutant receptor is nonfunctioning and that vitamin D signaling pathways other than those mediated through the classical nuclear receptor are of minor physiological importance. Furthermore, rapid, nongenomic responses to 1,25-(OH)(2)D(3) in osteoblasts were abrogated in homozygous mice, supporting the conclusion that the classical VDR mediates the nongenomic actions of 1,25-(OH)(2)D(3).


Overexpression of cyclooxygenase-2 correlates with tumor angiogenesis in endometrial carcinoma.
The inducible enzyme cyclooxygenase-2 (COX-2) is an important mediator of angiogenesis and tumor growth. Several reports have indicated that vascular endothelial growth factor (VEGF)-positive tumors are associated with an increased amount of COX-2 protein. This study evaluated the significance of COX-2 in 34 patients with endometrial carcinoma and its relationship to angiogenesis. Immunohistochemical expression of COX-2 and VEGF was analyzed on paraffin-embedded tissue sections. Microvessel density (MVD) of endometrial carcinoma was also determined with anti-CD(34) as the label. COX-2 messenger RNA (mRNA) was analyzed by reverse transcription-polymerase chain reaction. The expression rate of COX-2 in 34 cases was 64.7% but not in control endometrium. COX-2 mRNA was higher in tumor specimens than in normal tissues. The level of COX-2 expression was higher in grade 2 tumors than in grade 3 tumors (P < 0.05). MVD was higher in COX-2-positive and VEGF-positive cases than in COX-2-negative and VEGF-negative cases (P < 0.05). The expression of COX-2 was positively correlated with the expression of VEGF and MVD (P < 0.05 and P < 0.01, respectively). The present findings suggest that overexpression of COX-2 may induce the expression of VEGF, increase angiogenesis, and enhance tumor growth.


The effect of Er:YAG laser irradiation on the bond stability of self-etch adhesives at different dentin depths.
The aim of this study was to evaluate the effect of Er:YAG laser irradiation on the micro-shear bond strength of self-etch adhesives to the superficial dentin and the deep dentin before and after thermocycling. Superficial dentin and deep dentin surfaces were prepared by flattening of the occlusal surfaces of extracted human third molars. The deep or superficial dentin specimens were randomized into three groups according to the following surface treatments: group I (control group), group II (Er:YAG laser; 1.2 W), and group III (Er:YAG laser; 0.5 W). Clearfil SE Bond or Clearfil S3 Bond was applied to each group's dentin surfaces. After construction of the composite blocks on the dentin surface, the micro-shear bond testing of each adhesive was performed at 24 h or after 15,000 thermal cycles. The data were analyzed using a univariate analysis of variance and Tukey's test (p < 0.05). Laser irradiation in superficial dentin did not significantly affect bond strength after thermocycling (p > 0.05). However, deep-dentin specimens irradiated with laser showed significantly higher bond strengths than did control specimens after thermocycling (p < 0.05). Thermocycling led to significant deterioration in the bond strengths of all deep-dentin groups. The stable bond strength after thermocycling was measured for all of the superficial-dentin groups. No significant difference was found between the 0.5 and 1.2 W output power settings. In conclusion, the effect of laser irradiation on the bond strength of self-etch adhesives may be altered by the dentin depth. Regardless of the applied surface treatment, deep dentin showed significant bond degradation.


Probing cellular mechanics with acoustic force spectroscopy.
A large number of studies demonstrate that cell mechanics and pathology are intimately linked. In particular, deformability of red blood cells (RBCs) is key to their function and is dramatically altered in the time course of diseases such as anemia and malaria. Due to the physiological importance of cell mechanics, many methods for cell mechanical probing have been developed. While single-cell methods provide very valuable information, they are often technically challenging and lack the high data throughput needed to distinguish differences in heterogeneous populations, while fluid-flow high-throughput methods miss the accuracy to detect subtle differences. Here we present a new method for multiplexed single-cell mechanical probing using acoustic force spectroscopy (AFS). We demonstrate that mechanical differences induced by chemical treatments of known effect can be measured and quantified. Furthermore, we explore the effect of extracellular vesicles (EVs) uptake on RBC mechanics and demonstrate that EVs uptake increases RBC deformability. Our findings demonstrate the ability of AFS to manipulate cells with high stability and precision and pave the way to further new insights into cellular mechanics and mechanobiology in health and disease, as well as potential biomedical applications.


Infrared Absorption Spectra of Jahn-Teller Systems: Application to the Transition-Metal Trifluorides MnF3 and NiF3.
The theory for the calculation of vibronic absorption spectra within a Jahn-Teller (JT) active electronic state from first principles has been developed. The infrared absorption spectra of the 5E' ground state, the low-lying 5E″ excited state of MnF3, and the 4E' state of NiF3 have been computed and analyzed. Dipole moment derivatives have been determined by a linear-plus-quadratic expansion of nuclear dipole moment functions in the JT-active coordinates. Electronic transition dipole moments have been taken into account in the Condon approximation in the diabatic representation. The initial and final vibronic states have been expanded in a product of diabatic electronic states and vibrational basis functions. The effect of spin-orbit coupling on the vibronic infrared spectra of these molecules in their JT-active electronic states has been investigated, by employing the Breit-Pauli spin-orbit operator. The effect of temperature on the vibronic infrared spectra has also been explored. These results represent the first theoretical study of vibronic infrared spectra of JT-active states in transition metal compounds.


