Credentialing dementia training: the Florida experience.
Florida is a leader in requiring that all direct care staff employed in assisted living, nursing homes, hospice, adult day care and home health undergo Alzheimer's disease (AD) training. Legislative requirements prescribe the curricula components and require a review of curricular content and minimum standards for the training providers. We describe Florida's AD training program review process, and report the results of our review of 445 curricula received over four and a half years. On initial submission, over 90% of curricula submitted did not include learning objectives, time formats or didactic approach. During a review of content we often found inaccurate information, language that was not person-centered, and missing required training components. Form and content problems were prevalent across all curricular types. We propose the Florida credentialing program as a model to ensure that accurate and educationally sound curricula are used to train direct care workers.


Transglutaminase 2 mediates polymer formation of I-kappaBalpha through C-terminal glutamine cluster.
Recently we reported that transglutaminase 2 (TGase 2) activates nuclear factor-kappaB (NF-kappaB) independently of I-kappaB kinase (IKK) activation, by inducing cross-linking and protein polymer formation of inhibitor of nuclear factor-kappaBalpha (I-kappaBalpha). TGase 2 catalyzes covalent isopeptide bond formation between the peptide bound-glutamine and the lysine residues. Using matrix-assisted laser desorption ionization time-of-flight mass spectra analysis of I-kappaBalpha polymers cross-linked by TGase 2, as well as synthetic peptides in an in vitro competition assay, we identified a glutamine cluster at the C terminus of I-kappaBalpha (amino acids 266-268) that appeared to play a key role in the formation of I-kappaBalpha polymers. Although there appeared to be no requirement for specific lysine residues, we found a considerably higher preference for the use of lysine residues at positions 21, 22, and 177 in TGase 2-mediated cross-linking of I-kappaBalpha. We demonstrated that synthetic peptides encompassing the glutamine cluster at amino acid positions 266-268 reversed I-kappaBalpha polymerization in vitro. Furthermore, the depletion of free I-kappaBalpha in EcR/TG cells was completely rescued in vivo by transfection of mutant I-kappaBalphas in glutamine sites (Q266G, Q267G, and Q313G) as well as in a lysine site (K177G). These findings provide additional clues into the mechanism by which TGase 2 contributes to the inflammatory process via activation of NF-kappaB.


[Family history of liver cancer increases the risk of liver cancer incidence: a 20-year prospective cohort study in Qidong, China].
To evaluate whether first-degree family history of liver cancer plays a role in liver cancer incidence by prospective evaluation of a patient cohort in Qidong, China over a 20-year period. In May 1992, 708 hepatitis B surface antigen (HBsAg) carriers and 730 HBsAg-negadve controls from Qidong city were enrolled for participation in a prospective cohort study ending in November 2012.Follow-up was carried out every 6 to 12 months, and evaluations included serum assays to measure concentrations of alpha fetoprotein (AFP), HBsAg and alanine aminotransferase (ALT), as well as abdominal ultrasound to assess liver disease.The relationship between baseline (study entry) information of patients with first-degree family history of liver cancer and liver cancer incidence during the two decades of study was statistically assessed. There were 172 newly diagnosed liver cancer cases in the cohort during 25 753 person-years (py) of follow-up, representing an incidence of 667.88/100 000 py.The incidence rates of liver cancer among participants with or without liver cancer family history were 1 244.36/100 000 py and 509.70/100 000 py respectively, and the between-group difference reached the threshold for statistical significance (P less than 0.01, Relative Risk (RR):2.44, 95% Confidence Interval (CI):1.80-3.31).The incidence rates of liver cancer among participants who had a sibling with liver cancer and participants who had a parent with liver cancer were not significantly different (P > 0.05), but the liver cancer incidence among participants who had a mother with liver cancer was significantly higher than that of participants who had a father with liver cancer (P < 0.05, RR:1.86, 95% CI:1.03-3.36). Among the participants with liver cancer family history, 56.52% (39/69) were diagnosed before 50 years old, and this rate was significantly higher than that of participants without a family history of liver cancer (40.78%, 42/103, P less than 0.05).The incidence rate of liver cancer among the participants who were family history-positive and HBsAg-positive was significantly higher than that of participants who were family history-negative but HBsAg-positive (P < 0.01, RR:1.75, 95% CI:1.29-2.38), and was 59.59 times higher than for participants who were family history-negative and HBsAgnegative.Subgroup analysis of liver cancer incidence among participants who were family history-positive but HBsAg-negative and participants who were family history-negative and HBsAg-negative produced anRR of 2.60, but there was no statistically significant difference between the two subgroups (P > 0.05).At the study's end, the incidence rates of liver cancer for the different subgroups were 32.21% for the family history-positive and HBsAgpositive participants, 19.80% for the family history-negative and HBsAg-positive participants, 1.71% for the family history-positive and HBsAg-negative participants, and 0.65% for the family history-negative and HBsAg-negative participants. First-degree family history of liver cancer is a risk factor of liver cancer in Chinese patients from Qidong, and exhibits synergism with HBsAg-positivity for incidence of liver cancer.


Combining MYC, BCL2 and TP53 gene and protein expression alterations improves risk stratification in diffuse large B-cell lymphoma.
Translocations affecting both MYC and BCL2 are associated with a poor prognosis in diffuse large B-cell lymphomas. We have examined genetic aberrations combined with analyses of protein expression of respective gene products. Fluorescence in situ hybridization (FISH) for translocations of BCL2 and MYC and del17p13 was performed. Immunohistochemistry analyses included BCL2, MYC and TP53 protein expression. Sixty-seven patients with high-risk DLBCL participating in a prospective multicenter study were included. Six patients with simultaneous translocations of BCL2 and MYC had impaired overall (OS) (p = 0.009) and progression-free survival (PFS) (p = 0.009). Six patients with high coexpression of MYC and BCL2 proteins also had impaired OS (p = 0.004) and PFS (p = 0.002). Combining these groups identified nine patients with impaired OS (p = 0.004) and PFS (p = 0.005). Sixteen patients had double-hit translocation or protein expression and/or del17p13 and/or high TP53. This combined endpoint was associated with impaired OS (p = 0.008) and PFS (p = 0.036), and identified 70% of all deaths.


Positron emission tomography features of canine necrotizing meningoencephalitis.
A Yorkshire terrier and a Chihuahua were referred for acute onset, generalized tonic-clonic seizures and were suspected to have meningoencephalitis based on magnetic resonance (MR) imaging findings. Brain lesions appeared hyperintense with T2-weighted imaging and hypointense with T1-weighted imaging, and were characteristic of necrotizing meningoencephalitis. Both dogs were diagnosed with necrotizing meningoencephalitis based on pathologic findings. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) was performed on both animals before euthanasia with the permission of the owner. In FDG-PET images, these lesions seen in MR images were characterized by multifocal or diffuse hypometabolism. Our FDG-PET results provided evidence of glucose hypometabolism in areas of necrosis and cavitation associated with necrotizing meningoencephalitis. FDG-PET has the potential to provide valuable diagnostic information in dogs with suspected necrotizing encephalitis.


Development of a chemically defined serum- and protein-free medium for growth of human peripheral lymphocytes.
A chemically defined, protein-free medium (designated CFBI 1000, where CFBI = Clayton Foundation Biochemical Institute) that supports human peripheral lymphocyte proliferation has been developed. This medium allows exploration of individual metabolic differences by varying the medium composition as well as providing a base to explore further the mechanisms of lymphocyte activation in a system initially free of added macromolecular species other than mitogen. The peripheral blood lymphocyte is an ideal system for metabolic studies because it is easily obtained, is a primary resting cell that can be activated to proliferate, and presumably reflects both the genetic makeup and biochemical environmental history of the individual at the time the cells were formed. Examination of the role of various factors in lymphocyte activation and subsequent events may be simplified by the utilization of a medium that is protein-free and chemically defined. The CFBI 1000 medium supports the growth response of human peripheral lymphocytes to mitogen as measured by [3H]thymidine incorporation to an extent comparable to other media used widely in assessment of lymphocyte proliferation.


Succinic acid production by Anaerobiospirillum succiniciproducens ATCC 29305 growing on galactose, galactose/glucose, and galactose/lactose.
Succinic acid-producing Anaerobiospirillum succiniciproducens was anaerobically grown on galactose, galactose/glucose, or galactose/lactose in order to study its galactose fermentation. Unlike a previous report, A. succiniciproducens was found to efficiently metabolize galactose as the sole carbon source at a rate of 2.4 g/g-DCW/h and produced succinic acid with as high a yield of 87% as with using glucose. When glucose and galactose were present, A. succiniciproducens metabolized both sugars simultaneously. Furthermore, when lactose and galactose coexisted, lactose did not inhibit the galactose fermentation of A. succiniciproducens. Therefore, co-utilization of galactose and other sugars can improve the productivity and economy of bio-based succinic acid processes.


Does H3O+ Really Act as a Ligand in the Solid State?
The evidence for the existence of metal complexes containing H3O+ as a ligand in the solid state is examined. Each of the 68 examples in the Cambridge Structural Database in which H3O+ is bound to a transition metal, lanthanoid, actinoid, or main group metal ion is detailed and critically appraised. It is concluded that none of the reported examples of complexes containing coordinated H3O+ have been unequivocally characterized and that they result from either curation errors or misinterpretations of the crystallographic data. These conclusions are supported by computational techniques, which show that three purported H3O+ complexes based on the 1,4,7,10,13,16,21,24-octa-azabicyclo(8.8.8)hexacosane azacryptand skeleton are better described as aqua complexes, with protonation occurring at the amine ligand.


BNIP3/Bcl-2-mediated apoptosis induced by cyclic tensile stretch in human cartilage endplate-derived stem cells.
The present study aimed to investigate the molecular mechanisms of cyclic stretch-induced apoptosis in human intervertebral disc cartilage endplate-derived stem cells (CESCs). CESCs were stretched by the Flexercell-4000™ Tension Plus system, the effect on cell viability was measured by a Cell Counting Kit-8 assay, while cell apoptosis was detected by flow cytometry. Western blot analysis was used to evaluate the expression of B-cell lymphoma 2 (Bcl-2)/adenovirus E1B 19 kDa interacting protein 3 (BNIP3), Bcl-2, Bcl-2 homologous antagonist killer (Bak), Bcl-2-associated X protein (Bax), Bcl extra large (Bcl-xl) and the activity of caspase-3, while Z-VAD-FMK was used to inhibit caspase-3. Compared with the control group, the cell viability decreased in a time-dependent manner after stretching. Furthermore, cell apoptosis and the activity of caspase-3 were increased in a time-dependent manner. The ratio of pro-death factor BNIP3 to anti-apoptotic protein Bcl-2 was significantly increased. When cells were stretched for 36 h, the apoptosis-associated proteins Bak and Bax were increased, while Bcl-xl was decreased. The viability and apoptotic ratio of stretched cells were significantly restored after caspase-3 was repressed. In conclusion, cyclic tensile stretch induced apoptosis of CESCs, which was probably due to upregulation of the expression of BNIP3.


