Population genetic characterization of (Aedes albopictus) mosquitoes (Diptera: Culicidae) from the Yangtze River Basin of China based on rDNA-ITS2.
Aedes albopictus is an important vector of many mosquito-borne viral diseases, including dengue fever and Zika. In recent years, it has spread and colonized tropical, subtropical and temperate regions worldwide. Monitoring of Ae. albopictus population dynamics is an important tool for early warning of mosquito-borne infections. Because the genetic diversity and genetic structure of natural populations are the genetic bases of population dynamics, studies of population genetics can reveal the origin, differentiation and dispersal characteristics of Ae. albopictus populations. Then, their evolutionary potential and environmental adaptability can be analyzed, providing a theoretical basis for the formulation of accurate Ae. albopictus surveillance and integrated control programs. In 2018, 552 Ae. albopictus larvae were collected during an invasive mosquito species surveillance project in China's Yangtze River Basin. Morphological analysis was performed to assign the adult mosquitoes to species, and then the genetic marker ITS2 was amplified and sequenced. There were 179 haplotypes among 552 ITS2 sequences. In total, 155/179 (86.59%) haplotypes were specific to individual populations, and 24/179 (13.41%) haplotypes were shared by populations. Hap4 (126), Hap7 (43), and Hap16 (34) were the most numerous haplotypes and the most widely distributed. The overall Hd was 0.928, π was 0.031, the mean nucleotide difference number (K) was 7.255, and the number of segregating sites was 169. TCS network maps mainly showed a single star-like scattered distribution. According to geographical location, there were no obvious haplotype groups, and the haplotypes were intricately connected. The genetic diversity of Ae. albopictus populations in the Yangtze River Basin was high. The molecular variance observed in the populations of Ae. albopictus mainly occurred among individuals within populations, accounting for 98.79% of the total, while that among populations accounted for only 1.21% of the total. Only the populations of Ae. albopictus in the Chongqing and Sichuan regions showed a moderate degree of population genetic differentiation, while genetic differentiation between the other regions were small, gene exchange was very common, and genetic differentiation within populations was minimal. According to this study, the genetic diversity of Ae. albopictus populations in the Yangtze River Basin is high, the genetic differentiation among populations is small, and gene exchange is common. In addition, frequent interregional exchange exacerbates the abnormal spread of vectors. This study highlighted the potential spread route of the vector Ae. albopictus in the Yangtze River Basin. There are three potential dispersal routes for Ae. albopictus populations in the Yangtze River Basin. The findings could be helpful for effective surveillance and early warning of Ae. albopictus vectors.


Control of carbendazim toxicity using banana peel powder in rats.
Carbendazim (CBZ) is a steady benzimidazole fungicide broadly exploited in cultivation for pre- and post-harvest treatment to dominate microorganisms infection on several plants. CBZ causes toxic effects in the different tissues of rat via influencing biochemical and hematological factors causing histopathological alterations in the liver and kidney of rats. Banana peel (BP) makes up about 38% of the whole banana weight, BP is usually disposed of as waste that is considered as an environmental problem. BP comprise bioactive a lot of compounds that can be exploited for their unique biological and pharmacological attributes. The current study was carried out to determine the protective effect of dried banana peels consumption against carbendazim toxicity in rats. The results indicated that banana peels had the ability to counteract the toxic effect of carbendazim on rats which was evident by the improvement in liver and kidney functions, lipid profile and histopathological examination.


Chronic atrophic gastritis aggravate chronic periodontitis with Helicobacter pylori infection and CD4+Th cytokines infiltration.
To investigate the potential effect of chronic atrophic gastritis on chronic periodontitis and further explore the possible mechanism. Local periodontal lesions were collected from periodontitis tissues of 30 CAG patients and 35 control adults without CAG (non-CAG). Clinical periodontal parameters were recorded, and the expression levels of distinct CD4+ Th specific cytokines at local periodontitis lesions were evaluated by real time PCR (RT-PCR). Helicobacter pylori (H. pylori) detection was carried out in both gastric and periodontitis lesions of CAG and non CAG patients. Clinical parameters analysis showed that the level of clinical attachment loss in periodontitis lesions of CAG group was significantly higher than non-CAG group. It was observed that the infection rate of H. pylori in the CAG group was higher than non-CAG group. Further cytokine analysis showed that Th17 associated cytokines IL-17, IL-21 and IL-23 were increased in periodontal lesions of CAG patients when compared with non-CAG patients. However, Th1, Th2, Th9 and Treg cells specific cytokines were not significantly increased in CAG group when compared with non-CAG group. Patients with CAG demonstrated that significant elevated attachment loss in periodontitis lesions, while elevated Th17 cytokines IL-17, IL-21 and IL-23 participate in immunopathogenesis of both diseases.


Fibular nailing for fixation of ankle fractures in patients at high risk of surgical wound infection.
Postoperative infection is a severe complication after operative treatment of ankle fractures, associated with age, comorbidities, and severe soft tissue injuries. We assessed the efficacy of intramedullary fibular nailing for treating ankle fractures in patients at high risk of wound complications. 41 high-risk patients were included in the study. We retrospectively reviewed the medical records to assess the risk profile, the treatment data, and possible infections and re-operations. After a minimum of 2 years eight patients had died, three had advanced-staged dementia and two were lost to follow-up. Remaining 28 patients reported the functional outcome and QoL through patient-reported questionnaires. Radiographs and cone-beam computed tomography were performed, as well as range-of-motion was measured. No surgical wound infections were found. The mean Olerud-Molander score was 67 points (SD 28 [20-100]). The osteoarthritis stages and the range-of-motion were significantly different between the injured and uninjured ankles, but we detected no significant effect on the QoL. Intramedullary fibular fixation appeared to be a safe treatment choice for ankle fractures in high-risk patients. IV.


Nicotinamide: a double edged sword.
Enrichment of diet with Nicotinamide in the West was introduced in the 1940s to prevent the dietary deficiency disorder Pellagra. Pellagra was caused by a particular form of poor vegetarian diet leading to Nicotinamide and Tryptophan deficiency. Arguably Pellagra would have disappeared if dietary measures suggested at the time had been implemented before Nicotinamide was even discovered. Diets may sometimes now be too high in selected pyridines and inadvertently we have exchanged one neurodegenerative disease for another. Parkinson's disease triggered in contrast to Pellagra by a particular form of rich omnivorous diet. Moderation of Nicotinamide intake would be easy to begin with compared with other dietary manipulations as there is no behavior change necessary for individuals. A substantial amount of Nicotinamide can be removed when and where there is too much that has been introduced artificially and inserted where there is too little because meat is unaffordable.


The relative effect of health literacy and patient activation on provider choice in the Netherlands.
Active provider choice by patients has become an important policy theme in western, countries over the last decades. However, not many patients and consumers exercise their right to, choose. Both health literacy and patient activation are likely to have an impact on the choice process. In, this article the relative effect of health literacy and patient activation on provider choice in the, Netherlands is studied. A questionnaire was sent to a representative sample of 2000 Dutch citizens. The questionnaire, included a measure of functional health literacy, the Dutch version of the Patient Activation Measure, and questions assessing active provider choice, reasons not to engage in it and other ways of provider, selection. The majority of respondents (59.6%) would not search for information on the basis of which they, could select the best provider or hospital. Most people rely on their general practitioner's advice. Both, low literacy and lower patient activation levels were negatively associated with active provider choice. In a regression analysis gender, education and patient activation proved the most important, predictors. The policy focus on active provider choice might result in inequity, with men, less educated, and less activated people being at a disadvantage.


Long non-coding RNAs associated with non-small cell lung cancer.
Lung cancer, with 80-85% being non-small cell lung cancer (NSCLC), is the leading cause of cancer-related death in both men and women. Long non-coding RNAs (lncRNAs), always defined as non-protein-coding RNA molecules longer than 200 nucleotides, are now thought as a new frontier in the study of human malignant diseases including NSCLC. As researches continue, increasing number of roles that lncRNAs play in NSCLC has been found, and more and more evidences show lncRNAs have a close relationship with patients' response to radiochemotherapy or molecular therapy. The aim of this review is to disclose the roles that lncRNAs play in NSCLC and how lncRANs influence the treatment of NSCLC.


Analytical variability and uncertainty in canine leukocyte ratios obtained with manual counts.
This study aimed to determine the analytical imprecision of calculated neutrophil to lymphocyte (NLR) and lymphocyte to monocyte ratios generated from manual differential white blood cell (WBC) counts in peripheral blood smears, and to describe how to report the uncertainty around a single WBC ratio result. No information on the analytical imprecision of WBC ratios in dogs is available. Coefficient of variations (CVs) of paired readings of one operator on 105 smears (intraoperator variability) and of three operators on 301 smears (interoperator variability) were calculated. The interoperator agreement was examined with the Fleiss' kappa coefficient (κ). Observed total errors (TEos), expanded measurement of uncertainty (EMU) and reporting intervals (RIs) were also calculated. Median CVs ranged from 3.14 to 28.28 (intraoperator) and from 5.39 to 53.85 (interoperator). No agreement among operators was found around the cut-offs. TEos were higher than allowable total errors in 32%-88% of smears. EMU ranged from 0.10 to 1.13. According to the RI, the calculated WBC ratios should be rounded to the nearest 10. WBC ratios should be interpreted cautiously in dogs. The EMU should be reported to make the clinician aware of the uncertainty of these parameters. For example, an NLR result of 17 is needed to have high confidence that the result is above a cut-off of 6.


Impact of acute and chronic ethanol exposure on prolactin in both male and female rats.
The deleterious effects of ethanol (EtOH) on reproduction have been well documented. This disruption is usually associated with alterations in prolactin (PRL) levels, which is relevant since this hormone is an important participant in the reproductive system. Reported EtOH-induced changes in PRL (i.e., stimulation or inhibition) have varied. These differences may have been owing to the gender or age/sexual maturity of the animal and the mode of the administration of EtOH. Therefore, to clarify the impact of EtOH on PRL, a series of experiments were conducted utilizing rats of both genders, exposed to EtOH acutely or chronically, as adults and as they progressed through puberty. In general, in younger animals of both genders, EtOH depressed serum PRL whether given acutely or chronically. In adult males, acute EtOH actually stimulated PRL levels while chronic administration had no effect. In adult females, EtOH's effect was highly dependent on the stage of the estrous cycle in which EtOH was given and during which PRL was measured. In conclusion, our studies have shown that the PRL response to EtOH is dependent on the gender and age/sexual maturity of the animals as well as on the mode of administration.