Ozone uptake on glassy, semi-solid and liquid organic matter and the role of reactive oxygen intermediates in atmospheric aerosol chemistry.
Heterogeneous and multiphase reactions of ozone are important pathways for chemical ageing of atmospheric organic aerosols. To demonstrate and quantify how moisture-induced phase changes can affect the gas uptake and chemical transformation of organic matter, we apply a kinetic multi-layer model to a comprehensive experimental data set of ozone uptake by shikimic acid. The bulk diffusion coefficients were determined to be 10(-12) cm(2) s(-1) for ozone and 10(-20) cm(2) s(-1) for shikimic acid under dry conditions, increasing by several orders of magnitude with increasing relative humidity (RH) due to phase changes from amorphous solid over semisolid to liquid. Consequently, the reactive uptake of ozone progresses through different kinetic regimes characterised by specific limiting processes and parameters. At high RH, ozone uptake is driven by reaction throughout the particle bulk; at low RH it is restricted to reaction near the particle surface and kinetically limited by slow diffusion and replenishment of unreacted organic molecules. Our results suggest that the chemical reaction mechanism involves long-lived reactive oxygen intermediates, likely primary ozonides or O atoms, which may provide a pathway for self-reaction and catalytic destruction of ozone at the surface. Slow diffusion and ozone destruction can effectively shield reactive organic molecules in the particle bulk from degradation. We discuss the potential non-orthogonality of kinetic parameters, and show how this problem can be solved by using comprehensive experimental data sets to constrain the kinetic model, providing mechanistic insights into the coupling of transport, phase changes, and chemical reactions of multiple species in complex systems.


Solifluction: a model experiment.
Laboratory experiments that subjected soil to repeated freeze-thaw cycles in an inclined container revealed every process of solifluction, especially of frost creep. Multiple slope-angle effects on the amount of particle movement on the soil surface in every cycle are interpreted by several characteristic processes of frost creep. Gelifluction was found to occur in thicker layers of soil, owing to the excess water retained in soil after thawing. For further development of the problem, a similarity law for the model experiment was derived from thermal considerations.


Supramolecular effects in dendritic systems containing photoactive groups
In this article are described dendritic structures containing photoactive groups at the surface or in the core. The observed supramolecular effects can be attributed to the nature of the photoactive group and their location in the dendritic architecture. The peripheric azobenzene groups in these dendrimeric compounds can be regarded as single residues that retain the spectroscopic and photochemical properties of free azobenzene moiety. The E and Z forms of higher generation dendrimer, functionalized with azobenzene groups, show different host ability towards eosin dye, suggesting the possibility of using such dendrimer in photocontrolled host-guest systems. The photophysical properties of many dendritic-bipyridine ruthenium complexes have been investigated. Particularly in aerated medium more intense emission and a longer excited-state lifetime are observed as compared to the parent unsubstituted bipyridine ruthenium complexes. These differences can be attributed to a shielding effect towards dioxygen quenching originated by the dendritic branches.


The Effect of Active Plus, a Computer-Tailored Physical Activity Intervention, on the Physical Activity of Older Adults with Chronic Illness(es)-A Cluster Randomized Controlled Trial.
eHealth interventions aimed at improving physical activity (PA) can reach large populations with few resources and demands on the population as opposed to centre-based interventions. Active Plus is a proven effective computer-tailored PA intervention for the older adult population focusing on PA in daily life. This manuscript describes the effects of the Active Plus intervention (N = 260) on PA of older adults with chronic illnesses (OACI), compared to a waiting list control group (N = 325). It was part of a larger randomized controlled trial (RCT) on the effects of the Active Plus intervention on cognitive functioning. OACI (≥65 years) with at least one chronic illness were allocated to one of the conditions. Intervention group participants received PA advice. Baseline and follow-up measurements were assessed after 6 and 12 months. Intervention effects on objectively measured light PA (LPA) and moderate-to-vigorous PA (MVPA) min/week were analysed with multilevel linear mixed-effects models adjusted for the clustered design. Intervention effects on self-reported MVPA min/week on common types of PA were analysed with two-part generalized linear mixed-effects models adjusted for the clustered design. The dropout rate was 19.1% after 6 months and 25.1% after 12 months. Analyses showed no effects on objectively measured PA. Active Plus increased the likelihood to perform self-reported cycling and gardening at six months and participants who cycled increased their MVPA min/week of cycling. Twelve months after baseline the intervention increased the likelihood to perform self-reported walking and participants who cycled at 12 months increased their MVPA min/week of cycling. Subgroup analyses showed that more vulnerable participants (higher degree of impairment, age or body mass index) benefitted more from the intervention on especially the lower intensity PA outcomes. In conclusion, Active Plus only increased PA behaviour to a limited extent in OACI 6 and 12 months after baseline measurements. The Active Plus intervention may yet be not effective enough by itself in OACI. A blended approach, where this eHealth intervention and face-to-face contact are combined, is advised to improve the effects of Active Plus on PA in this target group.


[Simplified method of differential diagnosis of dwarfism].
On the basis of analysis (with the aid of the "Minsk-22" computer) of the data on the information character of 485 signs in hypophyseal, hypothalamic, thyrogenic, somatogenic nanism spondylo-epyphyseal dysplasia ans Shereshevsky-Turner's syndrome the authors selected 50 signs with the greatest diagnostic value. These signs were assessed and graded by marks; a diagnostic table was elaborated with the aid of which a correct diagnosis with the probability of over 0.90 was established in 72 per cent of cases.


Conventional splenorenal shunts. A reconsideration.
From 1961 to 1971, 73 central splenorenal and 66 portacaval shunts were done for cirrhotic patients who had bled from esophageal varices. Comparative analysis revealed low (3% and 2%, respectively) operative mortality for elective operations, equal (93%) effectiveness in control of variceal bleeding, but substantial diferences in the incidence of postshunt encephalopathy. For patients who had mimal hepatic dysfunction before operation, disabling disorders in mentation developed in 5% of patients who had splenorenal shunts, in contrast to 50% of patients who had portacaval shunts. Survival rates after the two shunts were nearly identical. Thus, the advantages of splenorenal shunts concern the quality of life but not the length of survival. These observations are considered in relation to available therapeutic alternatives.


