The major clades of Loasaceae: phylogenetic analysis using the plastid matK and trnL-trnF regions.
Phylogenetic analyses of Loasaceae that apply DNA sequence data from the plastid trnL-trnF region and matK gene in both maximum-parsimony and maximum-likelihood searches are presented. The results place subfamily Loasoideae as the sister of a subfamily Gronovioideae-Mentzelia clade. Schismocarpus is the sister of the Loasoideae-Gronovioideae-Mentzelia clade. The Schismocarpus-Loasoideae-Gronovioideae-Mentzelia clade is the sister of Eucnide. Several clades in Loasoideae receive strong support, providing insights on generic circumscription problems. Within Mentzelia, several major clades receive strong support, which clarifies relationships among previously circumscribed sections. Prior taxonomic and phylogenetic hypotheses are modeled using topology constraints in parsimony and likelihood analyses; tree lengths and likelihoods, respectively, are compared from constrained and unconstrained analyses to evaluate the relative support for various hypotheses. We use the Shimodaira-Hasegawa (SH) test to establish the significance of the differences between constrained and unconstrained topologies. The SH test rejects topologies based on hypotheses for (1) the placement of gronovioids as the sister of the rest of Loasaceae, (2) the monophyly of subfamily Mentzelioideae as well as Gronovioideae and Loasoideae, (3) the monophyly of Loasa sensu lato as circumscribed by Urban and Gilg, and (4) the monophyly of Mentzelia torreyi and Mentzelia sect. Bartonia.


[Sensitive to change: neuroendocrinologic aspects of depression in women].
Depression is more prevalent among women than among men. There are several possible explanations for this. There are indications that the aetiology of this difference in prevalence has to do with fluctuations in the oestrogen level, which are a feature of the female reproductive system. The influence of oestrogens on the hypothalamic-pituitary-adrenal axis may play an important role. To cast light on the deregulating influence of oestrogen on the hypothalamic-pituitary-adrenal axis. This deregulation could lead to depression in a subgroup of women with a neuroendocrine stress response that is sensitive to hormonal fluctuations. PubMed was used to review the literature on the basis of the key words 'depression', 'estrogen', 'gender', 'gonadal hormones', 'hpa axis', 'stress' and 'women'. Deregulation of the hypothalamic-pituitary-adrenal axis plays a role in the aetiology of major depression. On the one hand, oestrogens stimulate the activity of this system. On the other hand, a lowering of the endogenous oestrogen level seems to be accompanied by reduced activity of the hypothalamic-pituitary-adrenal axis. Changing oestrogen levels characterise the female reproductive system. It is these changing levels--not the absolute oestrogen level--which have the potential to deregulate the hypothalamic-pituitary-adrenal axis.


Survival defects of Cryptococcus neoformans mutants exposed to human cerebrospinal fluid result in attenuated virulence in an experimental model of meningitis.
Cryptococcus neoformans is a fungal pathogen that encounters various microenvironments during growth in the mammalian host, including intracellular vacuoles, blood, and cerebrospinal fluid (CSF). Because the CSF is isolated by the blood-brain barrier, we hypothesize that CSF presents unique stresses that C. neoformans must overcome to establish an infection. We assayed 1,201 mutants for survival defects in growth media, saline, and human CSF. We assessed CSF-specific mutants for (i) mutant survival in both human bronchoalveolar lavage (BAL) fluid and fetal bovine serum (FBS), (ii) survival in macrophages, and (iii) virulence using both Caenorhabditis elegans and rabbit models of cryptococcosis. Thirteen mutants exhibited significant survival defects unique to CSF. The mutations of three of these mutants were recreated in the clinical serotype A strain H99: deletions of the genes for a cation ATPase transporter (ena1Δ), a putative NEDD8 ubiquitin-like protein (rub1Δ), and a phosphatidylinositol 4-kinase (pik1Δ). Mutant survival rates in yeast media, saline, and BAL fluid were similar to those of the wild type; however, survival in FBS was reduced but not to the levels in CSF. These mutant strains also exhibited decreased intracellular survival in macrophages, various degrees of virulence in nematodes, and severe attenuation of survival in a rabbit meningitis model. We analyzed the CSF by mass spectrometry for candidate compounds responsible for the survival defect. Our findings indicate that the genes required for C. neoformans survival in CSF ex vivo are necessary for survival and infection in this unique host environment.


Interactive preventive health record to enhance delivery of recommended care: a randomized trial.
Americans receive only one-half of recommended preventive services. Information technologies have been advocated to engage patients. We tested the effectiveness of an interactive preventive health record (IPHR) that links patients to their clinician's record, explains information in lay language, displays tailored recommendations and educational resources, and generates reminders. This randomized controlled trial involved 8 primary care practices. Four thousand five hundred patients were randomly selected to receive a mailed invitation to use the IPHR or usual care. Outcomes were measured using patient surveys and electronic medical record data and included IPHR use and service delivery. Comparisons were made between invited and usual-care patients and between users and nonusers among those invited to use the IPHR. At 4 and 16 months, 229 (10.2%) and 378 (16.8%) of invited patients used the IPHR. The proportion of patients up-to-date with all services increased between baseline and 16 months by 3.8% among intervention patients (from 11.4% to 15.2%, P <.001) and by 1.5% among control patients (from 11.1% to 12.6%, P = .07), a difference of 2.3% (P = .05). Greater increases were observed among patients who used the IPHR. At 16 months, 25.1% of users were up-to-date with all services, double the rate among nonusers. At 4 months, delivery of colorectal, breast, and cervical cancer screening increased by 19%, 15%, and 13%, respectively, among users. Information systems that feature patient-centered functionality, such as the IPHR, have potential to increase preventive service delivery. Engaging more patients to use systems could have important public health benefits.


Methods of performance analysis in team invasion sports: A systematic review.
The objective of this review was to systematically describe the traditional and contemporary data capture and analytic methods employed in performance analysis research in team invasion sports, evaluate the practicality of these methods, and formulate practical recommendations on methods for analysing tactics and strategies in team invasion sports. A systematic search of the databases SPORTDiscus, Web of Science, Scopus, MEDLINE and PubMed was performed. Keywords addressed performance analysis methods and team invasion sports, with all other disciplines of sports science excluded. A total of 537 articles were included in the review and six main themes of research identified. Themes included game actions, dynamic game actions, movement patterns, collective team behaviours, social network analysis and game styles. Performance analysis research has predominantly focused on identifying key performance indicators related to success by analysing differences in game actions between successful and less successful teams. However, these measures are outcome-focused and only provide limited insight into winning team's strategy. Team invasion sports are now viewed as dynamic, complex systems with opposing teams as interacting parts. Strategies and tactics should be analysed using a holistic process-orientated approach by recording dynamic actions, collective team behaviours and passing networks, and viewing them in game styles.