Phrenic Nerve Palsy Following Radiation Therapy for Patient With Breast Cancer.
Breast cancer is the most common malignancy affecting women in US today. Radiotherapy used after breast-conserving surgery has been shown to decrease local recurrence while minimizing side effects. Peripheral neuropathy remains a common and well-known complication of radiotherapy for breast cancer; however, it is rarely associated with phrenic nerve palsy after treatment of breast cancer. We describe a 66-year-old woman with a significant past medical history of chronic obstructive pulmonary disease and asthma who presented with hypoxia after completing radiotherapy for breast cancer. After ruling out other causes of hypoxemia, the patient was diagnosed with diaphragmatic dysfunction, likely caused by phrenic nerve palsy resulting from radiotherapy-induced neuropathy after treatment of breast cancer. This case is the first reported incidence of phrenic nerve palsy resulting from radiotherapy for breast cancer.


[Presence and characterization of somatostatin precursor in human growth hormone secreting pituitary gland tumor].
Previous studies have demonstrated that normal and tumoral pituitaries release in vitro somatostatin (SRIH) and contain messenger RNAs encoding the preproSRIH. In the present study, we document the presence and characterization of the SRIH precursor in a growth hormone (GH)-secreting human pituitary adenoma, using two biochemical procedures: Sephadex G50 filtration and high performance liquid chromatography (HPLC). Sephadex G50 filtration of a 2M acetic acid extract demonstrated the presence of three SRIH-like immunoreactive (SLI) peaks, distinct from SRIH 1-28 and SRIH 1-14 used as standard. Molecular mass of the SLI material present in each peak was estimated as 21, 17 and 12 kilodaltons (kDa). SRIH 1-28 and/or 1-14 were not detected in this extract. Reverse phase HPLC was performed on a C18 column; all the three forms of SLI material coeluted with the rat hypothalamic proSRIH indicating a high homology between the human pituitary proSRIH and that of the rat hypothalamus. These results demonstrate for the first time the presence of high molecular mass proSRIH forms in a GH-secreting pituitary adenoma, and thus enable us to conclude for a local pituitary production of SRIH.


COVID-19 severity: does the genetic landscape of rare variants matter?
Rare variants affecting host defense against pathogens may be involved in COVID-19 severity, but most rare variants are not expected to have a major impact on the course of COVID-19. We hypothesized that the accumulation of weak effects of many rare functional variants throughout the exome may contribute to the overall risk in patients with severe disease. This assumption is consistent with the omnigenic model of the relationship between genetic and phenotypic variation in complex traits, according to which association signals tend to spread across most of the genome through gene regulatory networks from genes outside the major pathways to disease-related genes. We performed whole-exome sequencing and compared the burden of rare variants in 57 patients with severe and 29 patients with mild/moderate COVID-19. At the whole-exome level, we observed an excess of rare, predominantly high-impact (HI) variants in the group with severe COVID-19. Restriction to genes intolerant to HI or damaging missense variants increased enrichment for these classes of variants. Among various sets of genes, an increased signal of rare HI variants was demonstrated predominantly for primary immunodeficiency genes and the entire set of genes associated with immune diseases, as well as for genes associated with respiratory diseases. We advocate taking the ideas of the omnigenic model into account in COVID-19 studies.


Embodied bidirectional simulation of a spiking cortico-basal ganglia-cerebellar-thalamic brain model and a mouse musculoskeletal body model distributed across computers including the supercomputer Fugaku.
Embodied simulation with a digital brain model and a realistic musculoskeletal body model provides a means to understand animal behavior and behavioral change. Such simulation can be too large and complex to conduct on a single computer, and so distributed simulation across multiple computers over the Internet is necessary. In this study, we report our joint effort on developing a spiking brain model and a mouse body model, connecting over the Internet, and conducting bidirectional simulation while synchronizing them. Specifically, the brain model consisted of multiple regions including secondary motor cortex, primary motor and somatosensory cortices, basal ganglia, cerebellum and thalamus, whereas the mouse body model, provided by the Neurorobotics Platform of the Human Brain Project, had a movable forelimb with three joints and six antagonistic muscles to act in a virtual environment. Those were simulated in a distributed manner across multiple computers including the supercomputer Fugaku, which is the flagship supercomputer in Japan, while communicating via Robot Operating System (ROS). To incorporate models written in C/C++ in the distributed simulation, we developed a C++ version of the rosbridge library from scratch, which has been released under an open source license. These results provide necessary tools for distributed embodied simulation, and demonstrate its possibility and usefulness toward understanding animal behavior and behavioral change.


Evaluation of rule-based autoverification protocols.
Autoverification is a technique that can help save time and dollars in today's modern laboratory. Most laboratorians, however, are afraid to use it. The authors describe a rules-based system based on the quality of the laboratory's instrumentation and the quality of the results generated to help decide if the laboratory should pursue the advantages of autoverification. This project was developed through a grant from Ortho-Clinical Diagnostics, Inc., a Johnson & Johnson Company.


Comparative Evaluations on Real-Time Monitoring of Temperature Sensors during Endoscopic Laser Application.
Temperature sensors, such as Fiber Bragg Grating (FBG) and thermocouple (TC), have been widely used for monitoring the interstitial tissue temperature during laser irradiation. The aim of the current study was to compare the performance of both FBG and TC in real-time temperature monitoring during endoscopic and circumferential laser treatment on tubular tissue structure. A 600-µm core-diameter diffusing applicator was employed to deliver 980-nm laser light (30 W for 90 s) circumferentially for quantitative evaluation. The tip of the TC was covered with a white tube (W-TC) in order to prevent direct light absorption and to minimize temperature overestimation. The temperature measurements in air demonstrated that the measurement difference in the temperature elevations was around 3.5 °C between FBG and W-TC. Ex vivo porcine liver tests confirmed that the measurement difference became lower (less than 1 °C). Ex vivo porcine esophageal tissue using a balloon-integrated catheter exhibited that both FBG and W-TC consistently showed a comparable trend of temperature measurements during laser irradiation (~2 °C). The current study demonstrated that the white tube-covered TC could be a feasible sensor to monitor interstitial tissue temperature with minimal overestimation during endoscopic laser irradiation. Further in vivo studies on gastroesophageal reflux disease will investigate the performance of the W-TC to monitor the temperature of the esophageal mucosa surface in real-time mode to warrant the safety of endoscopic laser treatment.


[State of the sympathetic-adrenal system in angina pectoris attacks].
In 14 patients with ischaemic heart disease the plasma noradrenaline and adrenalin levels were determined during anginal attacks and in the attack-free period, and daily catecholamines excretion was studied in 11 of them. The blood plasma and urine noradrenaline and adrenalin levels were determined with the help of the trioxyindol, fluorimetric method. The content of noradrenaline and adrenalin in the blood plasma during anginal attacks was statistically significantly higher than during the attack-free period. At the same time, in urine samples collected during 24 hours after the attack and during an attack-free period no significant differences in the concentration of both catecholamines was found. Consequently, hypercatecholaminemia observed during anginal attacks is brief. An elevation of the activity of the sympathodrenal system may favour the development of rhythm disorders and hamper the therapeutic measures.


Characterisation of the canine faecal virome in healthy dogs and dogs with acute diarrhoea using shotgun metagenomics.
The virome has been increasingly investigated in numerous animal species and in different sites of the body, facilitating the identification and discovery of a variety of viruses. In spite of this, the faecal virome of healthy dogs has not been investigated. In this study we describe the faecal virome of healthy dogs and dogs with acute diarrhoea in Australia, using a shotgun metagenomic approach. Viral sequences from a range of different virus families, including both RNA and DNA families, and known pathogens implicated in enteric disease were documented. Twelve viral families were identified, of which four were bacteriophages. Eight eukaryotic viral families were detected: Astroviridae, Coronaviridae, Reoviridae, Picornaviridae, Caliciviridae, Parvoviridae, Adenoviridae and Papillomaviridae. Families Astroviridae, Picornaviridae and Caliciviridae were found only in dogs with acute diarrhoea, with Astroviridae being the most common family identified in this group. Due to its prevalence, characterisation the complete genome of a canine astrovirus was performed. These studies indicate that metagenomic analyses are useful for the investigation of viral populations in the faeces of dogs. Further studies to elucidate the epidemiological and biological relevance of these findings are warranted.


Metabolomic Analysis of Combretum lanceolatum Plants Interaction with Diaporthe phaseolorum and Trichoderma spirale Endophytic Fungi through 1 H-NMR.
Endophytic fungi are an important class of microorganisms, able to interact with a host plant via a mutualistic mechanism without visible symptoms of the fungal colonization. The synergy between endophytic fungi and their host plant can promote morphological, physiological and biochemical changes through the expression of bioactive metabolites. This work aims to correlate metabolic changes in the Combretum lanceolatum plant metabolome with its endophytic fungi Diaporthe phaseolorum (Dp) and Trichoderma spirale (Ts), and to discover corresponding metabolite-biomarkers, with the principal focus being on its primary metabolism. The 1 H-NMR metabolomic analysis of qualitative and quantitative changes was performed through multivariate statistical analysis and the identification of primary metabolites was achieved on the Madison Metabolomics Consortium Database. The presence of Dp significantly impacted the plant's metabolic pathways, improving the biosynthesis of primary metabolites such as threonine, malic acid and N-acetyl-mannosamine, which are precursors of special metabolites involved in plant self-defence. This work represents a valuable contribution to advanced studies on the metabolic profiles of the interaction of plants with endophytes.