Ureteroscopy in the treatment of ureteral obstruction caused by papillary necrosis.
We report a case where renal papillary necrosis caused ureteral obstruction. Sloughed papillary bodies could be successfully removed from the ureter using a rigid ureteroscope.


Inherited salt sensitivity in normotensive humans as a cause of essential hypertension: a new concept.
The following concept of the pathogenesis of essential hypertension is proposed: there may be a continuous spectrum of noradrenergic sensitivity in normal subjects which is not only inherited but also modified later by different levels of psychological stress or by different types of behavior. The higher the noradrenergic sensitivity in a given subject, the greater the salt sensitivity and the greater the likelihood that hypertension will develop in later life if the usual high sodium-low potassium diet is consumed. Noradrenergic hypersensitivity may be linked to salt sensitivity in that it causes enhanced proximal tubular sodium reabsorption which is compensated for by pressure natriuresis. Enhanced pressure natriuresis requires persistently elevated blood pressure which leads to hypertension if maintained for many years. The phenomenon of salt sensitivity does not become apparent with a sodium intake of less than 50 mmol/day. Although enhanced noradrenergic sensitivity also persists with this low-sodium intake, salt-sensitive subjects are able to compensate for the enhanced rate of proximal tubular sodium reabsorption by reabsorbing less sodium at the distal tubules as compared with that reabsorbed by salt-resistant subjects. Enhanced noradrenergic sensitivity and enhanced proximal tubular sodium reabsorption, however, cannot be compensated for by fine-tuning aldosterone secretion while on the usual high sodium diet containing greater than 100 mmol/day. Under these conditions aldosterone secretion is already suppressed to its basal rate and cannot be suppressed more in salt-sensitive than in salt-resistant subjects. Therefore with the usual high sodium diet the enhanced rate of proximal tubular sodium reabsorption in salt-sensitive subjects is compensated for by enhanced pressure natriuresis.(ABSTRACT TRUNCATED AT 250 WORDS)


Spatial patterns of visual cortical fast EEG during conditioned reflex in a rhesus monkey.
A preliminary assay was made of the existence of time-space coherence patterns of fast EEG activity in the visual cortex of a Rhesus monkey. The primary intent of the present study was to evaluate the similarities and differences in relation to the olfactory bulb, where such coherences have been described and have been demonstrated to be associated with behaviour. Segments 1.5 s in duration were recorded simultaneously without averaging from 16 to 35 subdural electrodes fixed over the left occipital lobe in an array 3.6 cm X 2.8 cm. Each segment was taken during the delivery of a visual conditioned stimulus (CS) and the performance of a conditioned response (CR) by a well-trained Rhesus monkey. The EEGs appeared chaotic with irregular bursts lasting 75-200 ms, resembling those in the olfactory EEG but with lower peak frequencies. Fourier spectra showed broad distributions of power resembling '1/f noise' with multiple peaks in the range of 20-40 Hz. Time intervals were selected where coherent activity seemed to be present at a number of electrodes. A dominant component waveform that was common to all channels was extracted by principal components analysis (PCA) of each segment. The distribution of the power of this component across the electrodes (the factor loadings) was used to describe the spatial pattern of the coherent cortical activity. Statistical analyses suggested that different patterns could be associated to the CS and the CR, as has been found in the olfactory system. These patterns remained stable over a 6 week recording interval. The patterns can be better discriminated, when the factor loadings of each channel are normalized to zero mean and unit variance, to discard a basic pattern of power distribution, which may reflect anatomical and electrode positioning factors that are related to behavioral information processing by the cortex. The wide spatial distribution of the common patterns found suggests that EEG patterns that manifest differing states of the visual cortex may also be accessible with scalp electrodes.


Definition and solution of a stochastic inverse problem for the Manning's n parameter field in hydrodynamic models.
The uncertainty in spatially heterogeneous Manning's n fields is quantified using a novel formulation and numerical solution of stochastic inverse problems for physics-based models. The uncertainty is quantified in terms of a probability measure and the physics-based model considered here is the state-of-the-art ADCIRC model although the presented methodology applies to other hydrodynamic models. An accessible overview of the formulation and solution of the stochastic inverse problem in a mathematically rigorous framework based on measure theory is presented. Technical details that arise in practice by applying the framework to determine the Manning's n parameter field in a shallow water equation model used for coastal hydrodynamics are presented and an efficient computational algorithm and open source software package are developed. A new notion of "condition" for the stochastic inverse problem is defined and analyzed as it relates to the computation of probabilities. This notion of condition is investigated to determine effective output quantities of interest of maximum water elevations to use for the inverse problem for the Manning's n parameter and the effect on model predictions is analyzed.


A variant of nephrogenic fibrosing dermopathy with osteoclast-like giant cells: a syndrome of dysregulated matrix remodeling?
Nephrogenic fibrosing dermopathy (NFD) is a disorder characterized by dramatic thickening and hardening of skin in the extremities and trunk, which occurs in individuals on dialysis for renal disease. The pathophysiology is unknown. Increased transforming growth factor-beta (TGF-beta) and collagen deposition have been reported in a small group of patients studied by Jimenez et al.1 We report two patients with NFD and osteoclast-like giant cells in the fibrotic dermis; one patient also had dystrophic cutaneous calcification. These findings have been seen in a small percentage of NFD patients (estimated 2-5%) and may represent a variant of the disease. The hypothesis of altered matrix dysregulation due to altered TGF-beta, metalloproteinases, and activation of osteoclasts as an explanation for this variant is proposed.


The epidemiology of malignant neoplasms of the nasal cavities, the paranasal sinuses and the middle ear in Canada.
Canadian patterns of morbidity and mortality from malignancies of the nasal cavities, the paranasal sinuses and the middle ear for the periods 1970-1980 and 1970-1984 have been examined. Age-standardized morbidity rates have not changed significantly during 1970-1980 for either males (P = 0.65) or females (P = 0.96). Analysis of age-specific morbidity rates revealed that rates of change for male rates have also remained stable during this period for all age groups studied (P greater than 0.29). For females, rates of change for seven of eight age groups examined also failed to achieve statistical significance (P greater than 0.30). However, rates for females aged 45-54 have shown an increase of 0.35 additional new cases per 1,000,000 population per year. This finding is of borderline significance (P = 0.051). In contrast, age-standardized mortality rates have declined significantly during 1970-1984 by, on average, 0.08 and 0.07 fewer deaths per 1,000,000 population per year in males and females respectively. Analysis of age-specific mortality rates reveals that the declines in mortality are attributable to significant reductions in age-specific rates for males aged 65-74 and 85+ and females aged 0-24, 55-64, and 85+. In these groups rates have declined by as much as 4.1 fewer deaths per 1,000,000 population per year (P less than 0.045).


Atrial dyssynchrony and left atrial stiffness are risk markers for cryptogenic stroke in patients with patent foramen ovale.
The clinical and echocardiographic parameters associated with the risk predictors of cryptogenic stroke (CS) in patients with patent foramen ovale (PFO) still diverse and with a great debate. We hypothesized that left atrial stiffness (LASt) and atrial dyssynchrony may increase the risk of CS in patients with PFO. A total of 129 consecutive patients presented without clinical reasoning of stroke were recruited. Transesophageal echocardiographic assessment was performed to investigate the presence of PFO. PFO was identified in 52% (group I) and absent in 48% (group II). Utilizing speckle-tracking imaging LASt and atrial dyssynchrony was evaluated among patients with PFO (group I) vs those without PFO (group II). LASt was significantly increased in group I patients compared with group II (P < .001). Likewise patients with PFO had a significant LA dyssynchrony compared with those in group II (P < .001). Interatrial dyssynchrony and left atrial dyssynchrony were correlated with LASt (r = .47 and 0.51, respectively; P < .001). Cardiac arrhythmias were significantly encountered in group I patients (at presentation and with Holter monitoring) P < .001. Besides significantly increase in atrial dyssynchrony and in LASt in patients with arrhythmias compared with those without (P < .001). ROC analysis revealed that LASt index ≥ 0.61 and LA dyssynchrony ≥ 23.5 predicts cardiac arrhythmias in CS patients with PFO with (AUC: 0.85 and 0.87, respectively, P < .001). In conclusion, we demonstrated that LASt and atrial dyssynchrony might be risk markers of cryptogenic stroke in patients with PFO.


An application of the Dempster-Shafer theory of evidence to the classification of knee function and detection of improvement due to total knee replacement surgery.
This paper utilises a novel method for the classification of subjects with osteoarthritic and normal knee function. The classification method comprises a number of different components. Firstly, the method exploits the Dempster-Shafer theory of evidence allowing for a degree of ignorance in the subject's classification, i.e., a level of uncertainty as to whether a gait variable indicates osteoarthritis or not. Secondly, the inclusion of simplex plots allows both the classification of a subject, and the contribution of each associated gait variable to that classification, to be represented visually. As a result, the method is further able to highlight periodic changes in a subject's knee function due to total knee replacement surgery and subsequent recovery. The visual representation enables a simple clinical interpretation of the results from the quantitative analysis.


krox 20 messenger RNA and protein expression in the adult central nervous system.
krox 20 is an inducible immediate early response gene. To determine if krox 20 has a physiological role in the adult central nervous system (CNS), this study sought to demonstrate the presence of krox 20 in adult rat brain. RNA analysis showed the presence of krox 20 transcripts in the CNS, including the cortex. Polyclonal antibodies to a Krox 20 fusion protein demonstrated 79 and 55 kDa antigens in nuclear CNS homogenates. Neither RNA nor protein analysis was able to demonstrate an induction of krox 20 by a seizure at times when other immediate early response genes are known to be induced. Immunohistochemical analysis revealed staining at several levels throughout the nervous system. This staining was predominantly nuclear, consistent with the role of krox 20 as a transcription factor. These data show that krox 20 is present in the adult CNS, yet differs in response to stimuli as compared to other related transcription factors with a zinc finger motif, such as NGFI-A and NGFI-C.