Short-term morbidity and acceptability of 125iodine implantation for localized carcinoma of the prostate.
To report the short-term morbidity and acceptability of the first 50 patients treated with the percutaneous implantation of radioactive iodine seeds for localized carcinoma of the prostate at the Cookridge Hospital. Fifty patients were treated with transrectal ultrasonography-guided percutaneous implants with radioactive (125I) iodine seeds for localized carcinoma of the prostate. The mean hospital stay was 36 h and most patients were able to return to work or normal activity within one week of implantation. All patients developed urethritis which was most marked within the first 3 months of treatment; 8% of patients developed acute retention which resolved after temporary catheterization. At 3 months, 36% of patients still had moderate frequency and 18% moderate dysuria, but by 12 months these had resolved and only 5% of patients still complained of moderate nocturia. There were no cases of incontinence. The incidence of proctitis was very low, with only 2% still complaining of moderate symptoms at one year. Of those potent before implantation, 72% retained potency at one year. Although it is too early to comment either on late morbidity or on outcome, the results of this study show a side-effect profile similar to that reported by other centres using the same technique.


Lessons learnt from carotid artery trials.
The objective of the authors is to assess the natural history of carotid artery disease and the role of carotid intervention in preventing ipsilateral stroke. The development of endovascular techniques for correction of carotid artery stenoses made this less invasive technique very popular, with an inherent risk of unregulated overuse by a variety of medical specialists, who are not always well informed on the natural history of carotid artery disease. It re-opened the discussion on the value of carotid endarterectomy for stroke prophylaxis. This ongoing debate offers the opportunity to distil evidence-based guidelines for the management of extracranial carotid artery stenoses. In recent papers, some authors expressed doubts on the validity and general applicability of the results of the pivotal randomised trials of carotid endarterectomy. The excellent results in terms of operative outcome and long term stroke prevention would, according to certain comments, not be attainable in routine practice. Another criticism of carotid endarterectomy is its higher operative morbidity in terms of cranial nerve lesions and myocardial infarctions, compared to endovascular procedures. This consideration is, for some authors, the main reason to espouse carotid artery stenting as a better alternative to carotid endarterectomy. Any evidence supporting this point of view is missing. The supposed equivalence or non-inferiority of carotid artery stenting is purely speculative. The aim of this review paper is to summarize the crude data of carotid surgery trials. The authors aim to answer four questions. For which lesions is carotid endarterectomy most beneficial ? Are the results of randomised carotid surgery trials biased by the selection of patients ? Is operative morbidity, other than stroke, under-estimated ? Is carotid artery stenting safe and efficacious ? An in-depth review with a critical analysis is made of recently published and on-going trials, comparing carotid surgery with percutaneous carotid angioplasty.


The impact of the COVID-19 pandemic on radiotherapy services in England, UK: a population-based study.
The indirect impact of the COVID-19 pandemic on cancer outcomes is of increasing concern. However, the extent to which key treatment modalities have been affected is unclear. We aimed to assess the impact of the pandemic on radiotherapy activity in England. In this population-based study, data relating to all radiotherapy delivered for cancer in the English NHS, between Feb 4, 2019, and June 28, 2020, were extracted from the National Radiotherapy Dataset. Changes in mean weekly radiotherapy courses, attendances (reflecting fractions), and fractionation patterns following the start of the UK lockdown were compared with corresponding months in 2019 overall, for specific diagnoses, and across age groups. The significance of changes in radiotherapy activity during lockdown was examined using interrupted time-series (ITS) analysis. In 2020, mean weekly radiotherapy courses fell by 19·9% in April, 6·2% in May, and 11·6% in June compared with corresponding months in 2019. A relatively greater fall was observed for attendances (29·1% in April, 31·4% in May, and 31·5% in June). These changes were significant on ITS analysis (p<0·0001). A greater reduction in treatment courses between 2019 and 2020 was seen for patients aged 70 years or older compared with those aged younger than 70 years (34·4% vs 7·3% in April). By diagnosis, the largest reduction from 2019 to 2020 in treatment courses was for prostate cancer (77·0% in April) and non-melanoma skin cancer (72·4% in April). Conversely, radiotherapy courses in April, 2020, compared with April, 2019, increased by 41·2% in oesophageal cancer, 64·2% in bladder cancer, and 36·3% in rectal cancer. Increased use of ultra-hypofractionated (26 Gy in five fractions) breast radiotherapy as a percentage of all courses (0·2% in April, 2019, to 60·6% in April, 2020; ITS p<0·0001) contributed to the substantial reduction in attendances. Radiotherapy activity fell significantly, but use of hypofractionated regimens rapidly increased in the English NHS during the first peak of the COVID-19 pandemic. An increase in treatments for some cancers suggests that radiotherapy compensated for reduced surgical activity. These data will assist health-care providers in understanding the indirect consequences of the pandemic and the role of radiotherapy services in minimising these consequences. None.


Metabolic studies of hypoxia-inducible factor stabilisers IOX2, IOX3 and IOX4 (in vitro) for doping control.
The transcriptional activator hypoxia-inducible factor (HIF) is a vital arbitrator in the performance of cellular responses lacking oxygen supply in aerobic organisms. Because these compounds are capable of enhancing the organism's capacity for molecular oxygen transport, they possess great potential for abuse as a performance-enhancing agent in sports. A comprehensive study of the metabolic conversion of the most popular HIF stabilisers such as IOX2, IOX3 and IOX4 using equine liver microsomes (in vitro) is reported. The parents and their metabolites were identified and characterised by liquid chromatography-mass spectrometry in negative ionisation mode using a QExactive high-resolution mass spectrometer. Under the current experimental condition, a total of 10 metabolites for IOX2 (three phase I and seven phase II), nine metabolites for IOX3 (four phase I and five phase II) and five metabolites for IOX4 (three phase I and two phase II) were detected. The outcome of the present study is as follows: (1) all the three IOX candidates are prone to oxidation, results in subsequent monohydroxylated, and some dihydroxylated metabolites. (2) Besides oxidation, there is a possibility of hydrolysis and de-alkylation, which results in corresponding carboxylic acid and amide, respectively. (3) The glucuronide and sulphate conjugate of the parent drugs as well as the monohydroxylated analogues were observed in this study. The characterised in vitro metabolites can potentially serve as target analytes for doping control analysis.