Forest habitat parameters influence abundance and diversity of cadaver-visiting dung beetles in Central Europe.
Dung beetles provide crucial ecosystem services and serve as model organisms for various behavioural, ecological and evolutionary studies. However, dung beetles have received little attention as consumers of large cadavers. In this study, we trapped copronecrophagous dung beetles on above-ground exposed piglet cadavers in 61 forest plots distributed over three geographically distinct regions in Germany, Central Europe. We examined the effects of land use intensity, forest stand, soil characteristics, vascular plant diversity and climatic conditions on dung beetle abundance, species richness and diversity. In all three regions, dung beetles, represented mainly by the geotrupid species Anoplotrupes stercorosus and Trypocopris vernalis, were attracted to the cadavers. High beetle abundance was associated with higher mean ambient temperature. Furthermore, A. stercorosus and T. vernalis were more abundant in areas where soil contained higher proportions of fine sand. Additionally, an increased proportion of forest understorey vegetation and vascular plant diversity positively affected the species richness and diversity of dung beetles. Thus, even in warm dry monocultured forest stands exploited for timber, we found thriving dung beetle populations when a diverse understorey was present. Therefore, forestry practices that preserve the understorey can sustain stable dung beetle populations and ensure their important contribution to nutrient cycles.


[Prevention of osteoporosis: estrogen substitution paradigm].
There is an increasing belief among most physicians that hormone replacement therapy (HRT) is unquestionable efficacious to prevent osteoporotic fractures in women after the menopause. However, an analysis of the studies which are regarded as efficacy proof of HRT concerning the prevention of hip fractures--as the most important manifestation of osteoporosis--shows that the data are weaker than generally assumed: there are no randomised trials with regard to hip fracture prevention by HRT and the protective effect which is seen in the observational studies is inversely related to the methodical state of the respective type of study. Consequently, a bias cannot be excluded, while the so-called 'selection-by-health'-bias could play an outstanding role. For the efficacy proof of a treatment randomised controlled trials cannot be replaced by results of observational studies, however impressive they may be.


Interaction research on an antiviral molecule that targets the coat protein of southern rice black-streaked dwarf virus.
Southern rice black-streaked dwarf virus (SRBSDV) coat protein (P10) is the key protein required for viral transmission and host plant infection and is thus a promising target for anti-SRBSDV agent screening. In this study, P10 was obtained from Escherichia coli through cloning, expression, and purification. The antiviral agent Ningnanmycin was selected as control, and a series of antiviral compounds based on the structural scaffold of ferulic acid were analyzed. Size-exclusion chromatography analysis results showed that compound F27 can alter the aggregation of P10 proteins. Furthermore, fluorescence titration and microscale thermophoresis assay results indicated that F27 binds to P10 with KA of 5.75×105M-1 and KD of 7.81μM. The ligand- and receptor-based three-dimensional quantitative structure-activity analyses were performed to determine the requirements for the interaction between the carboxyl structures and P10s. On the basis of the obtained models and information, we provided insights regarding the design and optimization of novel molecules as anti-SRBSDV agents.


Bioassay-comparison of the antioxidant efficacy of hydrogen sulfide and superoxide dismutase in isolated arteries and veins.
Recent studies suggest that hydrogen sulfide (H2S) exhibits potent antioxidant capacity and improves vascular and tissue functions. Thus we aimed to compare the antioxidant efficacy of H2S to that of superoxide dismutase (SOD).Isometric force of isolated rat carotid arteries and gracilis veins was measured with a myograph. The vasomotor effect of the superoxide-generator pyrogallol (10-5M) was obtained in control conditions, and then in the presence of SOD (120 U/ml) or H2S (10-5M or 10-4M), respectively. Spectrophotometric measurements were performed to detect the effect of SOD and H2S on the auto-oxidation of pyrogallol.Pyrogallol increased the isometric force of carotid arteries (9.7 ± 0.8 mN), which was abolished by SOD (5.3 ± 0.8 mN), was not affected by 10-5M H2S (9.1 ± 0.5 mN), whereas 10-4M H2S slightly, but significantly reduced it (8.1 ± 0.7 mN). Pyrogallol significantly increased the isometric force of gracilis veins (1.3 ± 0.2 mN), which was abolished by SOD (0.9 ± 0.2 mN), whereas 10-5M (1.3 ± 0.2 mN), or 10-4M H2S (1.2 ± 0.2 mN) did not affect it. Pyrogallol-induced superoxide production was measured by a spectrophotometer (A420 = 0.19 ± 0.0). SOD reduced absorbance (A420 = 0.02 ± 0.0), whereas 10-5M H2S did not (A420 = 0.18 ± 0.0) and 10-4M H2S slightly reduced it (A420 = 0.15 ± 0.0).These data suggest that H2S is a less effective vascular antioxidant than SOD. We propose that the previously described beneficial effects of H2S are unlikely to be related to its direct effect on superoxide.


Mediators of gender effects on depression among cardiovascular disease patients in Palestine.
Among patients suffering from coronary heart disease (CHD) and comorbid depression, women experience a higher burden compared to men. Little is known on the characteristics that differentiate men and women with both diseases and whether these factors mediate gender effects on depression. This study assessed whether women are more likely to suffer from depression and which characteristics mediate gender effects on depression among a cardiac population in Palestine, specifically addressing the role of post-traumatic stress disorder (PTSD). Using a cross-sectional design, patients consecutively admitted with a CHD to one of the four main hospitals in Nablus, Palestine, were interviewed using a structured questionnaire with validated instruments. Data was also obtained from hospital medical records. Patients were assessed for depression using the Cardiac Depression Scale (CDS). Bivariate analysis was conducted to compare characteristics of women and men with and without depressive symptoms. Mediators (direct and indirect effects) of the association between gender and depression were evaluated using a structural equation model (SEM). Women were more likely to suffer from severe depression than men (28.7% vs. 18.8%). Female gender was positively associated with higher PTSD symptoms, comorbidities, somatic symptoms and income, and with lower resilience, self-esteem, quality of life, education, prevalence of smoking and physical activity. Structural equation modeling revealed negative indirect effects of gender on depression (CDS score) through resilience, self-esteem and physical activity, whereas positive indirect effects of gender on depression were observed through PTSD, comorbidities, somatic symptoms and smoking. There was no direct effect of gender on depression. This study found a higher prevalence of severe depression in female patients with cardiac disease compared to male cardiac patients. Our findings provide novel information on mediating factors of the association between gender and depression among cardiac patients, in particular PTSD. The results emphasize the need for further research on potential mediating factors that could account for gender differences in depression and the need to provide support programs for female patients with comorbid CHD and depression to improve their psycho-social well-being.