Infectious viral load in unvaccinated and vaccinated individuals infected with ancestral, Delta or Omicron SARS-CoV-2.
Infectious viral load (VL) expelled as droplets and aerosols by infected individuals partly determines transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RNA VL measured by qRT-PCR is only a weak proxy for infectiousness. Studies on the kinetics of infectious VL are important to understand the mechanisms behind the different transmissibility of SARS-CoV-2 variants and the effect of vaccination on transmission, which allows guidance of public health measures. In this study, we quantified infectious VL in individuals infected with SARS-CoV-2 during the first five symptomatic days by in vitro culturability assay in unvaccinated or vaccinated individuals infected with pre-variant of concern (pre-VOC) SARS-CoV-2, Delta or Omicron BA.1. Unvaccinated individuals infected with pre-VOC SARS-CoV-2 had lower infectious VL than Delta-infected unvaccinated individuals. Full vaccination (defined as >2 weeks after receipt of the second dose during the primary vaccination series) significantly reduced infectious VL for Delta breakthrough cases compared to unvaccinated individuals. For Omicron BA.1 breakthrough cases, reduced infectious VL was observed only in boosted but not in fully vaccinated individuals compared to unvaccinated individuals. In addition, infectious VL was lower in fully vaccinated Omicron BA.1-infected individuals compared to fully vaccinated Delta-infected individuals, suggesting that mechanisms other than increased infectious VL contribute to the high infectiousness of SARS-CoV-2 Omicron BA.1. Our findings indicate that vaccines may lower transmission risk and, therefore, have a public health benefit beyond the individual protection from severe disease.


The effect of gerbils (Tatera brantsii) on primary production and plant species composition in a southern African savanna.
Due to burrowing activity and selective feeding, the highveld gerbil, Tatera brantsii A. Smith, has a great influnce on grassland vegetation. Within old colonies, in comparison to control sites, total biomass of plants was reduced by 47.6% from an average of 234.0 g/m2 to 122.6 g/m2. Root biomass was reduced by 34% from 539 g/m2 to 355 g/m2. Correspondingly maximum vegetation heights decreased by 33.5% from 106.4 cm to 70.8 cm. The number of plant species was not different between disturbed and undisturbed sites but species diversity and evenness of plants were significantly increased in gerbil colonies, mainly due to the reduction in dominant grass species. In disturbed sites dicotyledone plants, especially legumes, were favoured and increased in biomass. The gerbils are considered an integral part of the system and necessary for the maintepance of a high species diversity of plants. The regular "disturbance" of savanna vegetation followed by the "recovery" of the system is driven by the movement of gerbil colonies across the area. The proposed mechanism and the alternating vegetation pattern on similar soils due to disturbances which are an integral part of the system is in agreement with Remmert's mosaic cycle theory.


Alterations of neuromuscular junctions in Duchenne muscular dystrophy.
The focus of this review is on Duchenne muscular dystrophy (DMD), which is caused by the absence of the protein dystrophin and is characterized as a neuromuscular disease in which muscle weakness, increased susceptibility to muscle injury, and inadequate repair appear to underlie the pathology. Considerable attention has been dedicated to studying muscle fiber damage, but data show that both human patients and animal models for DMD present with fragmented neuromuscular junction (NMJ) morphology. In addition to pre- and post-synaptic abnormalities, studies indicate increased susceptibility of the NMJ to contraction-induced injury, with corresponding functional changes in neuromuscular transmission and nerve-evoked electromyographic activity. Such findings suggest that alterations in the NMJ of dystrophic muscle may play a role in muscle weakness via impairment of neuromuscular transmission. Further work is needed to fully understand the role of the NMJ in the weakness, susceptibility to injury, and progressive wasting associated with DMD.


Chitin synthase III activity, but not the chitin ring, is required for remedial septa formation in budding yeast.
Chitin is a minor but essential component of the Saccharomyces cerevisiae cell wall. In wild-type, chitin synthase II is required for the formation of primary septa and chitin synthase III (CSIII) is not essential. However, in chs2 mutants CSIII becomes essential for the formation of aberrant septa. We examined which of two CSIII functions, the formation of a chitin ring at bud emergence or of chitin in the remedial septa, was required for viability. By using cell cycle synchronization in combination with nikkomycin Z, a specific inhibitor of CSIII, we inhibited chitin synthesis in a chs2 mutant, during formation of either the ring or the remedial septa. The results show that only synthesis of the chitin during aberrant septa formation is essential for viability. Thus, the unique function of the chitin ring seems to be maintenance of the integrity of the mother-bud neck, as we recently found, and the importance of chitin in septum closure, both in normal and abnormal situations, is underlined.


Probing the alpha-complementing domain of E. coli beta-galactosidase with use of an insertional pentapeptide mutagenesis strategy based on Mu in vitro DNA transposition.
Protein structure-function relationships can be studied by using linker insertion mutagenesis, which efficiently identifies essential regions in target proteins. Bacteriophage Mu in vitro DNA transposition was used to generate an extensive library of pentapeptide insertion mutants within the alpha-complementing domain 1 of Escherichia coli beta-galactosidase, yielding mutants at 100% efficiency. Each mutant contained an accurate 15-bp insertion that translated to five additional amino acids within the protein, and the insertions were distributed essentially randomly along the target sequence. Individual mutants (alpha-donors) were analyzed for their ability to restore (by alpha-complementation) beta-galactosidase activity of the M15 deletion mutant (alpha-acceptor), and the data were correlated to the structure of the beta-galactosidase tetramer. Most of the insertions were well tolerated, including many of those disrupting secondary structural elements even within the protein's interior. Nevertheless, certain sites were sensitive to mutations, indicating both known and previously unknown regions of functional importance. Inhibitory insertions within the N-terminus and loop regions most likely influenced protein tetramerization via direct local effects on protein-protein interactions. Within the domain 1 core, the insertions probably caused either lateral shifting of the polypeptide chain toward the protein's exterior or produced more pronounced structural distortions. Six percent of the mutant proteins exhibited temperature sensitivity, in general suggesting the method's usefulness for generation of conditional phenotypes. The method should be applicable to any cloned protein-encoding gene.


A simple graphical approach to predict local residue conformation using NMR chemical shifts and density functional theory.
The dependency of amino acid chemical shifts on φ and ψ torsion angle is, independently, studied using a five-residue fragment of ubiquitin and ONIOM(DFT:HF) approach. The variation of absolute deviation of (13) C(α) chemical shifts relative to φ dihedral angle is specifically dependent on secondary structure of protein not on amino acid type and fragment sequence. This dependency is observed neither on any of (13) C(β) , and (1) H(α) chemical shifts nor on the variation of absolute deviation of (13) C(α) chemical shifts relative to ψ dihedral angle. The (13) C(α) absolute deviation chemical shifts (ADCC) plots are found as a suitable and simple tool to predict secondary structure of protein with no requirement of highly accurate calculations, priori knowledge of protein structure and structural refinement. Comparison of Full-DFT and ONIOM(DFT:HF) approaches illustrates that the trend of (13) C(α) ADCC plots are independent of computational method but not of basis set valence shell type.


Interaction of polymerases with 2'-deoxyuridine-5'-triphosphate spin-labeled at the 5-position.
2'-Deoxyuridine-5'-triphosphate spin-labeled at the 5-position with N-[1-oxyl-2,2,6,6-tetramethyl-4-piperidinyl]-O- was found to be an inhibitor of some DNA and RNA polymerases including avian myeloblastosis virus reverse transcriptase. Furthermore, the spin-labeled nucleotide was found to be incorporated internally into polydeoxythymidylic acid via reverse transcriptase to an extent of 1.0 spin-labeled base per 10(3) bases. The incorporation, monitored by electron spin resonance, is analogous to some other nucleotide inhibitors of polymerases, and the results indicate that it may be feasible to obtain sequence specific, spin-labeled DNA, enzymatically.


[Not Available].
A rapid immunochemical test system (immunofiltration, flow-through test) was developed for the simultaneous detection of seven mycotoxins, namely aflatoxin B1 (AFB1), fumonisin B1 (FB1), ochratoxin A (OA), deoxynivalenol (DON), T-2 toxin (T-2), diacetoxyscirpenol (DAS), and roridin A (RoA), respectively. A reusable test device, containing seven sample wells and one control well was produced. Sample extract solutions were dropped onto each sample well and the controll well, followed by toxin-enzyme conjugate solution, wash solution and colour delevoper solution. The test results were evaluated by visual comparison of colour intensity of sample wells and control well. The detection limits in buffer solution were at 0.5 ng/ml (AFB1), 5 ng/ml (FB1), 5 ng/ml (OA), 500 ng/ml (DON), 10 ng/ml (T-2), 0.5 ng/ml (DAS), and 25 ng/ml (RoA), respectively. Employing a simple extraction procedure, artificially contaminated cereal samples (wheat, maize) were analysed, with detection limits of 10 ng/g (AFB1), 50 ng/g (FB1), 50 ng/g (OA), 3500 ng/g (DON), 100 ng/g (T-2), 5 ng/g (DAS), and 250 ng/g (RoA), respectively.


Laxative use and mortality in patients on haemodialysis: a prospective cohort study.
Patients on haemodialysis (HD) are often constipated. This study aimed to assess the relationship between constipation and mortality in such patients. In this study, constipation was defined as receiving prescription laxatives, based on the investigation results of "a need to take laxatives is the most common conception of constipation" reported by the World Gastroenterology Organization Global Guidelines. This cohort study included 12,217 adult patients on HD enrolled in the Japan-Dialysis Outcomes and Practice Patterns study phases 1 to 5 (1998 to 2015). The participants were grouped into two based on whether they were prescribed laxatives during enrolment at baseline. The primary endpoint was all-cause mortality in 3 years, and the secondary endpoint was cause-specific death. Missing values were imputed using multiple imputation methods. All estimations were calculated using a Cox proportional hazards model with an inverse probability of treatment weighting using the propensity score. Laxatives were prescribed in 30.5% of the patients, and there were 1240 all-cause deaths. There was a significant association between laxative prescription and all-cause mortality [adjusted hazard ratio (AHR), 1.12; 95% confidence interval (CI): 1.03 to 1.21]. Because the Kaplan-Meier curves of the two groups crossed over, we examined 8345 patients observed for more than 1.5 years. Laxative prescription was significantly associated with all-cause mortality (AHR, 1.35; 95% CI: 1.17 to 1.55). The AHR of infectious death was 1.62 (95% CI: 1.14 to 2.29), and that of cancerous death was 1.60 (95% CI: 1.08 to 2.36). However, cardiovascular death did not show a significant inter-group difference. Constipation requiring use of laxatives was associated with an increased risk of death in patients on HD. It is important to prevent patients receiving HD from developing constipation and to reduce the number of patients requiring laxatives.