Regional quantitative analysis of NFT in brains of non-demented elderly persons: comparisons with findings in brains of late-onset Alzheimer's disease and limbic NFT dementia.
Brains of non-demented elderly people were divided into two groups according to the presence or absence of senile plaques (SP(+) and SP(-)). The regional number of NFT in each group were then quantitatively investigated and compared with that in the late-onset Alzheimer's disease (AD) group and the limbic NFT dementia (LNTD) group. NFT were divided into type 1, type 2 and type 3 according to the developmental stage. In addition, polymorphism of the apolipoprotein E (Apo E) gene was analyzed in all groups. The most frequent regions of NFT common to all groups were the transentorhinal cortex, the entorhinal cortex, the subiculum and cornu ammonis (CA)1 of the hippocampus. In the SP(+) group the proportion of type 3 was high in the transentorhinal cortex and entorhinal cortex, while type 1 or 2 were high in the subiculum and CA1, suggesting that NFT formation progresses from the parahippocampal cortex to the hippocampus. In the SP(-) group the proportion of type 3 was higher in the subiculum and CA1 than in the transentorhinal cortex and entorhinal cortex, suggesting that NFT formation is accelerated in the hippocampus. The late-onset AD group and LNTD group showed the patterns of NFT formation similar to those of the SP(+) group and SP(-) group, respectively. The frequency of the epsilon4 allele of the Apo E gene was significantly higher in the late-onset AD group and SP(+) group than in the LNTD group and SP(-) group, respectively. From these findings it is suggested that persons in the SP(+) group are likely to remain non-demented elderly persons or become a developmental matrix of late-onset AD with a risk factor of the epsilon4 allele, while those in the SP(-) group are likely to remain non-demented elderly persons or pass into LNTD without a risk factor of the epsilon4 allele.


Dehydration and cognitive performance.
Human neuropsychology investigates brain-behavior relationships, using objective tools (neurological tests) to tie the biological and behavior aspects together. The use of neuropsychological assessment tools in assessing potential effects of dehydration is a natural progression of the scientific pursuit to understand the physical and mental ramifications of dehydration. It has long been known that dehydration negatively affects physical performance. Examining the effects of hydration status on cognitive function is a relatively new area of research, resulting in part from our increased understanding of hydration's impact on physical performance and advances in the discipline of cognitive neuropsychology. The available research in this area, albeit sparse, indicates that decrements in physical, visuomotor, psychomotor, and cognitive performance can occur when 2% or more of body weight is lost due to water restriction, heat, and/or physical exertion. Additional research is needed, especially studies designed to reduce, if not remove, the limitations of studies conducted to date.


Age-dependent loss of dentate gyrus granule cells in APP/PS1KI mice.
Loss of neurons in the hippocampus and other brain regions is, besides the occurrence of plaques and tangles, a neuropathological feature of Alzheimer's disease (AD). In recent years a plethora of transgenic mouse models overexpressing mutant amyloid precursor protein (APP) has been developed, which represent valuable research tools. Whereas extracellular plaque pathology is a common feature of these models, neuronal loss is a rather rare characteristic. In the present study, we quantified the number of neurons in the dentate gyrus granule layer (GCL) in 2- and 12-month-old APP/PS1KI mice, a mouse model that has been previously shown to have significant loss of neurons in the CA1 layer of the hippocampus. Stereological analysis revealed a strongly significant decrease of GCLs in aged APP/PS1KI mice, compared to age-matched PS1KI control animals (-44%), however, the volume of the GCL was not different.


Non-alcoholic fatty liver disease in women with polycystic ovary syndrome: assessment of non-invasive indices predicting hepatic steatosis and fibrosis.
Insulin resistance contributes to the pathogenesis of both polycystic ovary syndrome (PCOS) and non-alcoholic fatty liver disease (NAFLD). The main aim of the present study was the evaluation of non-invasive indices of hepatic steatosis and fibrosis in PCOS women with or without metabolic syndrome (MetS). In this cross-sectional study, three non-invasive indices for hepatic steatosis [NAFLD liver fat score, lipid accumulation product (LAP) and hepatic steatosis index (HIS)] and four for fibrosis [FIB-4, aspartate aminotransferase (AST)-to-Platelet Ratio Index (APRI), body mass index (BMI)-Age-Alanine aminotransferase (ALT)-Triglycerides (BAAT) and BMI AST/ALT Ratio Diabetes (BARD)] were calculated in 314 PCOS women (77 with, 237 without MetS) and 78 controls. All steatosis indices were significantly higher in the PCOS than the control group (NAFLD liver fat score: -0.139 ± 0.117 vs. -0.976 ± 0.159, p<0.001; LAP: 43.3 ± 1.9 vs. 34.7 ± 3.1, p=0.036; HIS: 44.6 ± 0.5 vs. 42.1 ± 0.8, p=0.016). FIB-4 and BAAT [fibrosis stage (F)2-4] were higher in the PCOS group (0.480 ± 0.020 vs. 0.400 ± 0.013, p<0.001; and 15.6% vs. 5.1%, respectively), whereas APRI and BARD were not. All steatosis indices were significantly higher in PCOS women with than without MetS (NAFLD liver fat score: 1.874 ± 0.258 vs. -0.793 ± 0.099, p<0.001; LAP: 76.8 ± 4.9 vs. 33.4 ± 1.4, p<0.001; and HIS: 49.8 ± 1 vs. 43 ± 0.5, p<0.001). Of the fibrosis indices, only BAAT (F2-4: 50.6% vs. 4.2%) was higher in PCOS women with MetS. Non-invasive indices of hepatic steatosis were significantly higher in PCOS, especially in the presence of MetS, whereas indices of hepatic fibrosis yielded controversial results. Further studies are warranted to evaluate the long-term outcomes of hepatic steatosis and fibrosis indices in PCOS women.


The Impact of Sleep Interventions on Athletic Performance: A Systematic Review.
Sleep is essential for maximal performance in the athletic population. Despite that, the sport context has many factors that can negatively influence athletes' sleep and subsequent recovery. The purpose of this systematic review was to synthesize the most recent literature regarding sleep interventions aimed at improving sleep and subsequent performance in athletes. The present systematic review was conducted based on the PRISMA guidelines and the PICOS approach. The search was conducted in May 2022 using the electronic database PubMed, SPORTDiscus via EBSCOhost, and Web of Science. Once extracted, studies were included if they met the following criteria: (1) participants were athletes of individual or team sports; (2) implemented an intervention aimed at improving sleep; (3) measured at least one objective performance/recovery outcome; and (4) reported the relationship between sleep and performance. The search returned 1584 records. Following the screening, a total of 25 studies met our inclusion criteria. All the included articles were intervention studies published between 2011 and 2021. The included studies implemented various sleep interventions, such as sleep hygiene, naps, sleep extension, light manipulation, cold water immersion, mindfulness, or a combination of two or more strategies. Sleep extension and naps were the most representative and most effective strategies to improve sleep and performance. Mindfulness and light manipulation demonstrated promising results, but more studies are needed to confirm these findings. Sleep hygiene, removing electronic devices at night, and cold water immersion had no effects on sleep and subsequent performance/recovery, but these results are based on a few studies only. While acknowledging the limited amount of high-quality evidence reviewed, it appears that increasing sleep duration at night or through napping was the most effective interventions to improve physical and/or cognitive performance. Protocol Registration This protocol was registered in the International Platform of Registered Systematic Review and Meta-Analysis Protocols (INPLASY) on May 11, 2022, with the registration number INPLASY202250069.


Kit expression in small cell carcinomas of the lung: effects of chemotherapy.
A significant number of small cell lung carcinomas shows overexpression of the proto-oncogene c-kit product, a tyrosine kinase known as Kit or CD117. This molecular pathway seems somewhat implicated in promoting the neoplastic growth of small cell lung carcinoma. The current pharmacological availability of its selective inhibitor, together with the promising clinical results in the management of CD117-positive neoplasms such as advanced gastrointestinal stromal tumors, aroused great interest among oncologists in also adopting this therapeutic strategy in other CD117-positive tumors. We evaluated a series of 27 small cell lung carcinomas, comparing the expression of CD117 of the primary naïve tumor (before first-line chemotherapy) with the expression of the same neoplasm after postchemotherapy relapse. All the patients underwent similar chemotherapeutic regimens (cisplatin/carboplatin plus etoposide). At diagnosis, 21 of 27 cases (78%) showed strong immunoreactivity for CD117. Among these 21 originally positive tumors, CD117 remained overexpressed in 10 after relapse (48%), whereas the other 11 cases became negative. No originally CD117-negative small cell carcinomas displayed immunoreactivity after chemotherapy. CD117 expression was not statistically correlated with overall survival, occurrence of chemoresistance, or clinical response to chemotherapy. We also evaluated CD117 expression in a series of 46 surgically resected non-small cell lung carcinomas (8 squamous cell carcinomas, 10 adenocarcinomas, 5 pleomorphic carcinomas, 10 typical and 3 atypical carcinoids, and 10 large cell neuroendocrine carcinomas). Apart from small cell carcinomas, CD117 overexpression was observed in 6 of 10 large cell neuroendocrine carcinomas, whereas all the other histotypes resulted unstained. We speculate that loss of CD117 expression after chemotherapy in a high proportion of SCLC indicates that in this tumor, Kit unlikely represents the product of a constitutive mutation, as instead shown in gastrointestinal stromal tumors. Keeping this finding in mind, oncologists could re-test CD117 expression in relapsing small cell lung carcinomas in order to establish the best candidates for enrollment in ongoing clinical trials with Kit inhibitors. Practically speaking, CD117 may be helpful in discriminating between pulmonary high-grade neuroendocrine tumors and other histotypes, but pathologists should be aware that treated small cell lung carcinomas may remain unstained in a not insignificant number of cases.


Universal prophylaxis or preemptive strategy for cytomegalovirus disease after liver transplantation: a systematic review and meta-analysis.
We systematically reviewed and meta-analyze the efficacy of universal prophylaxis (UP) and preemptive (PE) strategies (using ganciclovir or valganciclovir) in preventing cytomegalovirus (CMV) disease (CMD) among liver transplant recipients (LTRs). We performed an electronic search of MEDLINE, EMBASE and the Cochrane Database till December 2013. Studies that assessed UP or PE for preventing CMD in LTRs were included. The risk of bias was assessed using the Newcastle-Ottawa scale. The primary outcome was CMD, secondary outcomes being acute cellular rejection (ACR), graft loss (GL) and mortality. Due to the heterogeneity of comparative studies, an indirect comparison was performed. Pooled incidence rates with 95% confidence interval (CI) are calculated for each outcome using a random-effects model. Thirty-two studies involving 2456 LTRs were included. The majority of the studies were of low risk of bias. Irrespective of donor/recipient CMV sero-status, CMD was 10% with UP (95% CI: 6-14; I(2) = 87%; 16 studies, n = 1581) and 7% with PE (95% CI: 3-10; I(2) = 84%; 16 studies, n = 875) (mean difference 2.6; 95% CI: -3.25 to 8.45, p = 0.34). Likewise, ACR and mortality were similar with the two strategies. However, GL was significantly lower in the UP group, regardless of donor/recipient sero-status. In indirect comparison, the incidence of CMD, ACR and mortality in LTRs were similar with two strategies. Trials comparing the two strategies directly are needed.