Ferrous iron transport in Streptococcus mutans.
Radioiron uptake from 59FeCl3 by Streptococcus mutans OMZ176 was increased by anaerobiosis, sodium ascorbate, and phenazine methosulfate (PMS), although there was a 10-min lag before PMS stimulation was evident. The reductant ascorbate may have provided ferrous iron. The PMS was reduced by the cells, and the reduced PMS then may have generated ferrous iron for transport; reduced PMS also may have depleted dissolved oxygen. We conclude that S. mutans transports only ferrous iron, utilizing reductants furnished by glucose metabolism to reduce iron prior to its uptake.


Structure of a novel enzyme that catalyzes acyl transfer to alcohols in aqueous conditions.
The unusual architecture of the enzyme (MsAcT) isolated from Mycobacterium smegmatis forms the mechanistic basis for favoring alcoholysis over hydrolysis in water. Unlike hydrolases that perform alcoholysis only under anhydrous conditions, MsAcT demonstrates alcoholysis in substantially aqueous media and, in the presence of hydrogen peroxide, has a perhydrolysis:hydrolysis ratio 50-fold greater than that of the best lipase tested. The crystal structures of the apoenzyme and an inhibitor-bound form have been determined to 1.5 A resolution. MsAcT is an octamer in the asymmetric unit and forms a tightly associated aggregate in solution. Relative to other structurally similar monomers, MsAcT contains several insertions that contribute to the oligomerization and greatly restrict the shape of the active site, thereby limiting its accessibility. These properties create an environment by which MsAcT can catalyze transesterification reactions in an aqueous medium and suggests how a serine hydrolase can be engineered to be an efficient acyltransferase.


Confounding factors and diagnostic accuracy of imprint cytology.
Eradication of malignant tumors at the primary site with oncological safe margin is a critical requirement for obtaining better survival rate and less recurrence. Touch imprint cytology (TIC) has proven itself as a quick, simple, inexpensive, highly accurate and reliable intraoperative technique to assess surgical margins in squamous cell carcinomas of the oral cavity. However, it is still unclear how the mode of excision, i.e. by scalpel (SC) and electrocautery (EC), or the method of staining, i.e. Papanicolaou (PAP) and cytohaem, affect the diagnostic accuracy of TIC. To study the influence of confounding factors like mode of excision (EC/SC) and staining (PAP/cytohaem) on the diagnostic accuracy of intraoperative TIC technique for assessing surgical margins in oral squamous cell carcinoma in comparison to paraffin-embedded HE-stained sections. Thirty patients underwent surgical treatment for primary oral squamous cell carcinoma. Three hundred and forty-eight touch imprint slides were prepared from 174 margins of 30 resected tumor specimens. Two adjacent tissues from the margin to be evaluated were imprinted to observe differences between surfaces excised by EC and SC. The set of imprint from each margin tissue was stained with PAP and cytohaem. The TIC results of 180 EC-excised margins and 168 SC-excised margins were compared. Results of 174 imprints stained with RAPID-PAP were compared to their counterpart comprising of 174 cytohaem-stained imprints. The slides were diagnosed as positive, negative or suspicious for tumor. Finally, TIC results were checked against their respective histopathological sections. No statistically significant difference was found between the results of imprints from EC/SC-excised margins (Z = 0.44, p = 0.70) or the imprints stained with PAP/cytohaem (Z = 0.44, p = 0.70). Confounding factors like mode of excision and staining procedure do not significantly influence the results of imprint cytology.


Conformational dynamics of aqueous hydrogen peroxide from first principles molecular dynamics simulations.
We performed first principles molecular dynamics simulations of a relatively dilute aqueous hydrogen peroxide (H2O2) solution to examine its structural alterations and relevant dynamics upon solvation. The internal rotation of the OH groups about the O-O bond facilitates the flexible structure of H2O2. Structural calculations reveal dihedral angle fluctuations in the aqueous solution. Water molecules make stronger hydrogen bonds through the hydrogen atom of the solute than the oxygen atom leading to distinct hydrogen bonding configurations inside the first solvation shell. Time-dependent dihedral angle alterations result in conformational changes and the normalized dihedral angle distribution plot displays characteristic peaks at ∼100-120° and ∼230°, illustrating various conformational states. Within the simulation time, flexibility-induced interconversion of hydrogen peroxide gives rise to several cisoid and transoid conformers. In this study, we examine the relative population of the associated conformational states and the lifetime of the cisoid and transoid conformers from the torsion angle variations. We also determine the free energy landscape of the rotational isomerization process in H2O2 and explore two distinct energy barriers during such interconversion.


Screening for trisomy 21 by maternal age, fetal nuchal translucency thickness, free beta-human chorionic gonadotropin and pregnancy-associated plasma protein-A.
To derive a model and examine the performance of first-trimester combined screening by maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). Prospective combined screening for trisomy 21 was carried out at 11 + 0 to 13 + 6 weeks in 56,771 singleton pregnancies, including 56,376 cases with a normal karyotype or delivery of a phenotypically normal baby (unaffected group) and 395 cases with trisomy 21. The blood test and ultrasound scan were carried out in the same visit. In each case the maternal age-related risk for trisomy 21 at term was calculated and adjusted according to the gestational age at the time of screening to derive the a-priori risk. The measured NT was transformed into a likelihood ratio using the mixture model of NT distributions. The measured free beta-hCG and PAPP-A were converted into a multiple of the median (MoM) for gestational age, adjusted for maternal weight, ethnicity, smoking status, method of conception and parity, and a likelihood ratio was subsequently calculated. The likelihood ratios for NT and for the biochemical markers were multiplied by the a-priori risk to derive the patient-specific risk. Detection rates and false-positive rates were calculated by taking the proportions with risks above a given risk threshold after adjustment for maternal age according to the distribution of pregnancies in England and Wales in 2000-2002. These standardized rates were compared with detection and false-positive rates estimated using Monte Carlo methods to sample from the modeled Gaussian distributions. The performance of screening based on the model was in good agreement with that observed in our population. In a strategy for first-trimester combined screening where the blood test and scan are carried out in the same visit it was estimated that, for false-positive rates of 3% and 5%, the detection rates were 92% and 94%, respectively, at 11 weeks, 85% and 90% at 12 weeks, and 79% and 83% at 13 weeks. In an alternative strategy, with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks, the estimated detection rates were 94% and 96% for false-positive rates of 3% and 5%, respectively. The aim of the first-trimester scan is not just to screen for trisomy 21 but also to diagnose an increasing number of fetal malformations. In this respect the ability to visualize fetal anatomy is better at 12-13 weeks than at 11 weeks. Consequently, the ideal gestation for combined testing in the same visit would be 12 weeks. An alternative strategy, with the blood taken at 10 weeks and the measurement of NT performed at 12 weeks, is associated with higher detection rates of trisomy 21. However, the cost of two-stage screening would be higher and, in addition, the potential advantage in terms of detection rate may be eroded by the likely increased non-compliance with the additional step.