Magnesium and certain other elements and cardiovascular disease.
Cardiovascular disease (CVD) continues to be the major cause of mortality in developed countries. For the past two-and-a-half decades the inverse relationship between water hardness and CVD mortality has stimulated interest among epidemiologists, clinicians and experimental researchers. Much progress has been made in elucidating which element in the water may account for this situation. After reviewing those elements found to have a role in cardiovascular function the authors present the epidemiological evidence and its consistency with recent findings: aside from various trace elements emphasis is placed on magnesium which is recognized as having a vital role.


Sensitivity study of an OCDD environmental fate screening model in soils in the presence of PCP wood-preserving oil.
In order to better understand the fate of polychloro dibenzo-p-dioxins and furans (PCDD/Fs) in soils around pentachlorophenol (PCP) treated poles, a model was developed to assess the influence of wood-preserving oil and PCP on the vertical migration of octachloro-dibenzo-p-dioxin (OCDD). Simulations were performed for three soil types: sand, clay and organic. OCDD fate was modeled in the absence of co-contaminant and in the presence of oil with or without 5% (w/w) PCP. A variance propagation study was conducted to evaluate the model sensitivity to a small variation in input parameters, to determine the uncertainty on the migration depth modeled for each soil, and to understand the variability of this migration observed between different soil types. The model predicts a different OCDD fate depending on the soil type with a significant migration in the case of sand and an absence of migration in the case of organic soil. No migration is predicted in the absence of co-contaminants and a migration depth of 7-600 cm is predicted in the presence of oil (with and without PCP). Model sensitivity also depends on the soil type: the predicted OCDD migration depth is, respectively, 22 cm+/-10 cm for organic soils, 71 cm+/-20 cm for clay and 566 cm+/-200 cm for sand after 60 days of emissions from a class 3, 12.2m long pole. Even if the input parameters have a significant uncertainty due to the lack of available data, the model results seem reliable as a first approximation to screen an eventual PCDD/F migration.


Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia.
Aggregation and cytoplasmic mislocalization of TDP-43 are pathological hallmarks of amyotrophic lateral sclerosis and frontotemporal dementia spectrum. However, the molecular mechanism by which TDP-43 aggregates form and cause neurodegeneration remains poorly understood. Cyclophilin A, also known as peptidyl-prolyl cis-trans isomerase A (PPIA), is a foldase and molecular chaperone. We previously found that PPIA interacts with TDP-43 and governs some of its functions, and its deficiency accelerates disease in a mouse model of amyotrophic lateral sclerosis. Here we characterized PPIA knock-out mice throughout their lifespan and found that they develop a neurodegenerative disease with key behavioural features of frontotemporal dementia, marked TDP-43 pathology and late-onset motor dysfunction. In the mouse brain, deficient PPIA induces mislocalization and aggregation of the GTP-binding nuclear protein Ran, a PPIA interactor and a master regulator of nucleocytoplasmic transport, also for TDP-43. Moreover, in absence of PPIA, TDP-43 autoregulation is perturbed and TDP-43 and proteins involved in synaptic function are downregulated, leading to impairment of synaptic plasticity. Finally, we found that PPIA was downregulated in several patients with amyotrophic lateral sclerosis and amyotrophic lateral sclerosis-frontotemporal dementia, and identified a PPIA loss-of-function mutation in a patient with sporadic amyotrophic lateral sclerosis . The mutant PPIA has low stability, altered structure and impaired interaction with TDP-43. These findings strongly implicate that defective PPIA function causes TDP-43 mislocalization and dysfunction and should be considered in future therapeutic approaches.


Bovine surgery of the skin.
Occasionally, the bovine practitioner is presented situations requiring application of techniques regarding wound repair and healing. Less commonly encountered in bovine practice than equine practice for example, principles and management of traumatic wound healing should be regarded as similar. Frequently, bovine practitioners need to apply knowledge of healing principles when wounds are surgically induced during horn and mass removal. Consideration of surgical approach, tension-relieving techniques, and dermal transposition flaps (see the ocular surgery article by Schulz in this issue) can be applied effectively in bovine practice.


Increasing early exposure to mother's own milk in premature newborns.
Increase the proportion of ≤33 weeks newborns exposed to mother's own milk (MOM) oral care by 12 h of age by 20% over 2 years to support a healthier microbiome. We implemented interventions to support early expression of colostrum and reliable delivery of resultant MOM to premature newborns. Statistical process control charts were used to track progress and provide feedback to staff. Proportions of newborns exposed to MOM by 12 h were compared relative to baseline. There were 46, 66, and 46 newborns in the baseline, implementation, and sustainability periods, respectively. The primary outcome improved from 48% to 61% in the implementation period (relative change 1.27, 95% CI 0.89, 1.81, p = 0.2), to 69% in sustainability period (relative to baseline 1.45, 95% CI 1.02, 2.08, p = 0.03). An interdisciplinary team-based, multicycle, quality improvement intervention resulted in increased rates of early exposure to MOM.


Overweight, hypertension and renal dysfunction in adulthood of neonatally overfed rats.
Accelerated growth in early infancy has been associated with later cardiovascular and metabolic diseases. We investigated the influence of overnutrition during neonatal periods on the development of renal pathophysiological changes in adult offspring rats. Three or 10 male pups per mother were assigned to either the small litter (SL) or normal litter (NL) control groups during the first 21 days of life. The effects of early postnatal overnutrition on body weight, blood pressure and renal changes were determined at 3 and 6 months. Pups in the SL group weighed more than controls between 7 days and 6 months of age (P<.05). In the SL group, serum creatinine levels were higher at 3 and 6 months (P<.05), and at 6 months, blood pressure levels were higher than those of the controls (P<.05). The number of ED-1 positive macrophages in renal cortex and glomerulosclerosis index increased in the SL group at 3 and 6 months (P<.05). Additionally, cortical apoptotic cells increased in the SL group at 6 months (P<.05). Immunoblotting and immunohistochemistry showed that matrix metalloproteinase (MMP)-9 protein expressions decreased and tissue inhibitor of MMP-1, tumor necrosis factor-α, osteopontin and adiponectin expressions increased in the SL group at 3 months (P<.05). However, at 6 months, MMP-9 expression was elevated, and osteopontin expression remained elevated in the SL group (P<.05). Early postnatal overfeeding can lead to lasting overweight, hypertension and renal dysfunction and place a greater burden on the kidney.


Cholesterol gallstone disease.
With a prevalence of 10-15% in adults in Europe and the USA, gallstones are the most common digestive disease needing admission to hospital in the West. The interplay between interprandial and postprandial physiological responses to endogenous and dietary lipids underscores the importance of coordinated hepatobiliary and gastrointestinal functions to prevent crystallisation and precipitation of excess biliary cholesterol. Indeed, identifying the metabolic and transcriptional pathways that drive the regulation of biliary lipid secretion has been a major achievement in the field. We highlight scientific advances in protein and gene regulation of cholesterol absorption, synthesis, and catabolism, and biliary lipid secretion with respect to the pathogenesis of cholesterol gallstone disease. We discuss the physical-chemical mechanisms of gallstone formation in bile and the active role of the gallbladder and the intestine. We also discuss gaps in our knowledge of the pathogenesis of gallstone formation and the potential for gene targeting in therapy.


Embolisation of the splenic artery as an alternative to splenectomy for treating hereditary spherocytosis.
In 48 years old men with microspherocytosis constantly refusing splenectomy an experimental embolisation of the spleen artery with Spongostan was performed. 5 years of follow-up confirm the efficiency of this method of management. Further observations, however, are needed to formulate the indication for this method of treatment.


Draft genomic sequence of Armillaria gallica 012m: insights into its symbiotic relationship with Gastrodia elata.
Armillaria species (Basidiomycota, Physalacriaceae) are well known as plant pathogens related to serious root rot disease on various trees in forests and plantations. Interestingly, some Armillaria species are essential symbionts of the rare Chinese medicinal herb Gastrodia elata, a rootless and leafless orchid used for over 2000 years. In this work, an 87.3-M draft genome of Armillaria gallica 012m strain, which was symbiotic with G. elata, was assembled. The genome includes approximately 23.6% repetitive sequences and encodes 26,261 predicted genes. In comparison with other four genomes of Armillaria, the following gene families related to pathogenicity/saprophytic phase, including cytochrome P450 monooxygenases, carbohydrate-active enzyme AA3, and hydrophobins, were significantly contracted in A. gallica 012m. These characteristics may be beneficial for G. elata to get less injuries. The genome-guided analysis of differential expression between rhizomorph (RH) and vegetative mycelium (VM) showed that a total of 2549 genes were differentially expressed, including 632 downregulated genes and 1917 upregulated genes. In the RH, most differentially expressed genes (DEGs) related to pathogenicity were significantly upregulated. To further elucidate gene function, Gene Ontology enrichment analysis showed that the upregulated DEGs significantly grouped into monooxygenase activity, hydrolase activity, glucosidase activity, extracellular region, fungal cell wall, response to xenobiotic stimulus, response to toxic substance, etc. These phenomena indicate that RH had better infection ability than VM. The infection ability of RH may be beneficial for G. elata to obtain nutrition, because the rhizomorph constantly infected the nutritional stems of G. elata and formed the hyphae that can be digested by G. elata. These results clarified the characteristics of A. gallica 012m and the reason why the strain 012m can establish a symbiotic relationship with G. elata in some extent from the perspective of genomics.


Analyses of movement and contact of two nucleated cells using a gas-driven micropipette aspiration technique.
Adhesion between two nucleated cells undergoes specific significances in immune responses and tumor metastasis since cellular adhesive molecules usually express on two apposed cell membranes. However, quantification of the interactions between two nucleated cells is still challenging in microvasculature. Here distinct cell systems were used, including three types of human cells (Jurkat cell or PMN vs. MDA-MB-231 cell) and two kinds of murine native cells (PMN vs. liver sinusoidal endothelial cell). Cell movement, compression to, and relaxation from the counterpart cell were quantified using an in-house developed gas-driven micropipette aspiration technique (GDMAT). This assay is robust to quantify this process since cell movement and contact inside a pipette are independent of the repeated test cycles. Measured approaching or retraction velocity follows well a normal distribution, which is independent on the cycle period. Contact area or duration also fits a Gaussian distribution and moreover contact duration is linearly correlated with the cycle period. Cell movement is positively related to gas flux but negatively associated to medium viscosity. Cell adhesion tends to reach an equilibrium state with increase of cycle period or contact duration. These results further the understanding in the dynamics of cell movement and contact in microvasculature.