Brucella melitensis prosthetic joint infection.
Periprosthetic joint infection (PJI) due to Brucella spp. is rare. We report a case in a 75-year-old man and review 29 additional cases identified in a literature search. The diagnosis of Brucella PJI is challenging, in particular in non-endemic countries. Serological tests prior to joint aspiration or surgical intervention are reasonable. Involvement of infection control and timely information to laboratory personnel is mandatory upon diagnosis. There is no uniform treatment concept, neither with respect to surgical intervention nor for the duration of antimicrobials. Most cases have a successful outcome, irrespective of surgical modality, and with an antimicrobial combination regimen for 12 or more weeks.


Disturbances of desmofibrinogenesis in pateints suffering from acute myeloblastic leukemia.
Significantly decreased levels of blood plasma clotting factor XIII (FSF) were found in the blood of 20 patients with acute myeloblastic leukemia as compared to the control values. It was found that after administration of cytostatic drugs (Cerubidyne and Cytosar) FSF deficiency was higher. This effect was associated with a proteolytic activity detectable in plasma which destroys FSF in vitro. This proteolytic activity was neither inhibited by EACA nor by Trasylol. These results indicate that in patients with acute myeloblastic leukemia beside DIC the treatment with cytostatic drugs as well as the presence of proteases from leukemic cells in the plasma will cause an impairment of transformation of soluble fibrin polymer into insoluble desmofibrin.


CT Pulmonary Angiography: Using Decision Rules in the Emergency Department.
The aim of this study was to assess the appropriateness of utilization and diagnostic yields of CT pulmonary angiography (CTPA), comparing two commonly applied decision rules, the pulmonary embolism (PE) rule-out criteria (PERC) and the modified Wells criteria (mWells), in the emergency department (ED) setting. Institutional review board approval was obtained for this HIPAA-compliant, prospective-cohort, academic single-center study. Six hundred two consecutive adult ED patients undergoing CTPA for suspected PE formed the study population. The outcome was positive or negative for PE by CTPA and at 6-month follow-up. PERC and mWells scores were calculated. A positive PERC score was defined as meeting one or more criteria and a positive mWells score as >4. The percentage of CT pulmonary angiographic examinations that could have been avoided and the diagnostic yield of CTPA using PERC, mWells, and PERC applied to a negative mWells score were calculated. The diagnostic yield of CTPA was 10% (61 of 602). By applying PERC, mWells, and PERC to negative mWells score, 17.6% (106 of 602), 45% (273 of 602), and 17.1% (103 of 602) of CT pulmonary angiographic examinations, respectively, could have been avoided. The diagnostic yield in PERC-positive patients was higher than in mWells-positive patients (10% [59 of 602] vs 8% [49 of 602], P < .0001). Among PERC-negative and mWells-negative patients, the diagnostic yields for PE were 1.9% (2 of 106) and 4% (12 of 273), respectively (P = .004). The diagnostic yield of a negative PERC score applied to a negative mWells score was 1.9% (2 of 103). The use of PERC in the ED has the potential to significantly reduce the utilization of CTPA and misses fewer cases of PE compared with mWells, and it is therefore a more efficient decision tool.


Gluteal Necrotizing Soft Tissue Infection and Hip Osteomyelitis due to Candida Glabrata.
Necrotizing soft tissue infection (NSTI) is a rapidly progressive and often fatal infection of the soft tissue. Classically, it is attributed to bacterial infection and immunocompromised patients are particularly vulnerable. However, NSTI due to fungal infection rarely does occur, including from Candida species, and can pose a diagnostic challenge for unfamiliar providers. Expedient clinical recognition, surgical debridement, fungal tissue culture, and initiation of antifungal therapy are key. We report a 39-year-old obese male with long-standing history of poorly controlled diabetes who presented to a community hospital, noted to have NSTI of the sacrum, bilateral buttocks, and left hip, and was treated only with antibiotics. After transfer to an academic center, the patient underwent aggressive debridement and tissue diagnosis of Candida glabrata NSTI was made. He received broad-spectrum antibiotic and antifungal therapy for several months. Over the course of 4 months, his infection was cleared, and his large tissue defects were reconstructed with rotation flaps and the patient was discharged home. Fungal NSTI is a rare entity, especially when due to Candida species. It can be exceedingly difficult to diagnose and manage, as these patients may suffer higher mortality than those with NSTI due to bacteria. A high index of suspicion for the entity, rapid debridement, intraoperative tissue culture, and treatment with appropriate antifungal therapy offers the greatest chance of survival.


Current vector control challenges in the fight against malaria.
The effective and eco-friendly control of Anopheles vectors plays a key role in any malaria management program. Integrated Vector Management (IVM) suggests making use of the full range of vector control tools available. The strategies for IVM require novel technologies to control outdoor transmission of malaria. Despite the wide number of promising control tools tested against mosquitoes, current strategies for malaria vector control used in most African countries are not sufficient to achieve successful malaria control. The majority of National Malaria Control Programs in Africa still rely on indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs). These methods reduce malaria incidence but generally have little impact on malaria prevalence. In addition to outdoor transmission, growing levels of insecticide resistance in targeted vectors threaten the efficacy of LLINs and IRS. Larvicidal treatments can be useful, but are not recommended for rural areas. The research needed to improve the quality and delivery of mosquito vector control should focus on (i) optimization of processes and methods for vector control delivery; (ii) monitoring of vector populations and biting activity with reliable techniques; (iii) the development of effective and eco-friendly tools to reduce the burden or locally eliminate malaria and other mosquito-borne diseases; (iv) the careful evaluation of field suitability and efficacy of new mosquito control tools to prove their epidemiological impact; (v) the continuous monitoring of environmental changes which potentially affect malaria vector populations; (vi) the cooperation among different disciplines, with main emphasis on parasitology, tropical medicine, ecology, entomology, and ecotoxicology. A better understanding of behavioral ecology of malaria vectors is required. Key ecological obstacles that limit the effectiveness of vector control include the variation in mosquito behavior, development of insecticide resistance, presence of behavioral avoidance, high vector biodiversity, competitive and food web interactions, lack of insights on mosquito dispersal and mating behavior, and the impact of environmental changes on mosquito ecological traits. Overall, the trans-disciplinary cooperation among parasitologists and entomologists is crucial to ensure proper evaluation of the epidemiological impact triggered by novel mosquito vector control strategies.


RDJ2 (DNAJA2) chaperones neural G protein signaling pathways.
A number of structurally divergent proteins with J domains, called J proteins, interact with and activate the ATPase of Hsp70s, thereby harnessing the ATPase activity for conformational work on target proteins. The precise role of most mammalian J proteins remains undefined. In this paper, we demonstrate that transient expression of the J protein, Rdj2, in HEK 293 cells increased cellular cyclic adenosine monophosphate (cAMP) levels in the presence of the beta-adrenergic agonist isoproterenol. In CNS-derived catecholaminergic neuronal cell line (CAD) neuroblastoma cells, expression of Rdj2 increased isoproterenol-stimulated phosphorylation of cAMP response element binding protein (CREB). Moreover, we have characterized the binding properties of Rdj2 and observed a direct interaction between Rdj2 and receptor-coupled trimeric GTP-binding proteins (G proteins). We further show that the composition of the Rdj2-chaperone complex and the cysteine string protein (CSPalpha)-chaperone complex, another J protein, is distinct. Our data demonstrate that Rdj2 modulates G protein signaling and further suggest that chaperoning G proteins is an emerging theme of the J protein network.


Kin17, a mouse nuclear zinc finger protein that binds preferentially to curved DNA.
Kin17 is a 45 kDa protein encoded by the KIN17 gene located on mouse chromosome 2, band A. The kin17 amino acid sequence predicts two domains, which were shown to be functional: (i) a bipartite nuclear localization signal (NLS) that can drive the protein to the cell nucleus, (ii) a bona fide zinc finger of the C2H2 type. The zinc finger is involved in kin17 binding to double-stranded DNA since a mutant deleted of the zinc finger, kin17 delta 1, showed reduced binding. Single-stranded DNA was bound poorly by kin17. Interestingly, we found that kin17 protein showed preferential binding to curved DNA from either pBR322 or synthetic oligonucleotides. Binding of kin17 to a non-curved DNA segment increased after we had inserted into it a short curved synthetic oligonucleotide. Kin17 delta 2, a mutant deleted of 110 amino acids at the C-terminal end, still exhibited preferential binding to curved DNA and so did kin17 delta 1, suggesting that a domain recognizing curved DNA is located in the protein core.


Utilization of low-molecular-weight heparin prophylaxis in pediatric and adolescent trauma patients.
The objective of this study was to use trauma registry data to describe the number and characteristics of patients 21 years or younger receiving thromboprophylaxis with low-molecular-weight heparin at 2 pediatric and 2 adult level 1 trauma centers. Among 706 patients, the average age was 18.5 years, and 94.6% were hospitalized at adult centers. The most common injuries were lower extremity fractures (35.6%) and head injuries (20.4%). Major bleeding was reported in 3 patients (0.4%), and thrombotic events were reported in 15 patients (2.1%). Despite a lack of scientific evidence, low-molecular-weight heparin prophylaxis is being used in young trauma patients (primarily those 14 years or older). Prospective multicenter studies are needed to accurately describe the risks and benefits of low-molecular-weight heparin prophylaxis in young trauma patients, thereby identifying those who truly benefit from this intervention.


NAD+ : A key metabolic regulator with great therapeutic potential.
Nicotinamide adenine dinucleotide (NAD+ ) is a ubiquitous metabolite that serves an essential role in the catabolism of nutrients. Recently, there has been a surge of interest in NAD+ biology, with the recognition that NAD+ influences many biological processes beyond metabolism, including transcription, signalling and cell survival. There are a multitude of pathways involved in the synthesis and breakdown of NAD+ , and alterations in NAD+ homeostasis have emerged as a common feature of a range of disease states. Here, we provide an overview of NAD+ metabolism and summarise progress on the development of NAD+ -related therapeutics.