Intrinsic specificity of the reactive site loop of alpha1-antitrypsin, alpha1-antichymotrypsin, antithrombin III, and protease nexin I.
Members of the serpin (serine protease inhibitor) family share a similar backbone structure but expose a variable reactive-site loop, which binds to the catalytic groove of the target protease. Specificity originates in part from the sequence of this loop and also from secondary binding sites that contribute to the inhibitor function. To clarify the intrinsic contribution of the reactive-site loop, alpha1-antichymotrypsin has been utilized as a scaffold to construct chimeras carrying the loop of antithrombin III, protease nexin 1, or alpha1-antitrypsin. Reactive-site loops not only vary in sequence but also in length; therefore, the length of the reactive-site loop was also varied in the chimeras. The efficacy of the specificity transfer was evaluated by measuring the stoichiometry of the reaction, the ability to form an SDS-stable complex, and the association rate constant with a number of potential targets (chymotrypsin, neutrophil elastase, trypsin, thrombin, factor Xa, activated protein C, and urokinase). Overall, substitution of a reactive-site loop was not sufficient to transfer the specificity of a given serpin to alpha1-antichymotrypsin. Specificity of the chimera partly matched that of the loop donor and partly that of the acceptor, whereas the behavior as an inhibitor or a substrate depended upon the targeted protease. Results suggest that, aside from the contributions of the loop sequence and the framework-specific secondary binding sites, an intramolecular control may be essential for productive interaction.


Gut feelings about the endocannabinoid system.
Stemming from the centuries-old and well known effects of Cannabis on intestinal motility and secretion, research on the role of the endocannabinoid system in gut function and dysfunction has received ever increasing attention since the discovery of the cannabinoid receptors and their endogenous ligands, the endocannabinoids. In this article, some of the most recent developments in this field are discussed, with particular emphasis on new data, most of which are published in Neurogastroenterology & Motility, on the potential tonic endocannabinoid control of intestinal motility, the function of cannabinoid type-1 (CB1) receptors in gastric function, visceral pain, inflammation and sepsis, the emerging role of cannabinoid type-2 (CB2) receptors in the gut, and the pharmacology of endocannabinoid-related molecules and plant cannabinoids not necessarily acting via cannabinoid CB1 and CB2 receptors. These novel data highlight the multi-faceted aspects of endocannabinoid function in the GI tract, support the feasibility of the future therapeutic exploitation of this signaling system for the treatment of GI disorders, and leave space for some intriguing new hypotheses on the role of endocannabinoids in the gut.


Visual acuity results following treatment of persistent hyperplastic primary vitreous.
The visual acuity outcome of patients with persistent hyperplastic primary vitreous (PHPV) was reviewed. A total of 48 patients with the diagnosis of PHPV were seen at the University of Iowa, Iowa City, from 1971 through 1984. Twenty-five patients were managed nonsurgically, of which 23 had a poor visual acuity outcome (less than or equal to 5/200). Two with mild cases had visual acuities of 20/100 and 20/30. Twenty-three patients were treated surgically. Five of these had no further postoperative rehabilitation. Eighteen patients underwent surgery and aggressive optical and occlusion therapy. Eight of these 18 patients (44%) had postoperative visual acuities of 20/200 or better. These eight patients represent 17% of the study population. Therefore, lensectomy-membranectomy procedures for the purpose of effecting visual development are reasonable therapeutic options in patients with PHPV in whom the findings are primarily anterior in nature, surgery is performed at an early age, and aggressive amblyopia therapy is instituted.


Effects of neonatal allopregnanolone manipulations and early maternal separation on adult alcohol intake and monoamine levels in ventral striatum of male rats.
Changes in endogenous neonatal levels of the neurosteroid allopregnanolone (AlloP) as well as a single 24h period of early maternal separation (EMS) on postnatal day (PND) 9 affect the development of the central nervous system (CNS), causing adolescent/adult alterations including systems and behavioural traits that could be related to vulnerability to drug abuse. In rats, some behavioural alterations caused by EMS can be neutralised by previous administration of AlloP. Thus, the aim of the present work is to analyse if manipulations of neonatal AlloP could increase adult alcohol consumption, and if EMS could change these effects. We administered AlloP or finasteride, a 5α-reductase inhibitor, from PND5 to PND9, followed by 24h of EMS at PND9. At PND70 we measured alcohol consumption using a two-bottle free-choice model (ethanol 10% (v/v)+glucose 3% (w/v), and glucose 3% (w/v)) for 15days. Ventral striatum samples were obtained to determine monoamine levels. Results revealed that neonatal finasteride increased both ethanol and glucose consumption, and AlloP increased alcohol intake compared with neonatal vehicle-injected animals. The differences between neonatal groups in alcohol consumption were not found in EMS animals. In accordance, both finasteride and AlloP animals that did not suffer EMS showed lower levels of dopamine and serotonin in ventral striatum. Taken together, these results reveal that neonatal neurosteroids alterations affect alcohol intake; an effect which can be modified by subsequent EMS. Thus, these data corroborate the importance of the relationship between neonatal neurosteroids and neonatal stress for the correct CNS development.