Longitudinal tibial epiphyseal bracket in Nievergelt syndrome.
A patient is described with lower extremity mesomelic dwarfism associated with bilateral congenital elbow, hip, and knee dislocations. Rhomboid-shaped tibiae and delayed ossification of the primary fibular ossification centers were demonstrated at birth. Plain films and magnetic resonance imaging revealed that the tibial deformities were due to the presence of longitudinal epiphyseal brackets. These brackets were observed at surgery and confirmed histologically. Recognition of the longitudinal epiphyseal bracket and its relationship to the tibial deformities seen in this patient with Nievergelt syndrome is important for planning surgical treatment.


Degradation and compatibility behaviors of poly(glycolic acid) grafted chitosan.
The films of poly(glycolic acid) grafted chitosan were prepared without using a catalyst to improve the degradable property of chitosan. The films were characterized by Fourier transform-infrared spectroscopy and X-ray photoelectron spectroscopy (XPS). The degradation of the poly(glycolic acid) grafted chitosan films were investigated in the lysozyme solution. In vitro degradation tests revealed that the degradation rate of poly(glycolic acid) grafted chitosan films increased dramatically compared with chitosan. The degradation rate of poly(glycolic acid) grafted chitosan films gradually increased with the increasing of the molar ratio of glycolic acid to chitosan. Additionally, the poly(glycolic acid) grafted chitosan films have good biocompatibility, as demonstrated by in vitro cytotoxicity of the extraction fluids. The biocompatible and biodegradable poly(glycolic acid) grafted chitosan would be an effective material with controllable degradation rate to meet the diverse needs in biomedical fields.


A spiritual education course to enhance nursing students' spiritual competencies.
The study aimed to determine the impact of an elective spiritual education course for nursing students on spiritual competencies. A convenience sample of nursing students (N = 92) was recruited from a baccalaureate school of nursing between February and July 2016. The intervention group (n = 45) was comprised of students enrolled in the elective spiritual education course which integrated non-Christian Eastern cultural beliefs; the control group was comprised of students not enrolled in the elective (n = 47). A quasi-experimental design examined pretest, posttest, and follow-up data from students' self-administered questionnaires. The intervention effect of the course was analyzed using generalized estimation equation. The results indicated posttest scores among nursing students in the intervention group were significantly better than the comparison group for spiritual health. Practicum stress and professional commitment were significantly better at follow-up. Spiritual care attitudes, caring behavior, and religious belief were significantly improved from pretest to posttest, and at follow-up for the intervention group compared with the control group. In conclusion, a spiritual education course should be considered as a regular course in the nursing curriculum, which could improve students' spiritual competencies, individual spiritual growth, and the ability to care for patients.


Indocyanine green videoangiographic findings in choroidal metastatic tumor.
Indocyanine green videoangiography (ICGV) has recently advanced and become widely available as a clinical tool. We tested the efficacy of ICGV in evaluating metastatic choroidal tumors. ICGV using Topcon 50-IA was performed in five patients with clinically diagnosed choroidal metastatic tumors. The findings were compared with those of conventional fluorescein angiography (FAG). Compared with FAG, ICGV demonstrated more smooth and regular hypofluorescent lesions, precisely indicating the exact size of the tumor. In all cases, no tumor vessels were found. The choroidal vascular integrity around the tumors was observed. FAG, however, was more sensitive in detecting the tumor development than ICGV when the extent of the hypofluorescent lesion could be seen clearly in the early phase. FAG provided more information regarding retinal pigment epithelial dysfunction in the outer blood retinal barrier overlying the tumor. Since ICGV enables visualization of tumors through the retina, it is very useful, particularly in cases of associated secondary retinal detachment around the tumors. ICGV combined with FAG provides more precise assessment of the tumors themselves and their response to treatment than FAG alone.


Cytisine modulates chronic voluntary ethanol consumption and ethanol-induced striatal up-regulation of ΔFosB in mice.
Chronic administration of ethanol induces persistent accumulation of ΔFosB, an important transcription factor, in the midbrain dopamine system. This process underlies the progression to addiction. Previously, we have shown that cytisine, a neuronal nicotinic acetylcholine receptor (nAChR) partial agonist, reduces various ethanol-drinking behaviors and ethanol-induced striatal dopamine function. However, the effects of cytisine on chronic ethanol drinking and ethanol-induced up-regulation of striatal ΔFosB are not known. Therefore, we examined the effects of cytisine on chronic voluntary ethanol consumption and associated striatal ΔFosB up-regulation in C57BL/6J mice using behavioral and biochemical methods. Following the chronic voluntary consumption of 15% (v/v) ethanol under a 24-h two-bottle choice intermittent access (IA; 3 sessions/week) or continuous access (CA; 24 h/d and 7 d/week) paradigm, mice received repeated intraperitoneal injections of saline or cytisine (0.5 or 3.0 mg/kg). Ethanol and water intake were monitored for 24 h post-treatment. Pretreatment with cytisine (0.5 or 1.5 mg/kg) significantly reduced ethanol consumption and preference in both paradigms at 2 h and 24 h post-treatment. The ΔFosB levels in the ventral and dorsal striatum were determined by Western blotting 18-24 h after the last point of ethanol access. In addition, cytisine (0.5 mg/kg) significantly attenuated up-regulation of ΔFosB in the ventral and dorsal striatum following chronic ethanol consumption in IA and CA paradigms. The results indicate that cytisine modulates chronic voluntary ethanol consumption and reduces ethanol-induced up-regulation of striatal ΔFosB. Further, the data suggest a critical role of nAChRs in chronic ethanol-induced neurochemical adaptations associated with ethanol addiction.


Evaluation of quantitative bacterial counts as an aid in the treatment of wounds in the horse.
Bacterial quantification was evaluated in 15 cases as a means of wound assessment. This study suggests that bacterial quantification may be used as an aid in the evaluation of treatment procedures and wound preparation in veterinary surgery.


Fusobacterium nucleatum induces excess methyltransferase-like 3-mediated microRNA-4717-3p maturation to promote colorectal cancer cell proliferation.
Fusobacterium nucleatum infection plays vital roles in colorectal cancer (CRC) progression. Overexpression of microRNA-4717-3p (miR-4717) was reported to be upregulated in F. nucleatum positive CRC tissues, however, the underlying mechanism is unknown. In this study, we found that miR-4717 promoted CRC cell proliferation in vitro and growth of CRC in vivo following F. nucleatum infection. MicroRNA-4717 suppressed the expression of mitogen-activated protein kinase kinase 4 (MAP2K4), a tumor suppressor, by directly targeting its 3'-UTR. Furthermore, we confirmed that methyltransferase-like 3 (METTL3)-dependent m6 A methylation could methylate primary (pri)-miR-4717, which further promoted the maturation of pri-miR-4717, and METTL3 positively regulated CRC cell proliferation through miR-4717/MAP2K4 pathways. In conclusion, F. nucleatum-induced miR-4717 excessive maturation through METTL3-dependent m6 A modification promotes CRC cell proliferation, which provides a potential therapeutic target and diagnostic biomarker for CRC.


Comparative dosimetric and radiobiological assessment among a nonstandard RapidArc, standard RapidArc, classical intensity-modulated radiotherapy, and 3D brachytherapy for the treatment of the vaginal vault in patients affected by gynecologic cancer.
To evaluate a nonstandard RapidArc (RA) modality as alternative to high-dose-rate brachytherapy (HDR-BRT) or IMRT treatments of the vaginal vault in patients with gynecological cancer (GC). Nonstandard (with vaginal applicator) and standard (without vaginal applicator) RapidArc plans for 27 women with GC were developed to compare with HDR-BRT and IMRT. Dosimetric and radiobiological comparison were performed by means of dose-volume histogram and equivalent uniform dose (EUD) for planning target volume (PTV) and organs at risk (OARs). In addition, the integral dose and the overall treatment times were evaluated. RA, as well as IMRT, results in a high uniform dose on PTV compared with HDR-BRT. However, the average of EUD for HDR-BRT was significantly higher than those with RA and IMRT. With respect to the OARs, standard RA was equivalent of IMRT but inferior to HDR-BRT. Furthermore, nonstandard RA was comparable with IMRT for bladder and sigmoid and better than HDR-BRT for the rectum because of a significant reduction of d(2cc), d(1cc), and d(max) (p < 0.01). Integral doses were always higher than HDR-BRT, although the values were very low. Delivery times were about the same and more than double for HDR-BRT compared with IMRT and RA, respectively. In conclusion, the boost of dose on vaginal vault in patients affected by GC delivered by a nonstandard RA technique was a reasonable alternative to the conventional HDR-BRT because of a reduction of delivery time and rectal dose at substantial comparable doses for the bladder and sigmoid. However HDR-BRT provides better performance in terms of PTV coverage as evidenced by a greater EUD.


Novel and Highly Compressed Schedules for the Treatment of Breast Cancer.
Our thinking about radiotherapy (RT) for early-stage breast cancer has evolved considerably over the last several years. Increasingly patients and physicians together are making the decision to use altered fractionation rather than standard 6-7 weeks of conventional whole breast treatment plus lumpectomy bed boost. Adjuvant hypofractionated whole breast irradiation is now viewed as a preferred strategy for many eligible women, and can be completed in 3-4 weeks. Adjuvant accelerated partial breast irradiation is another alternative that is typically delivered in 8-10 fractions over 4-5 days. With improvements in delivery techniques, there has been renewed interest in shortening treatment times even further, with novel intraoperative approaches and ultrashort courses of external beam RT. This article provides a summary of the status and future directions in intraoperative and ultrashort course RT schedules used in the treatment of breast cancer. Outlined are the benefits as well as the drawbacks of these techniques for abbreviated breast RT.


A genetic analysis of mancozeb resistance in Typhlodromus pyri (Acari: Phytoseiidae).
A field population of Typhlodromus pyri (Acari: Phytoseiidae) tolerant to mancozeb was selected in the laboratory. After 10 mancozeb selections the LC50 value for mancozeb was 73 times higher in the selected-10 strain compared to the standard susceptible strain. A genetic analysis using reciprocal crosses and backcrosses of female F1 progeny found no maternal effect. Resistance in the selected-10 strain was codominant in expression, dominance value was about -0.1. Backcrosses between F1 females and the susceptible strain indicate that the resistance to mancozeb could be principally conferred by a predominant gene, but additional factors would also be involved.