Pointing and tracking errors due to localized deformation in inter-satellite laser communication links.
Instead of Zernike polynomials, ellipse Gaussian model is proposed to represent localized wave-front deformation in researching pointing and tracking errors in inter-satellite laser communication links, which can simplify the calculation. It is shown that both pointing and tracking errors depend on the center deepness h, the radiuses a and b, and the distance d of the Gaussian distortion and change regularly as they increase. The maximum peak values of pointing and tracking errors always appear around h=0.2lambda. The influence of localized deformation is up to 0.7microrad for pointing error, and 0.5microrad for tracking error. To reduce the impact of localized deformation on pointing and tracking errors, the machining precision of optical devices, which should be more greater than 0.2?, is proposed. The principle of choosing the optical devices with localized deformation is presented, and the method that adjusts the pointing direction to compensate pointing and tracking errors is given. We hope the results can be used in the design of inter-satellite lasercom systems.


Chemotaxonomic significance of the terpene composition in natural populations of Pinus nigra J.F.Arnold from Serbia.
The essential-oil variability in seven native populations belonging to different infraspecific taxa of Pinus nigra (ssp. nigra, var. gocensis, ssp. pallasiana, and var. banatica) growing wild in Serbia was analyzed. In the needles of 195 trees from seven populations, 58 essential-oil components were identified. The major components were α-pinene (43.6%) and germacrene D (29.8%), comprising together 73.4% of the total oil composition. Based on the average chemical profile of the main terpene components (with contents >5%), the studied populations were found to be the most similar to populations from central Italy and Greece (ssp. nigra). Cluster analysis showed the division of the populations into three principal groups: the first group consisted of Populations I, II, III, IV, and V (considered as ssp. nigra group), the second of Population VI (ssp. pallasiana group), and the third of Population VII, which had the most distinct oil composition (ssp. banatica group). The taxonomic implications of the essential-oil profiles of the investigated taxa of this very complex species are discussed.


Stone-throwing by Japanese macaques: form and functional aspects of a group-specific behavioral tradition.
Throwing is a major behavioral component of hominid evolution. Comparison of this behavior across a broad range of non-human primate species is needed to elucidate the phylogenetic constraints on throwing behavior. In this study of stone-throwing in Japanese macaques, we present a systematic multi-group comparison of the frequency and prevalence of this behavior as well as detailed descriptions and quantitative data on the form, context, and possible social transmission of stone-throwing. Stone-throws were mainly underarm, performed from a tripedal posture, and often accompanied by repeated vertical leaps. We found marked individual hand preferences for throwing, but no consistent group-level handedness. Our results support the hypotheses relating body posture, throwing style, and handedness in throwing by primates. Based on the analysis of the contexts that may elicit the behavior, we postulate that unaimed stone-throwing in Japanese macaques may serve to augment the effect of agonistic displays, and accordingly, can be regarded as spontaneous tool-use. Our findings are consistent with the comparative data using modern non-human primate species to model the structural processes and functional aspects of throwing evolution in early hominids. This study supports the view that tool-use evolves from initially non-functional behaviors, such as stone handling, which is a form of object play. Stone-throwing by Japanese macaques meets several criteria of a behavioral tradition, including group-specificity. This first report of a stone-tool-use tradition in Japanese macaques is of direct relevance to the question of the evolution of stone technology in hominids.


Randomized controlled trial of transoral incisionless fundoplication vs. proton pump inhibitors for treatment of gastroesophageal reflux disease.
Transoral incisionless fundoplication (TIF) was developed in an attempt to create a minimally invasive endoscopic procedure that mimics antireflux surgery. The objective of this trial was to evaluate effectiveness of TIF compared with proton pump inhibition in a population consisting of gastroesophageal reflux disease (GERD) patients controlled with proton pump inhibitors (PPIs) who opted for an endoscopic intervention over lifelong drug dependence. Patients with chronic GERD were randomized (2:1) for TIF or continuation of PPI therapy. American Society of Anesthesiologists >2, body mass index >35 kg/m(2), hiatal hernia >2 cm, and esophageal motility disorders were exclusion criteria. Primary outcome measure was GERD-related quality of life. Secondary outcome measures were esophageal acid exposure, number of reflux episodes, PPI usage, appearance of the gastroesophageal valve, and healing of reflux esophagitis. Crossover for the PPI group was allowed after 6 months. A total of 60 patients (TIF n=40, PPI n=20, mean body mass index 26 kg/m(2), 37 male) were included. At 6 months, GERD symptoms were more improved in the TIF group compared with the PPI group (P<0.001), with a similar improvement of distal esophageal acid exposure (P=0.228) compared with baseline. The pH normalization for TIF group and PPI group was 50% and 63%, respectively. All patients allocated for PPI treatment opted for crossover. At 12 months, quality of life remained improved after TIF compared with baseline (P<0.05), but no improvement in esophageal acid exposure compared with baseline was found (P=0.171) and normalization of pH was accomplished in only 29% in conjunction with deteriorated valve appearances at endoscopy and resumption of PPIs in 61%. Although TIF resulted in an improved GERD-related quality of life and produced a short-term improvement of the antireflux barrier in a selected group of GERD patients, no long-term objective reflux control was achieved.


The muscle hypothesis: a model of chronic heart failure appropriate for osteopathic medicine.
Chronic heart failure is one of the most serious medical problems in the United States, affecting some 4 million persons. In spite of its common occurrence, and comprehensive literature regarding this condition, no unifying hypothesis has been accepted to explain the signs and symptoms of chronic heart failure. The cardiocirculatory and neurohormonal models place an emphasis on left ventricular ejection fraction and cardiac output and do not provide appropriate explanations for the symptoms of breathlessness and fatigue. The muscle hypothesis supplements these conventional models. It proposes that abnormal skeletal muscle in heart failure results in activation of muscle ergoreceptors, leading to an increase in ventilation and sensation of breathlessness, the perception of fatigue, and sympathetic activation. At least one fourth of patients with chronic heart failure are limited by skeletal muscle abnormalities rather than cardiac output. Cardiac rehabilitation exercise can lead to an increase in exercise capacity that is superior to that gained from digitalis or angiotensin-converting enzyme inhibitors. Exercise tends to reverse the skeletal muscle myopathy of chronic heart failure and reduces the abnormal ergoreflex. Other interventions that have been shown to have a favorable outcome include localized muscle group training, respiratory muscle training, and dietary approaches. The possibility that osteopathic manipulative treatment might be of benefit is an attractive, but untested, possibility.