Antibiotic resistance of lactic acid bacteria and Bifidobacterium spp. isolated from dairy and pharmaceutical products.
The outlines of antibiotic resistance of some probiotic microorganisms were studied. This study was conducted with the double purpose of verifying their ability to survive if they are taken simultaneously with an antibiotic therapy and to increase the selective properties of suitable media for the isolation of samples containing mixed bacterial populations. We isolated from commercial dairy and pharmaceutical products, 34 strains declared as probiotics, belonging to the genera Bifidobacterium and Lactobacillus, and 21 strains of starter culture bacteria. All the microorganisms have been compared by electrophoresis of the soluble proteins for the purpose of identifying them. A Multiplex-PCR with genus- and species-specific primers was used to detect for Bifidobacterium animalis subsp. lactis presence. All bifidobacteria were B. animalis subsp. lactis except one Bifidobacterium longum. Sometimes the identification showed that the used strain was not the one indicated on the label. The lactobacilli were Lactobacillus acidophilus, Lactobacillus casei, and Lactobacillus delbrueckii subsp. bulgaricus. The streptococci were all Streptococcus thermophilus. The minimal inhibitory concentration (MIC) of 24 common antibiotic substances has been valued by the broth microdilution method. All tested strains were susceptible to ampicillin, bacitracin, clindamycin, dicloxacillin, erytromycin, novobiocin, penicillin G, rifampicin (MIC(90) ranging from 0.01 to 4 microg/ml); resistant to aztreonam, cycloserin, kanamycin, nalidixic acid, polymyxin B and spectinomycin (MIC(90) ranging from 64 to >1000 microg/ml). The susceptibility to cephalothin, chloramphenicol, gentamicin, lincomycin, metronidazole, neomycin, paromomycin, streptomycin, tetracycline and vancomycin was variable and depending on the species.


Ethyl Formate as a Methyl Bromide Alternative for Phytosanitary Disinfestation of Imported Banana in Korea With Logistical Considerations.
Methyl bromide (MB) use for quarantine and phytosanitary purposes is being phased out. Several effective MB alternatives have been identified depending on the target system. Industry commitment for the shift to new technologies will depend not only on the efficacy of alternatives but also on their compatibility and integrability into existing operations. We compared the efficacy of MB and ethyl formate (EF) for disinfestation of Planococcus citri (Risso) (Hemiptera: Pseudococcidae) as a representative surface pest on banana and evaluated whether EF fumigation is compatible with the current packaging materials and loading ratio used by the South Korean banana import industry. Fumigation trials with P. citri adults and eggs showed that EF was at least as effective as MB at the EF and MB concentrations recommended under the current phytosanitary disinfestation guidelines. From a logistical standpoint, EF gas could not effectively penetrate plastic bagging typically used in banana cartons during commercial shipping. Also, EF sorption to bananas and packing materials (used as cushioning inside bagging) further lowered realized EF concentrations around bananas. These reductions in EF concentration translated into reduced mortality of P. citri eggs, indicating that despite similar efficacy of MB and EF for controlling P. citri, further consideration and optimization of other industry logistics such as packaging and loading ratio is necessary to enhance the adoption of this MB alternative.


Defeating Huanglongbing Pathogen Candidatus Liberibacter asiaticus With Indigenous Citrus Endophyte Bacillus subtilis L1-21.
Huanglongbing (HLB) has turned into a devastating botanical pandemic of citrus crops, caused by Candidatus Liberibacter asiaticus (CLas). However, until now the disease has remained incurable with very limited control strategies available. Restoration of the affected microbiomes in the diseased host through the introduction of an indigenous endophyte Bacillus subtilis L1-21 isolated from healthy citrus may provide an innovative approach for disease management. A novel half-leaf method was developed in vitro to test the efficacy of the endophyte L1-21 against CLas. Application of B. subtilis L1-21 at 104 colony forming unit (cfu ml-1) resulted in a 1,000-fold reduction in the CLas copies per gram of leaf midrib (107 to 104) in 4 days. In HLB-affected citrus orchards over a period of 2 years, the CLas incidence was reduced to < 3%, and CLas copies declined from 109 to 104 g-1 of diseased leaf midribs in the endophyte L1-21 treated trees. Reduction in disease incidence may corroborate a direct or an indirect biocontrol effect of the endophytes as red fluorescent protein-labeled B. subtilis L1-21 colonized and shared niche (phloem) with CLas. This is the first large-scale study for establishing a sustainable HLB control strategy through citrus endophytic microbiome restructuring using an indigenous endophyte.


Maternal hemoglobin and serum albumin and fetal growth.
Four hundred and eighty four pregnant women and their offsprings were studied to determine the relationship of maternal hemoglobin and serum protein levels on the birthweight of offspring. The correlation coefficient of maternal hemoglobin as well as serum albumin level (gamma = 0.1097 and 0.0936, respectively) with birthweight were not statistically significant. However, mean birthweight of neonates born to nonanemic mothers was significantly higher than of those born to anemic mothers. The prevalence of low birthweight babies was significantly higher among anemic mothers (p < 0.01); however, no such trend was observed in relation to maternal serum albumin (p > 0.05).


Enhanced visible light photocatalytic activity of Cu2O via cationic-anionic passivated codoping.
To improve the photocatalytic activity of Cu2O for hydrogen production through water splitting, the band edges of Cu2O should be modified to meet the electronic transition of angular momentum selection rules (Δl = ±1) and match with the hydrogen or oxygen production levels. Upon analyzing the band structure of Cu2O and the chemical potentials of the dopants, we show that passivated codopants such as (Sn + B) can induce superior modification in the band edges of Cu2O: the conduction band edge is changed from the d band character of Cu atoms to the p band character of the Sn atom and shifted slightly downwards, while the valence band edge keeps the d band character of the Cu atoms and energy unchanged, indicating that the stringent requirements get satisfied. Moreover, the optical absorption spectrum of (Sn + B) codoped Cu2O shows a greatly improved absorption of visible light. The calculated defect formation energy shows that the codoping is energetically more favorable than mono-doping due to the Coulomb interactions and charge compensation effects.


Bilateral Arteriovenous Shunting Through Pial and Perforating Vessels With Multiple Strokes in a Patient With Hepatopulmonary Syndrome.
Hepatopulmonary syndrome (HPS) is a condition characterized by chronic liver disease, intrapulmonary arteriovenous shunting, and increased alveolar-arterial oxygen gradient. This case report presents a 54-year-old male patient with a history of stroke, liver cirrhosis, portal vein thrombosis, hypertension, diabetes, and bladder cancer, who presented with worsening headaches and confusion over the course of five years. Digital subtraction angiogram (DSA) revealed multiple bilateral arteriovenous shunts, suggesting a shunting mechanism similar to that observed in HPS. We propose that this unique case could provide valuable insights into the parallels between the pathophysiology of HPS and diffuse arteriovenous shunting in the brain and the increased risk of ischemic and hemorrhagic events in both cases. Further studies are needed to establish a clearer understanding of this relationship and its implications for patients with chronic liver disease.


Voltage-induced formation of alamethicin pores in lecithin bilayer vesicles.
The interaction of alamethicin with lecithin bilayer vesicles in the presence of a transmembrane potential difference has been studied by proton magnetic resonance spectroscopy. Asymmetrical vesicles with alamethicin trapped within the intravesicular compartment were prepared and the formation of ion channels, were then triggered by imposing a suitable potassium ion gradient across the bilayer membrane in the presence of valinomycin. These alamethicin channels were found to permit the outward passage of europium ions into the extravesicular medium when the transmembrane potential is more positive for the inner compartment.


Follow-up of patients with curatively resected colorectal cancer: a practice guideline.
A systematic review was conducted to evaluate the literature regarding the impact of follow-up on colorectal cancer patient survival and, in a second phase, recommendations were developed. The MEDLINE, CANCERLIT, and Cochrane Library databases, and abstracts published in the 1997 to 2002 proceedings of the annual meeting of the American Society of Clinical Oncology were systematically searched for evidence. Study selection was limited to randomized trials and meta-analyses that examined different programs of follow-up after curative resection of colorectal cancer where five-year overall survival was reported. External review by Ontario practitioners was obtained through a mailed survey. Final approval of the practice guideline report was obtained from the Practice Guidelines Coordinating Committee. Six randomized trials and two published meta-analyses of follow-up were obtained. Of six randomized trials comparing one follow-up program to a more intense program, only two individual trials detected a statistically significant survival benefit favouring the more intense follow-up program. Pooling of all six randomized trials demonstrated a significant improvement in survival favouring more intense follow-up (Relative Risk Ratio 0.80 (95%CI, 0.70 to 0.91; p = 0.0008). Although the rate of recurrence was similar in both of the follow-up groups compared, asymptomatic recurrences and re-operations for cure of recurrences were more common in patients with more intensive follow-up. Trials including CEA monitoring and liver imaging also had significant results, whereas trials not including these tests did not. Follow-up programs for patients with curatively resected colorectal cancer do improve survival. These follow-up programs include frequent visits and performance of blood CEA, chest x-rays, liver imaging and colonoscopy, however, it is not clear which tests or frequency of visits is optimal. There is a suggestion that improved survival is due to diagnosis of recurrence at an earlier, asymptomatic stage which allows for more curative resection of recurrence. Based on this evidence and consideration of the biology of colorectal cancer and present practices, a guideline was developed. Patients should be made aware of the risk of disease recurrence or second bowel cancer, the potential benefits of follow-up and the uncertainties requiring further clinical trials. For patients at high-risk of recurrence (stages IIb and III) clinical assessment is recommended when symptoms occur or at least every 6 months the first 3 years and yearly for at least 5 years. At the time of those visits, patients may have blood CEA, chest x-ray and liver imaging. For patients at lower risk of recurrence (stages I and Ia) or those with co-morbidities impairing future surgery, only visits yearly or when symptoms occur. All patients should have a colonoscopy before or within 6 months of initial surgery, and repeated yearly if villous or tubular adenomas >1 cm are found; otherwise repeat every 3 to 5 years. All patients having recurrences should be assessed by a multidisciplinary team in a cancer centre.


Increased oxygen extraction fraction is associated with prior ischemic events in patients with carotid occlusion.
The purpose of our study was to investigate the relationship between misery perfusion (increased oxygen extraction fraction, OEF) and baseline risk factors in patients with carotid occlusion. One-hundred seventeen patients with atherosclerotic carotid occlusion were studied prospectively by clinical evaluation, laboratory testing, and positron emission tomography (PET). PET measurements of cerebral blood flow (CBF), cerebral blood volume (CBV), and OEF were made on enrollment in the study. Increased ipsilateral OEF was identified by comparison with 18 normal control subjects. Twenty-five baseline clinical, epidemiological, and arteriographic risk factors were assessed on study entry. Student t tests, chi(2) tests, and Fisher exact tests with Bonferroni correction were used to assess statistical significance (P<.05). Of 117 patients, 44 had increased OEF distal to the occluded carotid and 73 had normal OEFs. Thirty-nine of the 81 patients with prior ipsilateral ischemic symptoms had high OEFs (42%), whereas only 5 of the 31 asymptomatic patients had high OEFs (16%, P<.001). All of the other baseline risk factors were similar between the two groups of patients. Investigations of the relationship between hemodynamic factors and stroke risk must take into account the lower frequency of hemodynamic abnormalities in asymptomatic patients.