Beyond Corticoresistance, A Paradoxical Corticosensitivity Induced by Corticosteroid Therapy in Pediatric Acute Lymphoblastic Leukemias.
Known as a key effector in relapse of acute lymphoblastic leukemia (ALL), resistance to drug-induced apoptosis, is tightly considered one of the main prognostic factors for the disease. ALL cells are constantly developing cellular strategies to survive and resist therapeutic drugs. Glucocorticoids (GCs) are one of the most important agents used in the treatment of ALL due to their ability to induce cell death. The mechanisms of GC resistance of ALL cells are largely unknown and intense research is currently focused on this topic. Such resistance can involve different cellular and molecular mechanisms, including the modulation of signaling pathways involved in the regulation of proliferation, apoptosis, autophagy, metabolism, epigenetic modifications and tumor suppressors. Recently, several studies point to the paradoxical role of GCs in many survival processes that may lead to therapy-induced resistance in ALL cells, which we called "paradoxical corticosensitivity". In this review, we aim to summarize all findings on cell survival pathways paradoxically activated by GCs with an emphasis on previous and current knowledge on gene expression and signaling pathways.


The metabolic consequences of critical illness: acute effects on glutamine and protein metabolism.
Net protein loss and large decreases in plasma glutamine concentration are characteristics of critical illness. We have used [2-15N]glutamine and [1-13C]leucine to investigate whole body glutamine and leucine kinetics in a group of critically ill patients and matched healthy controls. Glutamine appearance rate (Ra,Gln) was similar in both groups. However, in the patients, the proportion of Ra,Gln arising from protein breakdown was higher than in the control group (43 +/- 3 vs. 32 +/- 2%, P < 0.05). Glutamine metabolic clearance rate (MCR) was 92 +/- 8% higher (P < 0.001), whereas plasma glutamine concentration was 38 +/- 5% lower (P < 0.001) than in the control group. Leucine appearance rate (whole body proteolysis) and nonoxidative leucine disposal (whole body protein synthesis) were 59 +/- 14 and 49 +/- 15% higher in the patients (P < 0.001). Leucine oxidation and MCR were increased in the patients by 104 +/- 37 and 129 +/- 39%, respectively (P < 0.05). These results demonstrate that critical illness is associated with a major increase in protein turnover. The acute decrease in plasma glutamine concentration and the unaltered plasma Ra,Gln suggest that the increase in proteolysis is insufficient to meet increased demand for glutamine in this severe catabolic state.


Urinary excretion of N-nitrosodiethanolamine administered orally to rats.
N-Nitrosodiethanolamine (NDE1A) was administered by gavage to male rats in single doses of 1000, 500 and 100 mg/kg body wt. More than 70% of a given dose was excreted unchanged in the urine, essentially within the first 24 h after exposure. This high excretion rate might explain the relatively low carcinogenic potential of NDE1A, and also offers a possible method of monitoring exposure to this compound under occupational and/or environmental conditions.


Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing.
Enteroviruses are suspected to contribute to insulin-producing β cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting β cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in β cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in β cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the β cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes.


FABP7 Regulates Acetyl-CoA Metabolism Through the Interaction with ACLY in the Nucleus of Astrocytes.
Fatty acid binding protein 7 (FABP7) is an intracellular fatty acid chaperon that is highly expressed in astrocytes, oligodendrocyte-precursor cells, and malignant glioma. Previously, we reported that FABP7 regulates the response to extracellular stimuli by controlling the expression of caveolin-1, an important component of lipid raft. Here, we explored the detailed mechanisms underlying FABP7 regulation of caveolin-1 expression using primary cultured FABP7-KO astrocytes as a model of loss of function and NIH-3T3 cells as a model of gain of function. We discovered that FABP7 interacts with ATP-citrate lyase (ACLY) and is important for acetyl-CoA metabolism in the nucleus. This interaction leads to epigenetic regulation of several genes, including caveolin-1. Our novel findings suggest that FABP7-ACLY modulation of nuclear acetyl-CoA has more influence on histone acetylation than cytoplasmic acetyl-CoA. The changes to histone structure may modify caveolae-related cell activity in astrocytes and tumors, including malignant glioma.


A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor.
Neurofibromatosis type 2 is a group of tumors caused by loss-of-function mutations of a tumor suppressor gene encoding NF2/merlin. Development of chemotherapeutics for this disease, which often threatens the life of young children, has been hampered by a limited information on the signaling function of NF2. NF2 can inhibit Ras-induced malignant transformation. However, the primary (signaling) target of NF2 in the oncogenic pathway has not been previously identified. Here, using a series of NF2 constructs, we show that NF2 inhibits directly the Rac/CDC42-dependent Ser/Thr kinase PAK1, which is essential for both Ras transformation and neurofibromatosis type 1 (NF1), through two separate domains. A mutant of NF2, that lacks the PAK1-inhibiting domain of 78 amino acids (NF78C, residues 447-524), fails to suppress Ras transformation. Furthermore, PAK1-specific inhibitors CEP-1347 and WR-PAK18 selectively inhibit the growth of NF2-deficient cancer cells, but not NF2-positive cells. These results suggest that PAK1 is essential for the malignant growth of NF2-deficient cells, and that PAK1-blocking drugs could be potentially useful forthe treatment of neurofibromatosis types 2, in addition to Ras-induced cancers and neurofibromatosis type 1.


'Eating disorders are not about food, they're about life': Client perspectives on anorexia nervosa treatment.
Poor success rates and high levels of dropout are common features in the treatment of anorexia nervosa. Using semi-structured interviews, this study elicited the views of 12 women who were recovered, or in recovery, for anorexia nervosa and had received treatment. Results derived from a thematic analysis revealed the women's high degree of dissatisfaction with treatment and their perception that the treatment system is overly focused on, and driven by, food and weight. In contrast, what the women really wanted was to be seen and treated as a 'whole person' and to have a 'real' relationship with their therapist.


Predictors of second COVID-19 booster dose or new COVID-19 vaccine hesitancy among nurses: A cross-sectional study.
To assess the levels of second COVID-19 booster dose/new COVID-19 vaccine hesitancy among nurses and explore the potential predictors of vaccine hesitancy. COVID-19 full vaccination seems to be highly effective against highly contagious variants of SARS-CoV-2. Healthcare workers are at high-risk group since they have experienced high levels of COVID-19-associated morbidity and mortality. An on-line cross-sectional study was carried out in Greece in May 2022, using a self-administered questionnaire. The study population included nurses in healthcare services who were fully vaccinated against COVID-19 at the time of study. We considered socio-demographic characteristics, COVID-19-related variables, and attitudes toward COVID-19 vaccination and pandemic as potential predictors of vaccine hesitancy. We applied the STROBE checklist in our study. Among 795 nurses, 30.9% were hesitant toward a second booster dose or a new COVID-19 vaccine. Independent predictors of hesitancy included lower educational level, absence of a chronic condition, good/very good self-perceived physical health, lack of flu vaccination during 2021, front-line nurses that provided healthcare to COVID-19 patients, nurses that had not been diagnosed with COVID-19 and nurses that had at least one relative/friend that has died from COVID-19. Moreover, increased compliance with hygiene measures, increased fear of a second booster dose/new COVID-19 vaccine and decreased trust in COVID-19 vaccination were associated with increased hesitancy. Our study shows that a significant percentage of nurses are hesitant toward a second booster dose/new COVID-19 vaccine. This initial hesitancy could be a barrier to efforts to control the COVID-19 pandemic. Nurses' role during the COVID-19 pandemic is essential since they are the front-line healthcare workers empowering the public with their passion and empathy. There is a need to communicate COVID-19 vaccine science in a way that is accessible to nurses in order to decrease COVID-19 vaccine hesitancy. No patient or public contribution.


Thioredoxin stimulates MMP-9 expression, de-regulates the MMP-9/TIMP-1 equilibrium and promotes MMP-9 dependent invasion in human MDA-MB-231 breast cancer cells.
Increased expression of thioredoxin (Trx)-1 and matrix metalloproteinase (MMP)-9 associates with malignant breast cancer progression. Here, we describe a functional relationship between Trx-1 and MMP-9 in promoting MDA-MB-231 breast cancer cell invasive behaviour. Trx-1 overexpression stimulated MMP-9 expression, de-regulated the MMP-9/TIMP-1 equilibrium and augmented MMP-9 involvement in a more invasive phenotype. Trx-1 augmented MMP-9 transcription through NF-κB, AP-1 and SP1 elements; stimulated p50/p65 NF-κB activity and recruitment to the MMP-9 promoter; and facilitated MMP-9 promoter-accessibility to NF-κB by preventing HDAC recruitment and maintaining MMP-9 promoter histone acetylation. Our data provide a functional basis for Trx-1 and MMP-9 association in malignant breast cancer and identify Trx-1 and NF-κB as potentially druggable targets for reducing MMP-9 involvement in malignant behaviour.


Food Insecurity Among College Students: An Analysis of US State Legislation Through 2020.
Many US college students experience food insecurity (FI). Given most students are excluded from receiving federal nutrition assistance, additional efforts are needed to alleviate student FI. This perspective discusses proposed and enacted state statutes, resolutions, and bills addressing college FI to date, which range in depth, breadth, and success. Overall, states have demonstrated their promising role in addressing FI; however, college FI promises to be a continuing challenge, particularly given continued widespread unemployment that began with the onset of coronavirus disease 2019 and the global struggle for economic recovery.


Performance Evaluation of Integrated Constructed Wetland for Domestic Wastewater Treatment.
Simple, budget friendly, laboratory-scale integrated constructed wetland (ICW) was designed to assess domestic wastewater treatment performance at a loading rate of 75 mm/d, planted with native plant species: Veronica-angallis aquatica and compared with non-vegetative control system at various residence times of 4, 8, 12, 16, 20, 24, and 28 days. Results revealed that the vegetated ICW demonstrated superior performance over non-vegetated control: 69.12 vs 17.12%, 67.77 vs 16.04%, 68 vs 16.48%, 71.19 vs 6.56%, 71.54 vs 14.80%, and 72.04 vs 11.41% for total dissolved solids, total suspended solids, phosphates (PO4(-)), sulfate (SO4(-)), nitrate (NO3(-)), and nitrite (NO2(-)), respectively, at 20 days residence times. Reduction in bacterial counts (2.79 × 10(4) CFU/mL) and fecal pathogens (345.5 MPN index/100 mL) was observed in V. aquatica at 20 days residence time. Therefore, the present study highlights not only the presence of vegetation but also appropriate residence time in constructed wetlands for better performances.