The impact of migration and antimicrobial resistance on the transmission dynamics of typhoid fever in Kathmandu, Nepal: A mathematical modelling study.
A substantial proportion of the global burden of typhoid fever occurs in South Asia. Kathmandu, Nepal experienced a substantial increase in the number of typhoid fever cases (caused by Salmonella Typhi) between 2000 and 2003, which subsequently declined but to a higher endemic level than in 2000. This epidemic of S. Typhi coincided with an increase in organisms with reduced susceptibility against fluoroquinolones, the emergence of S. Typhi H58, and an increase in the migratory population in Kathmandu. We devised a mathematical model to investigate the potential epidemic drivers of typhoid in Kathmandu and fit this model to weekly data of S. Typhi cases between April 1997 and June 2011 and the age distribution of S. Typhi cases. We used this model to determine if the typhoid epidemic in Kathmandu was driven by heightened migration, the emergence of organisms with reduced susceptibility against fluoroquinolones or a combination of these factors. Models allowing for the migration of susceptible individuals into Kathmandu alone or in combination with the emergence of S. Typhi with reduced susceptibility against fluoroquinolones provided a good fit for the data. The emergence of organisms with reduced susceptibility against fluoroquinolones organisms alone, either through an increase in disease duration or increased transmission, did not fully explain the pattern of S. Typhi infections. Our analysis is consistent with the hypothesis that the increase in typhoid fever in Kathmandu was associated with the migration of susceptible individuals into the city and aided by the emergence of reduced susceptibility against fluoroquinolones. These data support identifying and targeting migrant populations with typhoid immunization programmes to prevent transmission and disease.


Idiopathic immune-mediated polysynovitis in three horses.
This paper describes the clinical, laboratory and histological findings in three horses with immune-mediated polysynovitis; they had lost weight, suffered intermittent fever, were lethargic and stiff, and had effusions in several joints. Laboratory abnormalities included anaemia, leucocytosis, hyperfibrinogenaemia and hyperglobulinaemia. The diagnosis was based on the presence of a suppurative, non-septic inflammation in at least two different joints in each of the horses and the presence of immunoglobulins in the synovial membrane of one of them. The horses were treated with a combination of dexamethasone and azathioprine, and responded well to the initial treatment. Twenty months after its last re-evaluation, the first horse was being maintained on azathioprine because similar clinical signs had recurred after the cytotoxic drug was discontinued; the second horse was finishing a tapering course of prednisolone 15 months after its first examination, and the third horse was euthanased five months after it was first examined as a result of an unrelated injury.


Cost Analysis and Bundled Care of Hip and Knee Replacement.
Financial success in a bundled payment system requires knowledge of the costs of care throughout the period of risk. Understanding the significant cost-drivers of total joint arthroplasty (TJA) is crucial in this effort. This article inspects the basics of reimbursement under Medicare's bundled care programs as well as some common investigative tools used in the literature to measure cost. Additionally, the effects of standardized enhanced recovery clinical pathways on costs are reviewed. Finally, drivers of implant costs and several proven measures for implant cost-reduction are evaluated. This review provides surgeons and hospitals successful measures to reduce the cost of TJA via enhanced recovery pathways and reduced implant pricing. (Journal of Surgical Orthopaedic Advances 28(4):241-249, 2019).


An evaluation of the integration of non-traditional learning tools into a community based breast and cervical cancer education program: the Witness Project of Buffalo.
Breast and cervical cancer continue to represent major health challenges for African American women. among Caucasian women. The underlying reasons for this disparity are multifactorial and include lack of education and awareness of screening and early detection. Traditional educational methods have enjoyed varied success in the African American community and spawned development of novel educational approaches. Community based education programs employing a variety of educational models have been introduced. Successful programs must train and provide lay community members with the tools necessary to deliver strong educational programs. The Witness Project is a theory-based, breast and cervical cancer educational program, delivered by African American women, that stresses the importance of early detection and screening to improve survival and teaches women how to perform breast self examination. Implementing this program in the Buffalo Witness Project of Buffalo required several modifications in the curriculum, integration of non-traditional learning tools and focused training in clinical study participation. The educational approaches utilized included repetition, modeling, building comprehension, reinforcement, hands on learning, a social story on breast health for African American women, and role play conversations about breast and cervical health and support. Incorporating non-traditional educational approaches into the Witness Project training resulted in a 79% improvement in the number of women who mastered the didactic information. A seventy-two percent study participation rate was achieved by educating the community organizations that hosted Witness Project programs about the informed consent process and study participation. Incorporating non-traditional educational approaches into community outreach programs increases training success as well as community participation.


Native disulfide bonds greatly accelerate secondary structure formation in the folding of lysozyme.
To assess the respective roles of local and long-range interactions during protein folding, the influence of the native disulfide bonds on the early formation of secondary structure was investigated using continuous-flow circular dichroism. Within the first 4 ms of folding, lysozyme with intact disulfide bonds already had a far-UV CD spectrum reflecting large amounts of secondary structure. Conversely, reduced lysozyme remained essentially unfolded at this early folding time. Thus, native disulfide bonds not only stabilize the cfinal conformation of lysozyme but also provide, in early folding intermediates, the necessary stabilization that favors the formation of secondary structure.


Reduced risk for peritonitis in CAPD with the use of a UV connector box.
A common route for peritoneal infection is the bag transfer connecting site. To investigate possible reduction of such transfer infections with the use of a bag transfer set (UV-XD, Travenol, Baxter, Minneapolis), this study sampled patients using a transfer set with or without UV light sterilization. Calculations excluded peritonitis due to penetrating tunnel infection or defective peritoneal dialysis bag (4 episodes in 2 patients). The study included 51 patients with a median age of 62 years (range 25-81). Five were switched from manual connection (Travenol, Type II) to UV-XD, and each suffered from at least 2 peritonitis episodes during 9-24.5 months prior to the change to UV-XD. In this patient group, the incidence of peritonitis fell significantly from 1 peritonitis/4 to 1/21 months. The bag transfer set was used without UV light in 35 patients for a total of 178 months, producing an incidence of 1 episode/7.7 treatment months. These patients had significantly more peritonitis than 35 patients who used the UV light for a total of 416 months (1 episode/21 months). In 19 patients who used both techniques, there was less risk for peritonitis when UV light was used (p = 0.001). We conclude that the UV-XD device is simple to handle and may reduce the incidence of peritonitis, especially if the box is used in tandem with UV light sterilization.