Early fetal megacystis: Is it possible to predict the prognosis in the first trimester?
To evaluate the best management of fetal megacystis diagnosed in the first trimester and define the prognosis and the most appropriate follow-up as early as possible. This is a retrospective study of first-trimester fetal megacystis diagnosed in pregnant women who performed a combined screening for fetal aneuploidy. Megacystis was defined as a longitudinal bladder diameter (LBD) greater than 7 mm. All fetuses were divided into two groups according to the LBD: Group A with LBD > 15 mm and Group B with LBD < 15 mm. The fetal karyotype and associated anomalies were evaluated. Ultrasound monitoring was performed every 2 weeks (a second ultrasound scan after 2 weeks from diagnosis and a third ultrasound scan 2 weeks after the second one). Twenty-six cases were identified between 2011 and 2016; three cases of aneuploidy were excluded from the study. Of the remaining 23 cases, 11 were included in Group A and 12 in Group B. All Group A fetuses had an adverse outcome. In Group B: five (41.7%) cases had an adverse outcome and seven (58.3%) had a spontaneous resolution of megacystis. The ultrasound findings of both the ultrasound scans, the second and the third, were 100% concordant. An ultrasound scan performed 2 weeks after the megacystis diagnosis can predict the outcome in fetuses with an LBD < 15 mm as early as the end of the first trimester. The outcome of euploid fetuses with an LBD < 15 mm was favorable in 58.3% of the cases.


Detection and Characterization of Cucumis melo Cryptic Virus, Cucumis melo Amalgavirus 1, and Melon Necrotic Spot Virus in Cucumis melo.
Three RNA viruses-Cucumis melo cryptic virus (CmCV), Cucumis melo amalgavirus 1 (CmAV1), and melon necrotic spot virus (MNSV)-were identified from a melon (Cucumis melo) transcriptome dataset. CmCV has two dsRNA genome segments; dsRNA-1 is 1592 bp in size, containing a conserved RNA-dependent RNA polymerase (RdRp), and dsRNA-2 is 1715 bp in size, and encodes a coat protein (CP). The sequence alignment and phylogenetic analyses of the CmCV RdRp and CP indicated CmCV clusters with approved or putative deltapartitiviruses in well-supported monophyletic clade. The RdRp of CmCV shared an amino acid sequence identity of 60.7% with the closest RdRp of beet cryptic virus 3, and is <57% identical to other partitiviruses. CmAV1 is a nonsegmented dsRNA virus with a genome of 3424 bp, including two partially overlapping open reading frames (ORFs) encoding a putative CP and RdRp. The sequence alignment and phylogenetic analyses of CmAV1 RdRp revealed that it belongs to the genus Amalgavirus in the family Amalgaviridae. The RdRp of CmAV1 shares 57.7% of its amino acid sequence identity with the most closely related RdRp of Phalaenopsis equestris amalgavirus 1, and is <47% identical to the other reported amalgaviruses. These analyses suggest that CmCV and CmAV1 are novel species in the genera Amalgavirus and Deltapartitivirus, respectively. These findings enrich our understanding of new plant dsRNA virus species.


Efficacy of a penile variable tension loop for improving climacturia after radical prostatectomy.
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Climacturia is present in ∼20-40% of men after radical prostatectomy, and adversely affects sexual satisfaction. Although several strategies have been proposed for the treatment of climacturia, none have been systematically studied to date. This observational study shows that use of a penile variable tension loop can significantly reduce the degree and frequency of orgasm-associated incontinence, and the associated distress experienced by patients and partners. Climacturia resolves completely in half the patients, and occurs occasionally or rarely in the remainder. To define the impact of the use of a penile variable tension loop on climacturia and on the distress level experienced by patients and their partners as a result of climacturia. All patients presenting for sexual function assessment after radical prostatectomy (RP) were questioned regarding climacturia. The study population consisted of men who had undergone RP < 6 months before initial evaluation, had reported having climacturia on ≥25% attempts where orgasm was achieved, had agreed to use the variable tension loop consistently, and continued to have climacturia when not using the loop at follow-up. Patients were interviewed regarding the frequency and degree of climacturia, and their own and their partner's distress levels secondary to climacturia, both with and without the use of the variable tension loop. The study population comprised 124 men. At baseline, the degree of climacturia was small, moderate, and large in 16%, 72%, 12% of patients, respectively, and 28%, 26% and 0%, respectively, at follow-up (all P < 0.01). Climacturia occurred rarely, occasionally, most of the time, or always in 15%, 48%, 16% and 21% of cases, respectively, at baseline, and 48% of patients experienced no climacturia with use of the variable tension loop. Distress was experienced by 14% and 61% of patients and partners at baseline, and 2% and 11% of patients and partners at follow up (P < 0.01). Severity of distress was significantly lower at follow-up for both partners and patients (P < 0.01). Climacturia is a common complication of radical prostatectomy. Application of the variable tension loop can result in a significant decrease in the frequency and volume of climacturia. Use of the variable tension loop is a simple and non-invasive strategy for relieving the distress associated with climacturia in patients who have undergone RP and their partners.


Intentions to Undergo Lung Cancer Screening among Korean Men.
Opportunistic screening for lung cancer is commonly conducted in Korea in accordance with physician recommendations and screenee's preferences. However, studies have yet to thoroughly examine the public's understanding of the risks posed by lung cancer screening. This study was conducted to assess changes in intentions to undergo lung cancer screening in response to being informed about exposure to radiation during low-dose computed tomography (LDCT) tests and to identify factors with the greatest influence thereon among Korean men. We conducted sub-group interviews among men chosen from the 2013 Korea National Cancer Screening Survey (KNCSS), a nationwide, population-based, cross-sectional survey of men aged 40 to 74 years and women aged 30 to 74 years. From 4100 participants in the KNCSS, 414 men who underwent any cancer screening test within the last 2 years were randomly selected for inclusion in this study. Via face-to-face interviews, their intentions to undergo lung cancer screening were assessed before and after being informed about exposure to radiation during LDCT testing. Of the 414 participants, 50% were current smokers. After receiving information on the benefits of the test, 95.1% stated an intention to undergo screening; this decreased to 81.6% after they received information on the harms of the test. The average decrease in intention rate was 35.3%. Smoking status, household income, and education level were not associated with lowered intentions to undergo lung cancer screening. Participants who were older than 60 years old (OR=0.56; 95% CI=0.33-0.96) and those with less concern for radiation exposure (OR=0.56; 95% CI=0.36-0.89) were less likely to lower their screening intentions. The results of this study suggest that there is a need to educate both non-smokers and former smokers on the harms of lung cancer screening.


Skin sparing mastectomy and immediate breast reconstruction: a review.
Skin Sparing Mastectomy (SSM) is widely practised now in major centres which manage large numbers of breast cancer but anxiety still exists over the safety of SSM both from oncological and aesthetic points of view. We aim to review literature to date in SSM and summarise and discuss the current evidence. Studies were identified by an online search of the English language literature in the PubMed database till April 2012 followed by an extensive review of bibliographies from relevant articles. There is abundance of evidence with regards to the safety of SSM both oncologically and aesthetically especially in immediate breast reconstruction. The use of SSM technique broadens the repertoire of oncoplastic techniques and at the same time facilitates such techniques by preserving patient's native skin and anatomical landmarks. SSM is a safe technique providing better cosmetic outcome without compromising oncological safety as per the current evidence. However, prospective data collection of its application in various newer types of reconstructions, and continuing long-term follow-up of current data series would be prudent to evaluate long-term outcomes.


Neoral: the new cyclosporine.
Neoral is an improved formulation of cyclosporine which, through microemulsion technology, provides a more consistent rate of absorption and exposure. If patients are able to take less Neoral and still maintain the same cyclosporine level, there will also be a cost savings involved. A dose reduction of 30% yields pharmacoeconomic savings. With a more consistent rate of absorption, the risks of nephrotoxicity may be reduced.


Brain extracellular fluid protein changes in acute stroke patients.
In vivo human brain extracellular fluids (ECF) of acute stroke patients were investigated to assess the changes in protein levels associated with ischemic damages. Microdialysates (MDs) from the infarct core (IC), the penumbra (P), and the unaffected contralateral (CT) brain regions of patients suffering an ischemic stroke (n = 6) were compared using a shotgun proteomic approach based on isobaric tagging and mass spectrometry. Quantitative analysis showed 53 proteins with increased amounts in the IC or P with respect to the CT samples. Glutathione S-transferase P (GSTP1), peroxiredoxin-1 (PRDX1), and protein S100-B (S100B) were further assessed with ELISA on the blood of unrelated control (n = 14) and stroke (n = 14) patients. Significant increases of 8- (p = 0.0002), 20- (p = 0.0001), and 11-fold (p = 0.0093) were found, respectively. This study highlights the value of ECF as an efficient source to further discover blood stroke markers.


Implicit and explicit memory in amnesia: some explanations and predictions by the TraceLink model.
After a brief overview of some of the characteristics and neuroanatomy of amnesia, a new model of amnesia is described: the TraceLink model. One novel aspect of the model is that it makes specific and testable predictions regarding semantic dementia, a recently described disorder that is viewed here as being related to amnesia. The TraceLink model consists of: a trace system (roughly the neocortix), a link system (hippocampus and adjacent areas), and a modulatory system (certain basal forebrain nuclei). Different forms of learning in the TraceLink model are explained, followed by a discussion of implicit and explicit memory, prominence (ease of recall) and persistence (resistance to brain damage), consolidation, and Ribot gradients in retrograde amnesia. Patterns of recovery from retrograde amnesia are also discussed, and novel predictions are derived regarding implicit memory and various forms of amnesia.


Integrated Metagenomic and Metabolomic Analyses of the Effect of Astragalus Polysaccharides on Alleviating High-Fat Diet-Induced Metabolic Disorders.
Most herbal polysaccharides possess multiple benefits against metabolic disorders, such as non-alcoholic fatty liver disease (NAFLD) and obesity. However, the underlying mechanisms are largely unknown. Here, male C57BL/6J mice were fed with chow or high-fat diet (HFD) with or without Astragalus polysaccharides (APS) supplementation, and gut microbial profile and metabolite profile were studied by metagenomic sequencing and untargeted metabolomics, respectively. APS was effective in alleviating HFD-induced metabolic disorders, with the alteration of gut microbiota composition and function. A total of 188 species, which mainly from Bacteroidetes, Actinobacteria, Firmicutes, and Proteobacteria phyla, and 36 metabolites were markedly changed by HFD and revered by APS. Additionally, the altered glutathione metabolism and purine metabolism pathways were identified by both metagenomic function analysis and metabolite pathway enrichment analysis. Furthermore, the gut microbial alteration was associated with the changes of key intestinal metabolites. We found 31 and 20 species were correlated with purine metabolism and glutathione metabolism, respectively. Together, our results showed significant metagenomic and metabolomic changes after HFD feeding and APS intervention, revealed the potential correlation between gut microbial species and metabolites, and highlighted mechanisms of herb-derived polysaccharides by modulating gut microbiome and host metabolism underlying their benefits on metabolic disorders.