Electroencephalographic patterns during sleep in children with chromosome 15q11.2-13.1 duplications (Dup15q).
Our objective was to define the EEG features during sleep of children with neurodevelopmental disorders due to copy number gains of 15q11-q13 (Dup15q). We retrospectively reviewed continuous EEG recordings of 42 children with Dup15q (mean age: eight years, 32 with idic15), and data collected included background activity, interictal epileptiform discharges, sleep organization, and ictal activity. Three patterns were recognized: Pattern 1: Alpha–delta sleep was noted in 14 children (33%), not associated with any clinical changes. Pattern 2: Electrical status epilepticus in sleep was noted in 15 children (35%), all diagnosed with treatmentresistant epilepsy. Thirteen of the 15 children had clinical seizures. Pattern 3: Frequent bursts of high amplitude bifrontal predominant, paroxysmal fast activity (12–15 Hz) during non-REM sleep was noted in 15 children (35%). All 15 children had treatment-resistant epilepsy. This is the first report of electroencephalographic patterns during sleep of children with Dup15q reporting alpha-delta rhythms, CSWS, and high amplitude fast frequencies. Alpha-delta rhythms are described in children with dysautonomia and/or mood disorders and CSWS in children with developmental regression. The significance of these findings in cognitive function and epilepsy for the children in our cohort needs to be determined with follow-up studies.


Data pre-processing in liquid chromatography-mass spectrometry-based proteomics.
In a liquid chromatography-mass spectrometry (LC-MS)-based expressional proteomics, multiple samples from different groups are analyzed in parallel. It is necessary to develop a data mining system to perform peak quantification, peak alignment and data quality assurance. We have developed an algorithm for spectrum deconvolution. A two-step alignment algorithm is proposed for recognizing peaks generated by the same peptide but detected in different samples. The quality of LC-MS data is evaluated using statistical tests and alignment quality tests. Xalign software is available upon request from the author.


Gonadal hormones differentially modulate cocaine-induced conditioned place preference in male and female rats.
There is accumulating evidence that suggests there are sex differences in behavioral and subjective responses to cocaine. However, it is not known whether differences in cocaine reward contribute to sex differences in these responses or whether gonadal hormones affect the rewarding properties of cocaine. In the present study, conditioned place preference (CPP), a measure of non-contingent reward, was used to determine the effects of endogenous gonadal hormones and of estrogen and progesterone replacement on cocaine reward. Neurochemical measurements were also taken to identify monoaminergic substrates which underlie the behavioral phenotype. Although both intact and gonadectomized male and female rats showed a significant CPP for cocaine, ovariectomy attenuated the magnitude of CPP. These alterations coincided with a decrease in serum levels of corticosterone. In ovariectomized rats, pretreatment with progesterone inhibited cocaine CPP while estrogen plus progesterone potentiated the magnitude of CPP. Additionally, gonadectomy and ovarian hormone replacement in female rats affected serotonin/dopamine levels and turnover ratios in the ventral tegmental area and nucleus accumbens shell. While no effects of castration were observed, ovariectomy decreased levels of dopamine and serotonin in the ventral tegmental area. In females, progesterone replacement increased levels of serotonin and dopamine in the ventral tegmental area, while estrogen plus progesterone replacement increased dopamine levels in the nucleus accumbens. Collectively, these results indicate that ovarian hormones may influence cocaine reward by altering monoaminergic systems, which, in turn, may contribute to the current sex disparities in overall cocaine use.


Non-auditory Effects of Noise Pollution on Health: A Perspective.
Noise is an ever increasing product of our environment. The increased noise levels cause auditory as well as non-auditory effects on health. The relationship between noise and hearing loss has been well established. However non-auditory effects of noise on health though known are understudied and underreported. Hence awareness about the prevalence of these deleterious effects, its prevention and appropriate remedial measures is the need of the hour.


Design of dental implants, influence on the osteogenesis and fixation.
The fixation and the bone ingrowth at the interface of porous cylindrical implants (total porosity of 37% and average pores diameter of 480 microm) were compared in vivo to rough cylindrical implants (R (a) = 5.3 microm), both of commercially pure titanium, made by powder metallurgy. The implants were inserted into the tibias of 20 rabbits and the animals were sacrificed 4 and 8 weeks after surgery. The percentage of bone-implant contact observed in porous implant was significantly larger than in the rough ones for all of sacrifice periods, respectively, 57% vs. 46% after 4 weeks, and 59% vs. 50% after 8 weeks. The mechanical tests showed a significant increase in the shear strength of the porous implants for the two analyzed periods, 4 and 8 weeks (14 and 20 MPa), when compared with rough ones (4 and 13 MPa). These results suggest that porous implants improve the contact at the implant-bone interface and increase the fixation to the bone, improving the osseointegration. Thus, the porous implant might be an alternative to dental implant in less favorable conditions, and appear to be better fixed to bone, offering promising alternatives.


Filterability of freshly-collected sickle erythrocytes under venous oxygen pressure without exposure to air.
We previously found that blood samples collected from steady-state patients with sickle cell disease (SCD) without exposure to air contain a new type of reversibly sickled cells (RSCs) with blunt edges at a level of as high as 78%. Since partial oxygenation of once-deoxygenated sickled cells with pointy edges to near venous oxygen pressure generates similar sickled cells with blunt edges in vitro, we named them as partially oxygenated sickled cells (POSCs). On the other hand, partial deoxygenation of once-oxygenated SS cells to venous oxygen pressure generates partially deoxygenated sickled cells (PDSCs) with pointy edges. In this study, we obtained blood samples from 6 steady-state patients with SCD under venous oxygen pressure without exposure to air, subjected them to various oxygenation/deoxygenation/reoxygenation cycles, and studied their filterability through a membrane filter with pore diameter of 3μm, the theoretical minimum diameter of a capillary. Our results indicated that discocytes, POSCs with blunt edges, and irreversibly sickled cells could deform and pass through the filter, while PDSCs with pointy edges were rigid and could not. The filterability of SS cells seems to be related to the length and amount of deoxy-hemoglobin S fibers in the cells.


Long-term behavioral changes in rats following organophosphonate exposure.
The organophosphorus compound soman irreversibly inhibits cholinesterase in both the central and peripheral nervous systems. High doses of this compound produce seizures and death in animals. Surviving animals exhibit neural lesions and behavioral abnormalities. The behavioral effects of a single exposure to soman were evaluated in rats injected with 50 micrograms/kg or 85 micrograms/kg soman or with saline. Each rat was tested for either activity in an open field or performance in a 14 choice point multiple T-maze. All rats were then tested for reactivity to tactile stimuli. Some rats exposed to soman showed increased activity in the open field, learning deficits in the Stone maze, and increased reactivity to tactile stimuli, while others showed behavior similar to that of controls. An increase in reactivity was correlated with increased open field activity and with poor performance in the Stone maze. Rats which had received soman and were abnormal in behavioral tests were more likely to have abnormal brain pathology than rats which had received soman and were normal in behavioral tests.


Migration, personal physical safety and economic survival: drivers of risky sexual behaviour among rural-urban migrant street youth in Kampala, Uganda.
Despite the vulnerabilities associated with the youth migration process, knowledge on the drivers of risky sexual behaviour among migrant street youth is limited. This study sought to explore the pathways driving risky sexual behaviour among rural-urban migrant street youth in Kampala, Uganda. We conducted 11 focus-group discussions composed of 8-10 participants each, and 15 in-depth interviews with urban street adolescents and youth aged 12-24 years. We purposively recruited street youth who had migrated from other districts to Kampala, Uganda, and who identified themselves as street youth. Data were analysed thematically using an inductive approach facilitated by Dedoose software. The migration journey acted as a catalyst for risky sexual behaviour among the adolescents and youth moving from rural districts to Kampala. Three primary pathways were found to drive risky sexual behaviour of street youth: 1) rural-urban migration itself, through sexual exploitation of and violence toward street youth especially young girls during movement, 2) economic survival through engaging in casual jobs and sex work upon arrival in the city, and 3) personal physical safety through friendships and networks, which consequently lead to having multiple sexual partners and unprotected sex. Engagement in risky sexual behaviour, especially sex work, was found to be an adaptation to the challenging and complex street life within the city. This study highlights the migration process, personal physical safety and economic survival as major pathways driving risky sexual behaviour among rural-urban street youth in Kampala. Interventions to improve sexual health, physical safety and protection of street youth during the migration process and within the city spaces should be prioritised.


Evaluation of an animal model for teaching fibreoptic tracheal intubation.
Twenty-seven anaesthesia faculty, fellows and residents compared a standard intubating mannequin and an anaesthetized pig as models for teaching fibreoptic tracheal intubation. When likened to the clinical situation, the anatomic characteristics of the pig airway were rated as significantly more realistic than the airway characteristics of the mannequin with the exception of the appearance of the epiglottis. In addition, the overall score for the pig model was significantly higher than the score for the mannequin and 26 of 27 evaluators rated the anaesthetized pig as the more effective teaching model. We conclude that an anaesthetized, spontaneously breathing pig is a valid model for teaching fibreoptic endotracheal intubation.


Multiplanar reconstruction as an aid in CT diagnosis.
Multiplanar reconstructions of the orbit, brain, and spine were performed on 60 patients with a variety of disorders. They were thought to provide significant useful information in 22 cases, some useful information in 26 cases, and no useful information in 12 cases. It is suggested that on-line reconstruction is a useful adjunct to neurologic CT.


[Effect of various anion and cation concentrations in the diet on the utilization of calcium and phosphorus in swine].
Experiments on growing swine revealed that diets with an excess of anions or cations will cause calcium and phosphorus to be utilized less. This, in turn, results in markedly decreased weight gains of the pigs and poor nutrient utilization. The diet with an excessively high concentration of anions was found to have a more unfavourable effect than diets with excessive cations. It is, therefore, recommended to carefully calculate the acid-base balance when formulating complete feed mexes for fattening pigs. The economic effect of such a practice proved high.