King's formula for the mutation load with epistasis.
A formula by J. L. King gives the equilibrium mutation load as L = 2 sigma ui(1 - qi)/z - x) in which ui is the mutation rate to deleterious alleles at the ith locus, qi is the frequency of mutant alleles at this locus, x is the mean number of such mutant genes per individual before selection, z is the mean number in individuals eliminated by selection, and the summation is over all relevant loci. We show that this rule is inaccurate for intense selection and that a correct formula is L = 2 sigma ui(1 - qi) w/(z - x) = 2U w/(z - x) = 2U/(z - x + 2U) in which U is the mean number of new mutations per haploid genome in the population and w is the mean relative fitness before selection. If w/(z - x) less than 1/2, the mutation load is less than the Haldane value (U less than or equal to L less than or equal to 2U) and can be considerably less. In a diploid asexual population, however, with independent occurrence of mutations, L = 1 - e-2U regardless of the mode of selection.


Innate and adaptive immunity: the understudied driving force of heart valve disease.
Calcific aortic valve disease (CAVD), and its clinical manifestation that is calcific aortic valve stenosis, is the leading cause for valve disease within the developed world, with no current pharmacological treatment available to delay or halt its progression. Characterized by progressive fibrotic remodelling and subsequent pathogenic mineralization of the valve leaflets, valve disease affects 2.5% of the western population, thus highlighting the need for urgent intervention. Whilst the pathobiology of valve disease is complex, involving genetic factors, lipid infiltration, and oxidative damage, the immune system is now being accepted to play a crucial role in pathogenesis and disease continuation. No longer considered a passive degenerative disease, CAVD is understood to be an active inflammatory process, involving a multitude of pro-inflammatory mechanisms, with both the adaptive and the innate immune system underpinning these complex mechanisms. Within the valve, 15% of cells evolve from haemopoietic origin, and this number greatly expands following inflammation, as macrophages, T lymphocytes, B lymphocytes, and innate immune cells infiltrate the valve, promoting further inflammation. Whether chronic immune infiltration or pathogenic clonal expansion of immune cells within the valve or a combination of the two is responsible for disease progression, it is clear that greater understanding of the immune systems role in valve disease is required to inform future treatment strategies for control of CAVD development.


The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner.
Hepatitis E virus (HEV), a single-strand positive-sense RNA virus, is an understudied but important human pathogen. The virus can establish infection at a number of host tissues, including the small intestine and liver, causing acute and chronic hepatitis E as well as certain neurological disorders. The retinoic acid-inducible gene I (RIG-I) pathway is essential to induce the interferon (IFN) response during HEV infection. However, the pathogen-associated motif patterns (PAMPs) in the HEV genome that are recognized by RIG-I remain unknown. In this study, we first identified that HEV RNA PAMPs derived from the 3' untranslated region (UTR) of the HEV genome induced higher levels of IFN mRNA, interferon regulatory factor-3 (IRF3) phosphorylation, and nuclear translocation than the 5' UTR of HEV. We revealed that the U-rich region in the 3' UTR of the HEV genome acts as a potent RIG-I PAMP, while the presence of poly(A) tail in the 3' UTR further increases the potency. We further demonstrated that HEV UTR PAMPs induce differential type I and type III IFN responses in a cell type-dependent fashion. Predominant type III IFN response was observed in the liver tissues of pigs experimentally infected with HEV as well as in HEV RNA PAMP-induced human hepatocytes in vitro In contrast, HEV RNA PAMPs induced a predominant type I IFN response in swine enterocytes. Taken together, the results from this study indicated that the IFN response during HEV infection depends both on viral RNA motifs and host target cell types. The results have important implications in understanding the mechanism of HEV pathogenesis.IMPORTANCE Hepatitis E virus (HEV) is an important human pathogen causing both acute and chronic viral hepatitis E infection. Currently, the mechanisms of HEV replication and pathogenesis remain poorly understood. The innate immune response acts as the first line of defense during viral infection. The retinoic acid-inducible gene I (RIG-I)-mediated interferon (IFN) response has been implicated in establishing antiviral response during HEV infection, although the HEV RNA motifs that are recognized by RIG-I are unknown. This study identified that the U-rich region in the 3' untranslated region (UTR) of the HEV genome acts as a potent RIG-I agonist compared to the HEV 5' UTR. We further revealed that the HEV RNA pathogen-associated motif patterns (PAMPs) induced a differential IFN response in a cell type-dependent manner: a predominantly type III IFN response in hepatocytes, and a predominantly type I IFN response in enterocytes. These data demonstrate the complexity by which both host and viral factors influence the IFN response during HEV infection.


Long identical multispecies elements in plant and animal genomes.
Ultraconserved elements (UCEs) are DNA sequences that are 100% identical (no base substitutions, insertions, or deletions) and located in syntenic positions in at least two genomes. Although hundreds of UCEs have been found in animal genomes, little is known about the incidence of ultraconservation in plant genomes. Using an alignment-free information-retrieval approach, we have comprehensively identified all long identical multispecies elements (LIMEs), which include both syntenic and nonsyntenic regions, of at least 100 identical base pairs shared by at least two genomes. Among six animal genomes, we found the previously known syntenic UCEs as well as previously undescribed nonsyntenic elements. In contrast, among six plant genomes, we only found nonsyntenic LIMEs. LIMEs can also be classified as either simple (repetitive) or complex (nonrepetitive), they may occur in multiple copies in a genome, and they are often spread across multiple chromosomes. Although complex LIMEs were found in both animal and plant genomes, they differed significantly in their composition and copy number. Further analyses of plant LIMEs revealed their functional diversity, encompassing elements found near rRNA and enzyme-coding genes, as well as those found in transposons and noncoding DNA. We conclude that despite the common presence of LIMEs in both animal and plant lineages, the evolutionary processes involved in the creation and maintenance of these elements differ in the two groups and are likely attributable to several mechanisms, including transfer of genetic material from organellar to nuclear genomes, de novo sequence manufacturing, and purifying selection.


A novel apolipoprotein A-1 variant, Arg173Pro, associated with cardiac and cutaneous amyloidosis.
An American kindred was found to have hereditary amyloidosis with cutaneous and cardiac involvement. Characterization of fibrils isolated from skin identified the amyloid protein as the N-terminal 90 to 100 residues of apolipoprotein A-1. Sequence of the apolipoprotein A-1 gene was normal except for a G/C transversion at position 1638 which predicts an Arg to Pro substitution at residue 173. This mutation, unlike previously described amyloidogenic mutations is not in the N-terminal fragment which is incorporated into the fibril. The mutation is at the same residue as in apolipoprotein A-1 Milano (Arg173Cys) which does not result in amyloid formation. Decreased plasma HDL cholesterol levels in carriers of the Arg173Pro mutation suggest an increased rate of catabolism as has been shown for the amyloidogenic Gly26Arg mutation. This suggests that altered metabolism caused by the mutation may be a significant factor in apolipoprotein A-1 fibrillogenesis.