Specific sites of interaction between histones and DNA in chromatin.
Staphylococcal nuclease digestion of purified chromatin from duck reticulocytes or calf thymus results in the production of a series of double-stranded DNA fragments of discrete molecular size, ranging from about 130 to 45 base pairs, which can be detected by polyacrylamide gel electrophoresis. Similar patterns of protected DNA fragments are obtained from limit digests of chromatin "reconstituted" from purified DNA and chromatin proteins. The results obtained with reconstituted material do not depend upon the origin of the DNA, which may be derived from a bacterial, viral, or homologous source. The specificity of the protective mechanism, therefore, resides in the structure of the bound histones, and probably not in any special nucleotide sequences present in the DNA. Removal of lysine-rich histones from chromatin before digestion results principally in disappearance from the digest of a DNA fragment about 130 base pairs long. Our preliminary results suggest that other elements of the digest pattern can be assigned uniquely to the remaining histone components. These results indicate that the binding of histones to DNA in chromatin involves a limited number of specific and very well defined contacts between protein and nucleic acid, which arise from structural properties of the histones.


Effect of oral glutathione on hepatic glutathione levels in rats and mice.
Administration of oral glutathione (GSH) increases hepatic GSH levels in fasted rats, in mice treated with GSH depletors such as diethyl maleate and in mice treated with high doses of paracetamol. An increase in hepatic GSH levels after administration of oral GSH does not occur in animals treated with buthionine sulphoximine, an inhibitor of GSH synthesis. Administration of oral GSH leads to an increase in the concentration of L-cysteine, a precursor of GSH, in portal blood plasma. Oral administration of L-methionine produced a significant decrease of hepatic ATP in fasted rats, but not in fed rats. Administration of N-acetylcysteine or GSH did not affect the hepatic ATP levels. The results show that the oral intake of GSH is a safe and efficient form of administration of its constituent amino acids in cases when GSH synthesis is required to replete hepatic GSH levels.


Bronchoalveolar lavage in sarcoidosis.
There is no single cell type present in bronchoalveolar lavage (BAL) fluid that appears to be predictive for sarcoidosis. However, BAL fluid analysis can be very helpful in the differential diagnosis. A grouping of features, an elevated total cell count, predominantly lymphocytes, together with a nearly normal percentage of eosinophils and polymorphonuclear neutrophils and the absence of plasma cells, distinguish the most likely diagnosis of sarcoidosis from the most common interstitial lung diseases, extrinsic allergic alveolitis (EAA), nonspecific interstitial pneumonia (NSIP), and idiopathic pulmonary fibrosis (IPF). In sarcoidosis the majority of cases have an increased number of lymphocytes and a normal amount of eosinophils and neutrophils. Disease presentation or activity at the time the BAL is performed as well as the smoking status is crucial for interpretation of individual BAL fluid analysis results. In severe cases the number of neutrophils can be increased as well. For an individual case the CD4:CD8 ratio is of less importance because it can be increased, normal, and even decreased. In the follow-up depicting prognosis and response to treatment, BAL fluid analysis has less clinical relevance.


Multimodal imaging approach to examine biodistribution kinetics of Cabotegravir (GSK1265744) long acting parenteral formulation in rat.
Long-Acting Parenterals (LAPs) have been used in the clinic to provide sustained therapeutic drug levels at a target site, and thereby reducing the frequency of dosing required. In an effort to understand the factors associated with long-acting cabotegravir (GSK1265744 LAP) pharmacokinetic variability, the current study was designed to investigate the temporal relationship between intramuscular (IM) or subcutaneous (SC) drug depot morphology and distribution kinetics with plasma pharmacokinetics. Therefore, a multi-modal molecular imaging (MRI & MALDI IMS) approach was employed to examine the temporal GSK1265744 LAP biodistribution in rat following either IM or SC administration. Serial MRI was performed immediately post drug administration, and then at day 1 (24h post), 2, 3, 4, 7, and 14. In a separate cohort of rats, an MRI contrast agent, Feraheme® (USPIO), was administered 2days post IM drug injection in order to investigate the potential involvement of macrophages trafficking to the GSK1265744 LAP and Vehicle depot sites. The GSK1265744 LAP depot volume increased rapidly by day 2 in the IM injected rats (~3-7 fold) compared with a ~1 fold increase in the SC injected rats. In addition, the USPIO contrast agent labeled macrophages were shown to be present in the depot region of the GSK1265744 LAP injected gastrocnemius while the Vehicle injected gastrocnemius appeared to show reduced uptake. Matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (IMS) of muscle and abdominal tissue sections identified the drug content primarily within the depot. Co-registration of the GSK1265744 ion images with immunohistochemical images established that the drug was taken up by macrophages associated with the depot. Linear regression analysis demonstrated that the drug depot characteristics including volume, surface area, and perimeter assessed by MRI at day 2 correlated with early time point plasma drug concentrations. In summary, a multimodal molecular imaging approach was used to identify the drug depot location and volumetric/physiologic changes in both IM and SC locations following GSK1265744 LAP administration. The IM depot volume increased rapidly to a maximum volume at 2days post-GSK1265744 LAP administration, while the Vehicle depot did not suggesting that the active drug substance and/or related particle was a key driver for drug depot evolution. The depot expansion was associated with an increase in macrophage infiltration and edema in and around the depot region and was correlated to plasma drug concentration at early time points (0-4days). Consequently, molecular imaging approaches may be used in patients to help understand the biodistribution of GSK1265744 LAP and its associated pharmacokinetics.


MRI SPACE sequence confirmation of occluded MCA M2 dissection stump masquerading as a ruptured MCA aneurysm.
Intracranial vascular pathologies often have overlapping clinical presentations. Dissected vessel occlusions and bifurcation aneurysms can appear similar on pretherapeutic imaging. The medical management of these two entities is drastically different. The patient is a 51-year-old man who presented with severe, sudden-onset headache. Initial presentation was consistent with a ruptured middle cerebral artery (MCA) aneurysm and surgical clipping was recommended. However, further review of radiographic findings could not definitively differentiate an aneurysmal origin of the symptoms as opposed to intracranial dissection followed by occlusion of the M2 branch of the MCA. MRI sampling perfection with application optimised contrasts using different flip angle evolution (SPACE) was performed and showed thin flow signalling distal to the dissected vessel stump confirming the diagnosis. Accurate diagnosis is a crucial step in directing treatment for intracranial vascular lesions. MRI SPACE is a simple tool in the diagnostic armamentarium to adequately direct treatment and avoid the potential for unnecessary interventions.