Preparation, structural characterisation and release study of novel hybrid microspheres entrapping nanoselenium, produced by green synthesis.
The main goal of this study was to synthesise and characterise different formulations based on alginate and alginate/chitosan microspheres containing nanoselenium (nano-Se) for controlled delivery applications. Nanosize elemental selenium was produced by using probiotic yogurt bacteria (Lactobacillus casei) in a fermentation procedure. The structural and morphological characterisation of the microspheres was performed by Fourier transform infrared (FTIR), X-ray diffraction (XRD) and scanning electron microscopy (SEM) analysis. FTIR and XRD pattern indicated that was an effective cross-linking of selenium nanoparticles within the polymeric matrix in both cases. The SEM images reveal that selenium nanoparticles are mainly exposed on the surface of alginate, in contrast to porous structure of alginate/chitosan/nano-Se, interconnected in a regular network. This architecture type has a considerable importance in the delivery process, as demonstrated by differential pulse voltammetry. Selenium release from both matrices is pH sensitive. Moreover, chitosan blended with alginate minimise the release of encapsulated selenium, in simulated gastric fluid, and prolong the duration of release in intestinal fluid. The overall effect is the enhancement of total percentage release concomitant with the longer duration of action. The authors' formulation based on alginate/chitosan is a convenient matrix to be used for selenium delivery in duodenum, caecum and colon.


Tuning the Self-Assembled Morphology of Ti3C2Tx MXene-Based Hybrids for High-Performance Electromagnetic Interference Shielding.
Hybrid materials based on transition metal carbide and nitride (MXene) nanosheets have great potential for electromagnetic interference (EMI) shielding due to their excellent electrical conductivity. However, the performance of final products depends not only on the properties of constituent components but also on the morphology of the assembly. Here, via the controlled diffusion of positively charged poly(allylamine hydrochloride) (PAH) chains into the negatively charged Ti3C2Tx MXene suspension, MXene/PAH hybrids in the forms of thin films, porous structures, and fibers with distinguished internal morphologies are obtained. Our results confirm that PAH chains could effectively enhance the oxidation stability and integrity of wet and dry MXene structures. The flexibility to tune the structures allows for a thorough discussion of the relations between the morphology, electrical conductivity, and EMI shielding mechanism of the hybrids in a wide range of electrical conductivity (2.5 to 3347 S·cm-1) and thickness (7.7 to 1900 μm) values. The analysis of thin films shows the direct impact of the polymer content on the alignment and compactness of MXene nanosheets regulating the films' electrical conductivity/EMI shielding effectiveness. The colloidal behavior of the initial MXene suspension determines the interconnection of MXene nanosheets in MXene/PAH porous assemblies and the final electrical properties. In addition to the internal morphology, examining the laminated MXene/PAH fibers with geometrically different arrangements demonstrates the role of conductive network configuration on EMI shielding performance. These findings provide insights into tuning the EMI shielding effectiveness via the charge-driven bottom-up assembly of electrically conductive MXene/polyelectrolyte hybrids.


The key entity of a DCAR agonist, phosphatidylinositol mannoside Ac1PIM1: its synthesis and immunomodulatory function.
Ac1PIM1 is a potential biosynthetic intermediate for phosphatidylinositol mannosides (PIMs) from Mycobacterium tuberculosis. We achieved the first synthesis of Ac1PIM1 by utilizing an allyl-type protecting group strategy and regioselective phosphorylation of inositol. A very potent agonist of an innate immune receptor DCAR, which is better than previously known agonists, is demonstrated.


Primary spinal peripheral primitive neuroectodermal tumour: a report of 3 cases and review of the literature.
Peripheral primitive neuroectodermal tumours (PNETs) are rare and highly malignant tumours in the spine, with a predilection for young adults. There are no standard guidelines for treating these tumours. Surgical resection combined with postoperative radiotherapy and chemotherapy is a common and effective treatment at present. Even so, survival time of patients with these tumours is still very short. In this study, we present three rare cases of thoracic epidural PNETs and review the literature.


Late life: a new frontier for physiology.
Late life is a distinct phase of life that occurs after the aging period and is now known to be general among aging organisms. While aging is characterized by a deterioration in survivorship and fertility, late life is characterized by the cessation of such age-related deterioration. Thus, late life presents a new and interesting area of research not only for evolutionary biology but also for physiology. In this article, we present the theoretical and experimental background to late life, as developed by evolutionary biologists and demographers. We discuss the discovery of late life and the two main theories developed to explain this phase of life: lifelong demographic heterogeneity theory and evolutionary theory based on the force of natural selection. Finally, we suggest topics for future physiological research on late life.


Locally advanced small-bowel adenocarcinoma missed primarily by capsule endoscopy but diagnosed by push enteroscopy.
Wireless-capsule-endoscopy is a new painless method that is able both to visualize the entire small bowel and to detect even small lesions. We report here the case of a patient in whom a locally advanced small-bowel adenocarcinoma was initially missed on capsule endoscopy, but was diagnosed by subsequent push enteroscopy. Capsule endoscopy was carried out in a 47-year-old patient with a history of obscure gastrointestinal bleeding, iron-deficiency anemia, and a lack of symptoms suggestive of stenosis. The capsule imaging revealed angiodysplasias in the jejunum, but no other abnormalities. Push enteroscopy was carried out to allow argon plasma coagulation treatment of the angiodysplasias that had been detected; it revealed a polypoid tumor 20 mm in diameter at 150 cm from the incisors, with the capsule endoscope still located proximal to the tumor and with its optical dome turned towards the push enteroscope. Clinical staging and subsequent surgical resection showed a locally advanced adenocarcinoma (pT4, pN0 (0/7), pMx, G3).[nl]Small-bowel tumors within the reach of push enteroscopy may be missed by capsule endoscopy. Although wireless capsule endoscopy is a major advance in the investigation of the small bowel, well-designed clinical studies still need to define the precise algorithm for diagnostic work-up of suspected small-bowel diseases.


Commentary: UK perspective on competency to stand trial.
This commentary offers a perspective from another common law jurisdiction, specifically the law in England and Wales, where competency to stand trial on a criminal charge is known as fitness to plead. The commentary begins with a discussion on the principle of proportionality evident in health care decisions by way of comparison with the topic in the criminal arena. Fitness to plead is an historical legal concept and employs an intellectual test that has evolved very little since its appearance in case law. There have been amendments, through statute, to its procedure and outcomes following a determination of being unfit to plead. However, competency to stand trial in England and Wales remains a more marginal issue than in the United States. Recent developments in domestic and European jurisprudence have been related to consideration of the requirements for a fair trial, driven by the demands of the European Convention on Human Rights.


Infant color vision: moving tritan stimuli do not elicit directionally appropriate eye movements in 2- and 4-month-olds.
The purpose of the present study was to investigate the capacity of infants to code the direction of motion of moving tritan-modulated gratings. Infant and adult subjects were tested with 0.2 c/d sinusoidal gratings moving at a speed of 20 deg/sec. Three conditions were tested: luminance-modulated gratings, tritan-modulated gratings, and luminance- vs tritan-modulated gratings superimposed and moving in opposite directions in a chromatic motion nulling paradigm. Two-month-old infants were tested in all three conditions, while 4-month-olds were tested in only the first two conditions. For infant subjects, an adult observer reported the direction of the slow phase of the infant's eye movements; adult subjects judged the perceived direction of motion of the stimuli. Luminance-modulated gratings produced directionally appropriate eye movements (DEM) in all age groups. Tritan gratings presented alone did not produce DEM in either 2- or 4-month-olds, but did so in adults. Mean equivalent luminance contrasts were near zero in 2-month-olds, and small but reliably above zero in adults. In sum, the present study provides no evidence that infants can code the direction of motion of moving tritan gratings.


The Influence of Black Identity on Wellbeing and Health Behaviors.
The aim of this study was to investigate the influence of Black identity on wellbeing and health behaviors. Data from the third year (wave) of a longitudinal cohort study (N = 1316) from a large, majority Black, Protestant church of 16,000 members located in Houston, Texas, were used to conduct secondary data analyses. Univariate analyses were used to obtain participants' sociodemographic and health characteristics. ANCOVA and linear regression analyses and Bonferroni adjustments were used to examine the influence of the centrality, public and private regard aspects of Black identity as measured by the Multidimensional Inventory of Black Identity subscales on wellbeing (CES-D scores and self-reported general health) and health behaviors (diet and physical activity levels). Associations were noted between fruit consumption and centrality (F (95,1216) = 2.27) p = .046); soda consumption and private regard (F (5,1214) = 3.04; p = .010); public regard (F (2,1186) = 4.70; p = .009) and physical activity levels; self-reported general health status and private (F (4,1219) = 4.78; p = .001) and public regard (F (4,1211) = 8.53; p < .001). Psychological wellbeing was negatively associated with regard (private (B = -0.030; p < .001) and public regard (B = -0.060; p < .001)). Findings suggest that racial identity remain an important factor to consider in addressing health disparities. Racial identity influences mental health, general health, diet and the physical activity levels. Utilizing identity congruent health promotion interventions may positively impact mental, exercise levels, self-reported general health and diet.


Determination of free and total levels of phenytoin in human plasma from patients with epilepsy by MEKC: an adequate alternative to HPLC.
Phenytoin is a widely used anti-seizure agent, and a good correlation is observed between its concentration in plasma and the clinical effect. We developed a selective CE with UV detection at 200 nm for analysis of free and total levels of phenytoin in human plasma based on MEKC. A sample pretreatment by liquid-liquid extraction with ethyl acetate for determination of total level of phenytoin and serum ultrafiltrate was prepared by ultrafiltration technique (ultrafiltration membrane 30 kDa; 2000 g, 10 min) for determination of free level of phenytoin and subsequent quantification by MEKC was used. MEKC was performed in Tris buffer (25 mM; pH 10.5) containing SDS (180 mM) and EG (13%) as BGE. Hydrodynamic injection for phenytoin determination (0.5 psi 5 s for total level, 2 psi 5 s for free level) was used to introduce samples. The separation voltage was set at 20 kV. Data obtained by MEKC were compared with the results by a validated HPLC method. The MEKC assay of phenytoin exhibited a very good correlation with respect to HPLC by Bland-Altman method. The equations for the Passing-Bablok regression line were as follows: for total level: MEKC=1.0143 x HPLC+0.0976, r(2)=1; for free level: MEKC=1.0013 x HPLC-0.0016, r(2)=1. The proposed method was applied successfully to monitor free and total levels of phentoin in 20 patients with seizures.