What is the ideal combination therapy in de novo, oligometastatic, castration-sensitive prostate cancer?
To review current evidence regarding the management of de novo, oligometastatic, castration-sensitive prostate cancer (PCa). A literature search was conducted on PubMed/Medline and a narrative synthesis of the evidence was performed in August 2022. Oligometastatic disease is an intermediate state between localized and aggressive metastatic PCa defined by ≤ 3-5 metastatic lesions, although this definition remains controversial. Conventional imaging has limited accuracy in detecting metastatic lesions, and the implementation of molecular imaging could pave the way for a more personalized treatment strategy. However, oncological data supporting this strategy are needed. Radiotherapy to the primary tumor should be considered standard treatment for oligometastatic PCa (omPCa). However, it remains to be seen whether local therapy still has an additional survival benefit in patients with de novo omPCa when treated with the most modern systemic therapy combinations. There is insufficient evidence to recommend cytoreductive radical prostatectomy as local therapy; or stereotactic body radiotherapy as metastasis-directed therapy in patients with omPCa. Current data support the use of intensified systemic therapy with androgen deprivation therapy (ADT) and next-generation hormone therapies (NHT) for patients with de novo omPCa. Docetaxel has not demonstrated benefit in low volume disease. There are insufficient data to support the use of triple therapy (i.e., ADT + NHT + Docetaxel) in low volume disease. The present review discusses current data in de novo, omPCa regarding its definition, the increasing role of molecular imaging, the place of local and metastasis-directed therapies, and the intensification of systemic therapies.


Feasibility of percutaneous vagus nerve stimulation for the treatment of acute asthma exacerbations.
This study assessed the feasibility of an investigational vagus nerve stimulation (VNS) device for treating acute asthma exacerbations in patients not responding to at least 1 hour of initial standard care therapy. This was a prospective, nonrandomized study of patients treated in the ED for moderate to severe acute asthma (forced expiratory volume in 1 second [FEV(1)] 25% to 70% of predicted). Treatment entailed percutaneous placement of an electrode near the right carotid sheath and 60 minutes of VNS and continued standard care. VNS voltage was adjusted to perceived improvement, muscle twitching, or adverse events (AEs). All AEs, vital signs, FEV(1), perceived work of breathing (WOB), and final disposition were recorded. Twenty-five subjects were enrolled. There were no serious AEs and no significant changes in vital signs. No subject required terminating VNS. One patient had minor bleeding from the procedure, and one had a hematoma and withdrew prior to VNS. AEs related to VNS were temporary and included cough (1 of 24), swallowing difficulty (2 of 24), voice change (2 of 24), and muscle twitching (14 of 24). These resolved when VNS ended. The FEV(1) improved at 15 minutes (median = 15.8%, 95% confidence interval [CI] = 9.3% to 22.4%), 30 minutes (median = 21.3%, 95% CI = 8.1% to 36.5%), and 60 minutes (median = 27.5%, 95% CI = 11.3% to 43.5%). WOB improved at 15 minutes (median = 53.9%, 95% CI = 33.7% to 73.9%), 30 minutes (median = 69.1%, 95% CI = 56.4% to 81.8%), and 60 minutes (median = 81.0%, 95% CI = 68.5% to 93.5%). Percutaneous VNS did not result in serious AEs and was associated with improvements in FEV(1) and perceived dyspnea. Percutaneous VNS appears to be feasible for use in the treatment of moderate to severe acute asthma in patients unresponsive to initial standard care treatment.


Slower cortisol response during ACTH stimulation test in autistic children.
Autism is a hereditary, pervasive neurodevelopmental disorder that starts early in life. The main characteristics of the autism are impairment in social interactions, difficulties in adapting to novel environmental situations and improper reaction to stress. Since the Hypothalamic-Pituitary-Adrenocortical (HPA) axis plays a key role in the response to stress and because the previous research found abnormalities in HPA system, we conducted a study to test several elements of the HPA axis. Because autism is a heritable disorder, autistic subjects were studied as well as their parents. Cortisol circadian rhythm, cortisol daily secretion and its suppression response to dexamethasone had been measured from saliva or urine samples of the autistic children and their parents. Cortisol secretion response after ACTH stimulation was done with the autistic children only. The cortisol elevation after ACTH stimulation among the autistic individuals was slower (P = 0.017) than in healthy controls. No differences were found in salivary cortisol circadian rhythm or suppression response, as well as in cortisol daily excretion. These data indicate that, compared to healthy subjects, autistic individuals have fine differences in cortisol response to ACTH stimulation or possibly to other types of stress.


Detection of interleukin-1 and interleukin-6 in adult rat brain, following mechanical injury, by in vivo microdialysis: evidence of a role for microglia in cytokine production.
In vivo levels of interleukin-1 (IL-1) and IL-6, present in the interstitial spaces of brain, have been repeatedly monitored up to 7 days after insertion of a microdialysis probe, designed to induce mechanical trauma to the brain. IL-1 is barely detectable immediately after implantation but over a 24-48 h period a 15-fold increase is seen. In contrast IL-6 levels at day 0 are high, increasing slightly (10%) by day 1 but decreasing to 40% by day 2. The temporal pattern of IL-6 recovery in the cerebrospinal fluid was similar to that in the dialysate but the levels were significantly lower and may reflect diffusion from the site of the probe lesion. Cellular sources of these cytokines include macrophages and neutrophils, which have infiltrated the lesion and microglia resident in the brain, which can be identified at the lesion site within 24 h of probe implantation. The astrocytic response to injury, evidenced by increased glial fibrillary acidic protein staining occurs much later, by day 7, and is unlikely to be responsible for IL-1 and IL-6 production found at 24-48 h. Since upon isolation and stimulation of microglia in vitro with lipopolysaccharide IL-1 and IL-6 can be measured in the supernatant, it would appear that they have the capacity to produce cytokines in vivo. Localised synthesis of cytokines at sites of brain injury by microglia would further stimulate microglia in an autocrine manner and also propagate the astrocytic reaction.