Enhanced transformation of mouse 10T1/2 cells by 12-O-tetradecanoylphorbol-13-acetate following exposure to X-rays or to fission-spectrum neutrons.
Addition of the tumor promoter of 12-O-tetradecanoylphorbol-13-acetate (TPA) to C3H/10T1/2 cells after exposure to either X-rays or to fission-spectrum neutrons increases significantly the frequency of transformation without any effect on cell survival. However, treatment of unirradiated cells with 0.1 micrograms of TPA per ml alone results in a small increase in transformation frequency above background (i.e., from 1.1 x 10(-5) to 1.0 x 10(-4). Thus, besides being a promoter, TPA is also a weak initiator. Enhancement of radiation-induced transformation by TPA was relatively greater after low compared to high doses of either radiation. In addition, TPA causes the relative biological effectiveness of neutrons compared to X-rays to increase with increasing dose or with increasing frequency of transformation rather than to decrease, when TPA is not used. For X-ray doses from zero to approximately 120 rads, TPA raises transformation to frequencies approximately equal to those due to neutrons alone. Analysis of TPA enhancement in the context of the combined effect of two inducing agents, i.e., TPA plus a radiation, indicates that with either radiation TPA acts synergistically. Lastly, TPA was found to alter the dependence of transformation frequency on the density of viable cells. As opposed to a constant frequency of transformants per surviving (or viable) cell, which we observed after a fixed dose of X-rays or neutrons for a range of cell inocula, the addition of TPA increased the frequency of transformation for cell inocula (i.e., from approximately 20 to 6000 viable cells per 90-mm Petri dish). However, the frequency of transformation decreases with increasing size of the inoculum, a result that we interpret to indicate the combined effect of an interference with cell-to-cell communication by TPA plus the fading of initiation events due to the radiation.


Imaging of osteomyelitis with special reference to children.
Infection of bone in children represents a diagnostic and therapeutic challenge to the pediatrician, the surgeon, the radiologist, and the pathologist. The pattern of manifestation varies and is dependent on the site of involvement, the initiating event, the infecting organism, and the acute or chronic nature of the illness. Early diagnosis allows prompt treatment, which can prevent many of the dreaded complications of this disease. Plain radiographs remain the initial imaging modality used in the diagnosis and differential diagnosis of osteomyelitis. However, with the advent of newer imaging techniques such as scintigraphy, ultrasonography, computed tomography, and magnetic resonance imaging, a higher degree of accuracy in diagnosis and definition of the extent of the disease has been achieved. The time interval between the onset of symptoms and diagnosis has also been significantly reduced. Although magnetic resonance imaging has the additional advantage of multiplanar capability, greater anatomic detail, and excellent soft tissue resolution, it is a relatively expensive technique, which somewhat limits its use. Following a brief review of the classification and pathophysiology of osteomyelitis, we have tried to elucidate the utility of various imaging modalities in the diagnosis of osteomyelitis in children, outlining their relative strengths and weaknesses. Certain entities specific to children and a brief review of differential diagnosis are also presented.


[Relative Error between Organ Doses and Size-specific Dose Estimates for a Specific Location When the Mean CTDIvol Value Is Used for Calculation].
Size-specific dose estimates (SSDEs) are dose indices that account for differences in body shape in computed tomography (CT) scans, allowing the evaluation of approximate absorbed doses in any cross section that could not be obtained with the volume CT dose index (CTDIvol). When using automatic exposure control (AEC), CTDIvol is modulated in the body axis direction, but the value displayed after the examination is the mean CTDIvol for the entire scan, and it is expected that the SSDE value will change depending on which value is used in the calculation. In this study, using a human body phantom, we examined the influence of whether the mean CTDIvol or the modulation value for each slice is used to calculate the SSDE on local organ dose evaluation. A program to calculate water equivalent diameter according to the procedure in the American Association of Physicists in Medicine Report No. 220 was developed and compared. As a result, SSDE calculated using the mean CTDIvol (local-SSDEmean) overestimated organ doses in the lung region by 18%-56% compared with those calculated by a web system for evaluating CT exposure doses (WAZA-ARIv2, Japan). In contrast, local-SSDEmodulated, which was calculated using the modulated value of the CTDIvol, was able to estimate the organ dose with a relative error of 10%-13%. The average local-SSDE over the entire body axis direction was not significantly different between the two methods, regardless of which method was used for CTDIvol. If the mean CTDIvol is stored in the Digital Imaging and Communications in Medicine (DICOM) header tag (0018, 9345) of the CT image and the modulated CTDIvol value is not available for each slice, the calculated local SSDE will contain many errors and will not correctly reflect the organ doses at the scan region. In such cases, it is available to use the method of evaluating local organ doses by multiplying the SSDE, which is the average of the SSDE for the entire scan, by a factor for each organ.


Nanoparticles Internalization through HIP-55-Dependent Clathrin Endocytosis Pathway.
Nanoparticles are promising tools for biomedicine. Many nanoparticles are internalized to function. Clathrin-mediated endocytosis is one of the most important mechanisms for nanoparticle internalization. However, the regulatory mechanism of clathrin-mediated nanoparticle endocytosis is still unclear. Here, we report that the adapter protein HIP-55 regulates clathrin-mediated nanoparticle endocytosis. CdSe/ZnS quantum dots (QDs), a typical nanoparticle, enter cells through the HIP-55-dependent clathrin endocytosis pathway. Both pharmacological inhibitor and genetic intervention demonstrate that QDs enter cells through clathrin-mediated endocytosis. HIP-55 can interact with clathrin and promote clathrin-mediated QDs endocytosis. Furthermore, HIP-55 ΔADF which is defective in F-actin binding fails to promote QDs endocytosis, indicating HIP-55 promotes clathrin-mediated QDs endocytosis depending on interaction with F-actin. In vivo, HIP-55 knockout also inhibits endocytosis of QDs. These findings reveal that HIP-55 acts as an intrinsic regulator for clathrin-mediated nanoparticle endocytosis, providing new insight into the nanoparticle internalization and a new strategy for nanodrug enrichment in target cells.