Efficacy and safety of daily treatments for drug-susceptible pulmonary tuberculosis: a systematic review and network meta-analysis.
To evaluate and update the evidence on the comparative efficacy and safety of antimicrobial drugs regimens for treating pulmonary drug-susceptible tuberculosis (DS-TB). A systematic review was performed with searches in PubMed and Scopus (PROSPERO-CRD42019141463). We included randomised controlled trials comparing the effect of any antimicrobial regimen lasting at least 2 weeks. The outcomes of interest were culture conversion and incidence of adverse events. Bayesian network meta-analyses and surface under the cumulative ranking curve (SUCRA) analyses were performed. Results were reported as odds ratio with 95% credibility intervals. Fifteen studies were included the meta-analysis (n = 7560 patients). No regimen was statistically more effective than the WHO standard approach (rifampicin, isoniazid, ethambutol, and pyrazinamide). The use of rifapentine 450 mg instead of rifampicin in the standard regimen demonstrated to be statistically safer than all other options for serious adverse events (e.g. hepatotoxicity, arthralgia) (OR ranging from 0.0 [Crl 0.00-0.04] to 0.0 [0.00-0.97]; SUCRA probabilities of 10%). Therapies containing rifapentine (Rp1500HEZ, Rp900HEZ) and moxifloxacin (RMEZ, RHMZ) are effective regarding culture conversion, but statistical uncertainty on their safety profile exists. The WHO standard regimen remains an overall effective and safe alternative for DS-TB. For intensive phase treatments, drugs combinations with rifapentine and moxifloxacin seem to reduce treatment duration while maintaining efficacy.


Purification and membrane reconstitution of catalytically active Menkes copper-transporting P-type ATPase (MNK; ATP7A).
The MNK (Menkes disease protein; ATP7A) is a major copper- transporting P-type ATPase involved in the delivery of copper to cuproenzymes in the secretory pathway and the efflux of excess copper from extrahepatic tissues. Mutations in the MNK (ATP7A) gene result in Menkes disease, a fatal neurodegenerative copper deficiency disorder. Currently, detailed biochemical and biophysical analyses of MNK to better understand its mechanisms of copper transport are not possible due to the lack of purified MNK in an active form. To address this issue, we expressed human MNK with an N-terminal Glu-Glu tag in Sf9 [Spodoptera frugiperda (fall armyworm) 9] insect cells and purified it by antibody affinity chromatography followed by size-exclusion chromatography in the presence of the non-ionic detergent DDM (n-dodecyl beta-D-maltopyranoside). Formation of the classical vanadate-sensitive phosphoenzyme by purified MNK was activated by Cu(I) [EC50=0.7 microM; h (Hill coefficient) was 4.6]. Furthermore, we report the first measurement of Cu(I)-dependent ATPase activity of MNK (K0.5=0.6 microM; h=5.0). The purified MNK demonstrated active ATP-dependent vectorial 64Cu transport when reconstituted into soya-bean asolectin liposomes. Together, these data demonstrated that Cu(I) interacts with MNK in a co-operative manner and with high affinity in the sub-micromolar range. The present study provides the first biochemical characterization of a purified full-length mammalian copper-transporting P-type ATPase associated with a human disease.


Two-dimensional Brownian motion of anisotropic dimers.
We study the two-dimensional motion of colloidal dimers by single-particle tracking and compare the experimental observations obtained by bright-field microscopy to theoretical predictions for anisotropic diffusion. The comparison is based on the mean-square displacements in the laboratory and particle frame as well as generalizations of the self-intermediate scattering functions, which provide insights into the rotational dynamics of the dimer. The diffusional anisotropy leads to a measurable translational-rotational coupling that becomes most prominent by aligning the coordinate system with the initial orientation of the particles. In particular, we find a splitting of the time-dependent diffusion coefficients parallel and perpendicular to the long axis of the dimer which decays over the orientational relaxation time. Deviations of the self-intermediate scattering functions from pure exponential relaxation are small but can be resolved experimentally. The theoretical predictions and experimental results agree quantitatively.


Genetic studies in Ecuador: acetylator phenotypes, red cell enzyme and serum protein polymorphisms of Shuara Indians.
Population genetic studies of Shuara Indians in Ecuador are performed for GPT, AP, PGM1, Ak, EsD, 6-PGD, Hp, Gc, C3, Bg, ChE, Tf, Pi, Bf phenotypes, IgG, IgA, IgM, C3, C3-proactivator, C4 levels and acetylator phenotypes. Some systems having a polymorphism in many other populations showed a lack of some of those alleles in the population under study (C3, ChE, Tf, AK and almost absent 6-PGD, Bg, Bf).


IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice.
The effect of an IL-1 receptor antagonist on recurrence of hyperglycaemia after syngeneic pancreatic islet transplantation to spontaneously diabetic female NOD mice was investigated. The transplanted animals were treated with either the receptor antagonist (8.0 mg/kg body weight per day for 12-14 days) or PBS, delivered by subcutaneously implanted osmotic pumps. In the control animals, a transient normoglycaemia was achieved, but hyperglycaemia was generally observed 6 days after islet transplantation. Administration of IL-1 receptor antagonist had a clear protective effect against recurrence of hyperglycaemia until day 14, but after cessation of drug delivery hyperglycaemia re-appeared. The results indicate that continuous administration of the IL-1 receptor antagonist can prevent recurrence of the diabetogenic process in NOD mice. IL-1 receptor antagonist may therefore become a useful adjuvant immunomodulating therapy after human islet transplantation in insulin-dependent diabetes mellitus.


A novel method to increase specificity of sleep-wake classifiers based on wrist-worn actigraphy.
The knowledge of the distribution of sleep and wake over a 24-h day is essential for a comprehensive image of sleep-wake rhythms. Current sleep-wake scoring algorithms for wrist-worn actigraphy suffer from low specificities, which leads to an underestimation of the time staying awake. The goal of this study (ClinicalTrials.gov Identifier: NCT03356938) was to develop a sleep-wake classifier with increased specificity. By artificially balancing the training dataset to contain as much wake as sleep epochs from day- and nighttime measurements from 12 subjects, we optimized the classification parameters to an optimal trade-off between sensitivity and specificity. The resulting sleep-wake classifier achieved high specificity of 80.4% and sensitivity of 88.6% on the balanced dataset containing 3079.9 h of actimeter data. In the validation on night sleep of separate adaptation recordings from 19 healthy subjects, the sleep-wake classifier achieved 89.4% sensitivity and 64.6% specificity and estimated accurately total sleep time and sleep efficiency with a mean difference of 12.16 min and 2.83%, respectively. This new, device-independent method allows to rid sleep-wake classifiers from their bias towards sleep detection and lay a foundation for more accurate assessments in everyday life, which could be applied to monitor patients with fragmented sleep-wake rhythms.


The effect of high broiler litter diets as survival ration on the health of sheep.
The use of broiler litter as an emergency feed during droughts and other periods of feed shortages was evaluated in terms of its effect on the health of sheep. Pure broiler litter (i.e. excreta plus wood shavings), and litter mixed with 7.5 or 15% molasses were fed for 83 days to 2-year-old wethers. The addition of molasses to the litter caused a significant increase (p < 0.01) in feed intake and final body mass. Various parameters such as plasma enzyme activity, plasma metabolite concentrations and urine mineral and purine excretion did not differ among treatments. Histological evaluation revealed no liver or kidney pathology. Mild myocardial pathology was observed in all 3 treatment groups. This seems to be related to the presence of the ionophore-based coccidiostat, narasin, which was present in the litter at a concentration of 10 mg/kg. It is suggested that these histological lesions are of little practical significance and would not affect the health of sheep being fed the broiler litter as a survival feed.


Optimizing Lipofectamine LTX Complex and G-418 Concentration for Improvement of Transfection Efficiency in Human Mesenchymal Stem Cells.
Conventional cancer therapies, including surgery, radiotherapy, and chemotherapy, are not tumor site-specific and have cytotoxic and harmful side effects for normal cells. Mesenchymal stem cells (MSCs), due to their tumor-tropism migration property, are a promising alternative to deliver and produce antitumor agents. However, MSCs are difficult-to-transfect cells, and introducing the exogenous therapeutic gene into MSCs is challenging yet needs improvement. Transfection using chemical reagents, including Lipofectamine, is more convenient and less cytotoxic compared with different methods of introducing exogenous DNA into MSCs. Nonetheless, the major limitation of Lipofectamine is low transfection efficiency in MSCs. Therefore, the purpose of this study was to evaluate and suggest the optimum quantities of lipoplex components to enhance the transfection efficiency of human adipose tissue-derived MSCs (hASCs). Finding the best transgene expression time point and the optimum concentration of G-418 for antibiotic-based selection was another goal of this study. hASCs were transfected in a series of experiments with altering the quantities of Lipofectamine LTX® (Lip-LTX), the related "PLUS" reagent, and a plasmid DNA (pDNA) expressing the enhanced green fluorescent protein (eGFP). After transfection, the percentage of eGFP-expressing cells was evaluated using fluorescence microscopy and ImageJ software in 12-hour intervals for 48 hours. Also, the viability of hASCs exposed to different concentrations of G-418 was measured using an MTT assay. The results demonstrated that a combination of 2 µL Lip-LTX, 0.75 µL of its "PLUS" reagent, and 0.75 g pDNA (6484 bp) improve the transfection efficiency of hASCs (23.75%), and the best period for evaluation of fluorescence for these cells is 12 to 24h post-transfection. Also, the optimum concentration of G-418 for antibiotic-based selection of hASCs was 0.25mg/mL. In conclusion, this study indicates that the setting up of optimized quantities of lipoplex components and the golden time of evaluation for transgene expression could increase the possibility of transgene expression in hASCs before beginning research and clinical application. Also, the definition of optimal dose of selection antibiotic for purification of transfected hASCs seems to be necessary for maximum transgene expression effects in the cell population.


Extensive Scalp Melanoma in an Elderly Female: A Case Report and Literature Review.
Scalp melanoma is a rare and aggressive form of skin cancer. Its occurrence in the elderly population poses unique challenges due to factors such as delayed diagnosis and comorbidities. We present a case of extensive scalp melanoma in an elderly female to highlight the clinical presentation, diagnostic process, treatment modalities, and outcomes. Biopsy and histopathological analysis showed the presence of dysplastic nevi arising in pigmented melanocytic nevi, with uncertain pagetoid spread of atypical melanocytes. The management involved complete excision with safety margins and immunotherapy based on melanoma guidelines. This case underscores the importance of early detection and tailored treatment strategies in managing melanoma in elderly patients.