First Report of the Pale Potato Cyst Nematode Globodera pallida from Slovenia.
The potato cyst nematodes (PCN) Globodera rostochiensis (Woll.) Behrens and G. pallida (Stone) Behrens are considered the most important nematode threat to potato production worldwide, and they are subject to strict quarantine regulations in many countries. The first report of the PCN in Slovenia dates back to 1971, when a single cyst of G. rostochiensis was detected (3). In the last decade, G. rostochiensis was detected several times, mainly in the central and northern parts of the country (2). Interceptions of G. pallida in imported consignments of ware potato were made several times, but had not been detected in soil in Slovenia. Therefore, the country was declared as a protected zone for G. pallida in the European Union by the national authorities in 2003. During the official PCN systematic survey in autumn 2011, the pale potato cyst nematode, G. pallida, was found in a soil sample. Two viable cysts were extracted and the nematode species was identified. The posterior part of the cysts containing eggs and juveniles were used for morphometrical analysis, while the anterior parts were used for DNA extraction and molecular analyses. The ribosomal internal transcribed spacer (ITS) region was amplified using ITS5 and PITSp4 primers and detected in real-time PCR using ABI7500 (Applied Biosystems, Life Technologies, Carlsbad, CA,) (1). Also, the ribosomal DNA region that extends from the 3' end of the 18S ribosomal subunit and includes all of ITS1, 5.8S, and ITS2, to the 5' end of the 28S ribosomal subunit, was used to generate a DNA sequence. The sequence obtained was compared with those from several Globodera species, revealing unequivocal similarity to G. pallida. The infested soil sample originated from a ware potato field near Ivancna Gorica, central Slovenia. Subsequently, an additional 69 samples were taken from the surroundings and viable G. pallida cysts were found in another five samples taken from two neighboring fields (one of grassland and the other of clover). Three fields, totaling 1.9 ha, were declared as G. pallida-infested. The eradication of the pest will take place by enforcing strict phytosanitary measures. Ware potatoes originating from areas where the pests occur is considered to be the most probable pathway for the introduction of G. pallida in Slovenia. A ware potato processing facility is situated in very close proximity to the infested fields. The waste waters from potato tuber washing were discharging onto the grassland, never used for potato or other field crop production in which the G. pallida infestation was found. The facility processes imported ware potato from several European and non-European countries. This case demonstrates that ware potato may pose a serious risk for the introduction of such pests, and should be therefore subjected to more intensive phytosanitary inspection. References: (1) J. Bacic et al. Russ. J. Nematol. 16:63, 2008. (2) S. Širca et al. Phytopathol. Mediterr. 49:361, 2010. (3) G. Urek et al. Nematology 5:391, 2003.


Reading the Future from Body Movements -Anticipation in Handball.
In speed-based sports that require fast reactions, the most accurate predictions are made once the players have seen the ball trajectory. However, waiting for the ball trajectory does not leave enough time for appropriate reactions. Expert athletes use kinematic information which they extract from the opponent's movements to anticipate the ball trajectory. Temporal occlusion, where only a part of the full movement sequence is presented, has often been used to research anticipation in sports. Unlike many previous studies, we chose occlusion points in video-stimuli of penalty shooting in handball based on the domain-specific analysis of movement sequences. Instead of relying on randomly chosen occlusion points, each time point in our study revealed a specific chunk of information about the direction of the ball. The multivariate analysis showed that handball goalkeepers were not only more accurate and faster than novices overall when predicting where the ball will end up, but that experts and novices also made their decisions based on different kinds of movement sequences. These findings underline the importance of kinematic knowledge for anticipation, but they also demonstrate the significance of carefully chosen occlusion points.


Plasma and intracellular pharmacokinetics of tenofovir in patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide.
The aim of the study was to compare the intraindividual plasma and intracellular peripheral blood mononuclear cell (PBMC) pharmacokinetics of tenofovir (TFV) and its intracellular metabolite, TFV-diphosphate (TFV-DP) in patients switched from a fixed-dose combination (FDC) tablet of TFV disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir (EVG)/cobicistat (COBI) to a FDC containing TFV alafenamide (TAF)/FTC/EVG/COBI. A single-arm, prospective, nonrandomized, cross-over, pharmacokinetic study in patients receiving a TDF-containing regimen (TDF 300 mg/FTC 200 mg/EVG 150 mg/COBI 150 mg) switched to a TAF-containing FDC regimen (TAF 10 mg/FTC 200 mg/EVG 150 mg/COBI 150 mg). Single, sparse plasma and PBMC samples were collected during TDF therapy and 4-8 weeks post-switch to the TAF-containing regimen. Plasma TFV and cell associated TFV-DP concentrations were determined with validated liquid chromatography tandem mass spectrometry methods. PBMC cell enumeration was performed by quantification of RNaseP (RPP30) gene copy numbers using a highly sensitive droplet digital PCR assay. Plasma and PBMC pharmacokinetics were summarized as geometric mean and compared as a geometric mean ratio with a Wilcoxon signed-rank test. In 30 participants with evaluable data, TFV plasma concentrations decreased 90% [TDF: 99.98 (2.24) ng/ml vs. TAF: 10.2 (1.6) ng/ml, P < 0.001] after the switch while cell-associated TFV-DP increased 2.41-fold [TAF: 834.7 (2.49) vs. TDF: 346.85 (3.75) fmol/10 cells, P = 0.004]. Intraindividually, plasma TFV concentrations significantly decreased while cell associated TFV-DP concentrations significantly increased after switching from a TDF to a TAF-containing antiretroviral therapy regimen.


Obesity Definitions in Sarcopenic Obesity: Differences in Prevalence, Agreement and Association with Muscle Function.
Sarcopenic obesity (SO) is associated with poorer physical performance in the elderly and will increase in relevance with population ageing and the obesity epidemic. The lack of a consensus definition for SO has resulted in variability in its reported prevalence, poor inter-definitional agreement, and disagreement on its impact on physical performance, impeding further development in the field. While sarcopenia definitions have been compared, the impact of obesity definitions in SO has been less well-studied. To compare 3 widely-adopted definitions of obesity in terms of SO prevalence, inter-definitional agreement, and association with muscle function. Cross-sectional. GERILABS study, Singapore Participants: 200 community-dwelling, functionally-independent older adults. We utilized three commonly-used definitions of obesity: body mass index (BMI), waist circumference (WC) and DXA-derived fat mass percentage (FM%). Sarcopenia was defined using Asian Working Group for Sarcopenia criteria. For muscle function, we assessed handgrip strength, gait speed and Short Physical Performance Battery (SPPB). Subjects were classified into 4 body composition phenotypes (normal, obese, sarcopenic and SO), and outcomes were compared between groups. The prevalence rate for SO was lowest for BMI (0.5%) compared to FM% (10.0%) and WC (10.5%). Inter-definitional agreement was lowest between BMI and WC (κ=0.364), and at best moderate between FM% and WC (κ=0.583). SO performed the worst amongst body composition phenotypes in handgrip strength, gait speed and SPPB (all p<0.01) only when defined using WC. In regression analyses, SO was associated with decreased SPPB scores (β=-0.261, p=0.001) only for the WC definition. There is large variation in the prevalence of SO across different obesity definitions, with low-to-moderate agreement between them. Our results corroborate recent evidence that WC, and thus central obesity, is best associated with poorer muscle function in SO. Thus, WC should be further explored in defining obesity for accurate and early characterization of SO among older adults in Asian populations.