A clinical evaluation of patients with known mutations (plasminogen and factor XII) with a focus on prophylactic treatment.
Hereditary angioedema with normal C1-inhibitor (HAE-nC1-INH) is a rare genetic disease. The symptoms can resemble other forms of hereditary angioedema (HAE), but the specific laboratory values are inconspicuous. The knowledge about treatment strategies in HAE-nC1-INH remains insufficient; most of the drugs are only licensed and approved for other types of HAE. An analysis of all patients with HAE-nC1-INH was carried out in a certified angioedema treatment center in southern Germany. Only patients with a confirmed HAE-nC1-INH mutation were included. The impact of disease was monitored with validated questionnaires. Eighteen patients were included: two families with a factor XII mutation and seven families with a plasminogen mutation. All individuals received icatibant for on-demand therapy-efficient treatment response was reported. Three patients were severely affected, and prophylaxis was initiated with lanadelumab. According to the questionnaires, the clinical course and symptoms improved significantly under this prophylactic regime. This is one of the first descriptions of the clinical outcomes as a response to prophylactic treatment with lanadelumab in HAE-nC1-INH patients with a known mutation. The therapeutic management of HAE-1 and HAE-2 should also be the basis of HAE-nC1-INH, including prophylaxis.


Dual trajectories of physical activity and blood lipids in midlife women: The Study of Women's Health Across the Nation.
Physical activity (PA) has the potential to attenuate cardiovascular disease risk in midlife women through multiple pathways, including improving lipid profiles. Longitudinal patterns of PA and blood lipid levels have not been studied in midlife women. Our study identified trajectories of PA and blood lipids across midlife and characterized the associations between these trajectories. We evaluated 2,789 participants from the Study of Women's Health Across the Nation (SWAN), a longitudinal cohort study with follow-up over the menopause transition. Women reported PA using the Kaiser Physical Activity Survey at seven study visits across 17 years of follow-up. Serum high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides were measured at eight study visits across the same 17-year follow-up period. We used group-based trajectory models to characterize trajectories of PA and blood lipids over midlife and dual trajectory models to determine the association between PA and blood lipid trajectories adjusted for race/ethnicity, body mass index category, smoking, and lipid-lowering medication use. Women were 46 years old, on average, at study entry. Forty-nine percent were non-Hispanic white; 32 % were Black; 10 % were Japanese; and 9 % were Chinese. We identified four PA trajectories, three HDL cholesterol trajectories, four LDL cholesterol trajectories, and two triglyceride trajectories. The most frequently occurring trajectories were the consistently low PA trajectory (69 % of women), the low HDL cholesterol trajectory (43 % of women), the consistently moderate LDL cholesterol trajectory (45 % of women), and the consistently low triglycerides trajectory (90 % of women). In dual trajectory analyses, no clear associations were observed between PA trajectories and HDL cholesterol, LDL cholesterol, or triglycerides trajectories. The most frequently observed trajectories across midlife were characterized by low physical activity, low HDL cholesterol, moderate LDL cholesterol, and low triglycerides. Despite the absence of an association between long-term trajectories of PA and blood lipids in this study, a large body of evidence has established the importance of clinical and public health messaging and interventions targeted at midlife women to promote regular and sustained PA during midlife to achieve other cardiovascular and metabolic benefits.


Citrobacter freundii infection in glutaric aciduria type 1: adding insult to injury.
Glutaric aciduria type 1 (GA1) is an inborn error of organic acid metabolism, where the brain is the principal organ affected with exposure to toxic metabolic product, 3-hydroxyglutaric acid (3-OHGA). A 2-year-old boy with GA1 and delayed developmental milestones had an acute neurological crisis leading to massive brain abscess with Citrobacter freundi infection, a rare cause of neonatal meningitis and often associated with brain abscess. Both 3-OHGA and C. freundii can damage the blood-brain barrier and can cause significant trauma which demands immediate and appropriate management. Encephalopathic manifestations of GA1 may consequently increase the risk of meningeal infection and it has not been previously documented.


Effect of Nanostructured Domains in Self-Assembled Block Copolymer Films on Sequential Infiltration Synthesis.
There are broad interests in selective and localized synthesis in nanodomains of self-assembled block copolymers (BCPs) for a variety of applications. Sequential infiltration synthesis (SIS) shows promise to selectively grow a controllable amount of materials in one type of nanodomain of a self-assembled BCP film. However, the effects of nanostructured domains in a BCP film and SIS cycles on the material growth behavior of SIS are rarely studied. In this work, we investigated the growth behavior of TiO2 SIS within self-assembled polystyrene-block-poly(methyl methacrylate) (PS-b-PMMA) films and the two corresponding pure homopolymer films (PS and PMMA) by using in situ quartz crystal microbalance (QCM). According to the experimental results, reactant purge steps are essential to enable a high selectivity of SIS in PMMA nanodomains in the BCP films by eliminating the undesired homogeneous reactions. The continuous PS nanodomain acts as the main channel in transporting reactants to PMMA nanodomains in the self-assembled PS-b-PMMA BCP films. The segregated nanoscale PMMA nanodomains in the BCP films show dramatically different TiCl4 diffusion/reaction behavior than a continuous PMMA film. The mass gain per SIS cycle within PMMA nanodomains decreases quickly with increasing cycle number. After 7 TiO2 SIS cycles, TiO2 SIS can only take place at the interface between PS and PMMA nanodomains in the BCP film. The TiO2 SIS process can uniformly modify PMMA nanodomains throughout a self-assembled PS-b-PMMA film up to the diffusion depth owing to the unique nanostructure-enabled diffusion. SIS cycle number and chemistry of a BCP will strongly affect the material growth behavior of a SIS chemistry on the BCP film and, therefore, the final morphology of the resulting nanomaterial. Detailed studies are warranted for a SIS process on a self-assembled BCP film of different chemistry.