Interactions of substance P with putative mediators of inflammation and ATP.
Substance P has recently been localized in sensory nerves and has been suggested to be the mediator of antidromic vasodilatation. Interactions of substance P with putative mediators of inflammation and adenosine 5'-triphosphate were studied in rats using a quantitative Evans blue dye-leakage technique. Rats anaesthetized with either were given Evans blue. i.v. and intracutaneous injections of inflammatory agents were given into the shaved abdominal skin. Doses of substance P, 1-5 X 10(-10) mol, produced graded dye leakage. A low dose of substance P (5 X 10(-11) mol) potentiated responses to 5-hydroxytryptamine (2.5 X 10(-10) mol), bradykinin (5 X 10(-10) mol), prostaglandin E1 (5 X 10(-10) mol) and adenosine 5'-triphosphate (2.5 X 10(-7) mol) but no histamine (2 X 10(-8) mol). A higher dose of substance P (5 X 10(-10) mol) was potentiated by prostaglandin E1 (5 X 10(-11) mol) and adenosine 5'triphosphate (5 X 10(-9) mol) but but not by histamine (5 X 10(-10) mol) or bradykinin (5 X 10(-11 mol) and was inhibited by 5-hydroxytryptamine (5 X 10(-12) mol). If substance P is released from sensory nerves in some inflammatory states these interactions might be of importance in determining the response observed.


Investigations on the carcinogenic burden by air pollution in man. Intratracheal instillation studies with benzo(a)pyrene in bovine serum albumin in Syrian hamsters.
The chronic effect of benzo(a)pyrene (B(a)P) administered intratracheally in bovine serum albumin was studied in Syrian golden hamsters. Dose levels of 0.1 mg, 0.33 mg and 1.0 mg of B(a)P induced papillomas and carcinomas of the trachea, stem bronchi and bronchioles. In addition to such tumours, the mucosa of the respiratory tract revealed a variety of atypical epithelial alterations. Although survival time exhibited a dose-dependency, tumour incidence did not. The incidence of respiratory tract tumours was higher in female hamsters than in males. The results of these investigations are statistically evaluated.


Computer-aided automated diminutive colonic polyp detection in colonoscopy by using deep machine learning system; first indigenous algorithm developed in India.
Colonic polyps can be detected and resected during a colonoscopy before cancer development. However, about 1/4th of the polyps could be missed due to their small size, location or human errors. An artificial intelligence (AI) system can improve polyp detection and reduce colorectal cancer incidence. We are developing an indigenous AI system to detect diminutive polyps in real-life scenarios that can be compatible with any high-definition colonoscopy and endoscopic video- capture software. We trained a masked region-based convolutional neural network model to detect and localize colonic polyps. Three independent datasets of colonoscopy videos comprising 1,039 image frames were used and divided into a training dataset of 688 frames and a testing dataset of 351 frames. Of 1,039 image frames, 231 were from real-life colonoscopy videos from our centre. The rest were from publicly available image frames already modified to be directly utilizable for developing the AI system. The image frames of the testing dataset were also augmented by rotating and zooming the images to replicate real-life distortions of images seen during colonoscopy. The AI system was trained to localize the polyp by creating a 'bounding box'. It was then applied to the testing dataset to test its accuracy in detecting polyps automatically. The AI system achieved a mean average precision (equivalent to specificity) of 88.63% for automatic polyp detection. All polyps in the testing were identified by AI, i.e., no false-negative result in the testing dataset (sensitivity of 100%). The mean polyp size in the study was 5 (± 4) mm. The mean processing time per image frame was 96.4 minutes. This AI system, when applied to real-life colonoscopy images, having wide variations in bowel preparation and small polyp size, can detect colonic polyps with a high degree of accuracy.


Age-related mechanical properties of human skin: an in vivo study.
We have investigated in vivo how various viscoelastic parameters that describe the mechanical properties of the human skin may vary with age. Accordingly, we have used a mechanical device that records the torsional extensibility of the skin. When submitted to a low torque, the time-response curve of the skin affords the determination of the immediate extensibility (UE), the immediate recovery (UR), the viscoelastic part of the deformation (UV), the elastic recovery (UR/UE), and the creep relaxation time (tau). Because the skin thickness varies with age and primarily governs the mechanical properties, it was measured through an ultrasound technique at the same sites (forearm) where the torque was applied. The results show that the skin maintains its thickness and extensibility up to the seventh decade as opposed to its elasticity or recovery capacities, which decrease from an early age. The viscous part of the deformation is constant through life, whereas the creep relaxation time decreases linearily with age. Except for skin thickness, no differences in these parameters between men and women were detected. The significance of these results are discussed in terms of structure alterations. The determination of the elastic recovery (UR/UE) appears to be a parameter of choice for illustrating skin aging.


Controlling risk of SARS-CoV-2 infection in essential workers of enclosed food manufacturing facilities.
The SARS-CoV-2 global pandemic poses significant health risks to workers who are essential to maintaining the food supply chain. Using a quantitative risk assessment model, this study characterized the impact of risk reduction strategies for controlling SARS-CoV-2 transmission (droplet, aerosol, fomite-mediated) among front-line workers in a representative indoor fresh fruit and vegetable manufacturing facility. We simulated: 1) individual and cumulative SARS-CoV-2 infection risks from close contact (droplet and aerosols at 1-3 m), aerosol, and fomite-mediated exposures to a susceptible worker following exposure to an infected worker during an 8 h-shift; and 2) the relative reduction in SARS-CoV-2 infection risk attributed to infection control interventions (physical distancing, mask use, ventilation, surface disinfection, hand hygiene, vaccination). Without mitigation measures, the SARS-CoV-2 infection risk was largest for close contact (droplet and aerosol) at 1 m (0.96, 5th - 95th percentile: 0.67-1.0). In comparison, risk associated with fomite (0.26, 5th - 95th percentile: 0.10-0.56) or aerosol exposure alone (0.05, 5th - 95th percentile: 0.01-0.13) at 1 m distance was substantially lower (73-95%). At 1 m, droplet transmission predominated over aerosol and fomite-mediated transmission, however, this changed by 3 m, with aerosols comprising the majority of the exposure dose. Increasing physical distancing reduced risk by 84% (1-2 m) and 91% (1-3 m). Universal mask use reduced infection risk by 52-88%, depending on mask type. Increasing ventilation (from 0.1 to 2-8 air changes/hour) resulted in risk reductions of 14-54% (1 m) and 55-85% (2 m). Combining these strategies, together with handwashing and surface disinfection, resulted in <1% infection risk. Partial or full vaccination of the susceptible worker resulted in risk reductions of 73-92% (1 m risk range: 0.08-0.26). However, vaccination paired with other interventions (ACH 2, mask use, or distancing) was necessary to achieve infection risks <1%. Current industry SARS-CoV-2 risk reduction strategies, particularly when bundled, provide significant protection to essential food workers.


Long-term risk of salvage cystectomy after radiotherapy for muscle-invasive bladder cancer.
To establish the long-term outcome for muscle-invasive transitional cell carcinoma of the bladder treated by radiotherapy with or without neoadjuvant cisplatin. 159 patients with T2-T4a NX M0 bladder cancer were entered into a prospective randomized trial between June 1984 and June 1988. Follow-up was by 3-monthly cystoscopy in the first year, 6-monthly the next 2 years and yearly thereafter. Salvage surgery was performed at the discretion of the participating clinician. Minimum follow-up was 9 (median 11) years, at which time 29 patients (18%) remain alive. Median survival was 24 months with no difference between the treatment groups (chi(2) = 0.08, p = 0.77). Overall cystectomy rate was 24% (radiotherapy alone 20%, combined therapy 28%; p = 0.24). Median time to cystectomy from primary treatment was 12 months; range 56 days to 10 years. The risk of cystectomy was 11, 10 and 7% for the first, second and third years after radiotherapy respectively, and 8% in total after the third year. The proportion of patients alive in each successive year who had required a cystectomy was between 20 and 30% for 5 of the first 8 years after treatment. Salvage cystectomy is necessary in a quarter of patients after radiotherapy and this can be needed up to 10 years after treatment. During this time, multiple invasive procedures are likely to be performed, resulting in significant patient morbidity and cost. Patients should be fully counselled about the need for prolonged surveillance and the persisting risk of salvage surgery when deciding between primary cystectomy and radiotherapy.


Many or too many progesterone membrane receptors? Clinical implications.
Several receptors for nongenomically initiated actions of progesterone (P4) exist, namely membrane-associated P4 receptors (MAPRs), membrane progestin receptors (mPRs), receptors for neurosteroids [GABAA receptor (GABAAR), NMDA receptor, sigma-1 and -2 receptors (S1R/S2R)], the classical genomic P4 receptor (PGR), and α/β hydrolase domain-containing protein 2 (ABHD2). Two drugs related to this field have been approved: brexanolone (Zulresso™) for the treatment of postpartum depression, and ganaxolone (Ztalmy™) for the treatment of CDKL5 deficiency disorder. Both are derivatives of P4 and target the GABAAR. Several other indications are in clinical testing. CT1812 (Elayta™) is also being tested for the treatment of Alzheimer's disease (AD) in Phase 2 clinical trials, targeting the P4 receptor membrane component 1 (PGRMC1)/S2R complex. In this Review, we highlight emerging knowledge on the mechanisms of nongenomically initiated actions of P4 and its derivatives.


Oxidative-mechanical stress signals stem cell niche mediated Lrp5 osteogenesis in eNOS(-/-) null mice.
Calcific aortic valve disease (CAVD) is the most common indication for valve surgery in the USA. This study hypothesizes that CAVD develops secondary to Wnt3a/Lrp5 activation via oxidative-mechanical stress in eNOS null mice. eNOS(-/-) mice were tested with experimental diets including a control (n=20), cholesterol (n=20), cholesterol + Atorvastatin (n=20). After 23 weeks the mice were tested for the development of aortic stenosis by Echo, Histology, MicroCT, and RTPCR for bone markers. In vitro studies measured Wnt3a secretion from aortic valve endothelial cells and confirmed oxidative stress via eNOS activity. Anion exchange chromatography was performed to isolate the mitogenic protein. Myofibroblast cells were tested to induce bone formation. Cholesterol treated eNOS mice develop severe stenosis with an increase in Wnt3a, Lrp5, Runx2 (threefold increase (P<0.0001) in the bicuspid versus tricuspid aortic valves. Secretion of Wnt3a from aortic valve endothelium in the presence of abnormal oxidative stress was correlated with diminished eNOS enzymatic activity and tissue nitrite levels. Initial characterization of the architecture for a stem cell nice was determined by protein isolation using anion-exchange chromatography and cell proliferation via thymidine incorporation. Osteoblastogenesis in the myofibroblast cell occurred via Lrp5 receptor upregulation in the presence of osteogenic media. Targeting the Wnt3a/Lrp5 pathway in valve calcification and activation of osteogenesis is via an oxidative-mechanical stress in CAVD. These findings provide a foundation for treating this disease process by targeting the cross talk mechanism in a resident stem cell niche.