EMBRYONIC DEVELOPMENT AND A QUANTITATIVE MODEL OF PROGRAMMED DNA ELIMINATION IN MESOCYCLOPS EDAX (S. A. FORBES, 1891) (COPEPODA: CYCLOPOIDA).
The highly programmed fragmentation of chromosomes and elimination of large amounts of nuclear DNA from the presomatic cell lineages (i.e., chromatin diminution), occurs in the embryos of the freshwater zooplankton Mesocyclops edax (S. A. Forbes, 1891) (Crustacea: Copepoda). The somatic genome is reorganized and reduced to a size five times smaller even though the germline genome remains intact. We present the first comprehensive, quantitative model of DNA content throughout embryogenesis in a copepod that possesses embryonic DNA elimination. We used densitometric image analysis to measure the DNA content of polar bodies, germline and somatic nuclei, and excised DNA "droplets." We report: 1) variable DNA contents of polar bodies, some of which do not contain the amount corresponding to the haploid germline genome size; 2) presence of pronuclei in newly laid embryo sacs; 3) gonomeric chromosomes in the second to fourth cleavage divisions and in the primordial germ cell and primordial endoderm cell during the fifth cleavage division; 4) timing of early embryonic cell stages, elimination of DNA, and divisions of the primordial germ cell and primordial endoderm cell at 22°C; and 5) persistence of a portion of the excised DNA "droplets" throughout embryogenesis. DNA elimination is a trait that spans multiple embryonic stages and a knowledge of the timing and variability of the associated cytological events with DNA elimination will promote the study of the molecular mechanisms involved in this trait. We propose the "genome yolk hypothesis" as a functional explanation for the persistence of the eliminated DNA that might serve as a resource during postdiminution cleavage divisions.


Stubborn Predictions in Primary Visual Cortex.
Perceivers can use past experiences to make sense of ambiguous sensory signals. However, this may be inappropriate when the world changes and past experiences no longer predict what the future holds. Optimal learning models propose that observers decide whether to stick with or update their predictions by tracking the uncertainty or "precision" of their expectations. However, contrasting theories of prediction have argued that we are prone to misestimate uncertainty-leading to stubborn predictions that are difficult to dislodge. To compare these possibilities, we had participants learn novel perceptual predictions before using fMRI to record visual brain activity when predictive contingencies were disrupted-meaning that previously "expected" events became objectively improbable. Multivariate pattern analyses revealed that expected events continued to be decoded with greater fidelity from primary visual cortex, despite marked changes in the statistical structure of the environment, which rendered these expectations no longer valid. These results suggest that our perceptual systems do indeed form stubborn predictions even from short periods of learning-and more generally suggest that top-down expectations have the potential to help or hinder perceptual inference in bounded minds like ours.


Evaluation of monocytes as carriers for armed oncolytic adenoviruses in murine and Syrian hamster models of cancer.
Replication-competent (oncolytic) adenoviruses (OAV) can be adapted as vectors for the delivery of therapeutic genes, with the aim of extending the antitumor effect beyond direct cytolysis. Transgene expression using these vectors is usually intense but short-lived, and repeated administrations are hampered by the rapid appearance of neutralizing antibodies (NAbs). We have studied the performance of monocytes as cell carriers to improve transgene expression in cancer models established in athymic mice and immunocompetent Syrian hamsters. Human and hamster monocytic cell lines (MonoMac6 and HM-1, respectively) were loaded with replication-competent adenovirus-expressing luciferase. Intravenous administration of these cells caused a modest increase in transgene expression in tumor xenografts, but this effect was virtually lost in hamsters. In contrast, intratumoral administration of HM-1 cells allowed repeated cycles of expression and achieved partial protection from NAbs in preimmunized hamsters bearing pancreatic tumors. To explore the therapeutic potential of this approach, HM-1 cells were loaded with a hypoxia-inducible OAV expressing the immunostimulatory cytokine interleukin-12 (IL-12). Three cycles of treatment achieved a significant antitumor effect in the hamster model, and transgene expression was detected following each administration, in contrast with the rapid neutralization of the free virus. We propose monocytes as carriers for multiple intratumoral administrations of armed OAVs.


Effect of magnolol on cerebral injury and blood brain barrier dysfunction induced by ischemia-reperfusion in vivo and in vitro.
Magnolol, a neolignan compound isolated from traditional Chinese medicine Magnolia officinalis, has a potentially therapeutic influence on ischemic stroke. Previous studies have demonstrated that cerebral ischemia-reperfusion (I-R) and blood-brain barrier (BBB) are involved in the pathogeneses of stroke. Therefore, in vivo and in vitro studies were designed to investigate the effects of magnolol on I-R-induced neural injury and BBB dysfunction. In cerebral I-R model of mice, cerebral infarct volumes, brain water content, and the exudation of Evans blue were significantly reduced by intravenous injection with magnolol at the doses of 1.4, 7.0, and 35.0 μg/kg. When primary cultured microglial cells were treated with 1 μg/ml lipopolysaccharide (LPS) plus increasing concentrations of magnolol, ranging from 0.01 to 10 μmol/L, magnolol could statistically inhibit LPS-induced NO release, TNF-α secretion, and expression of p65 subunit of NF-κB in the nucleus of microglial cells. In the media of brain microvascular endothelial cells (BMECs), oxygen and glucose deprivation-reperfusion (OGD-R) could remarkably lead to the elevation of TNF-α and IL-1β levels, while magnolol evidently reversed these effects. In BBB model in vitro, magnolol dose- and time-dependently declined BBB hyperpermeability induced by oxygen and glucose deprivation (OGD), OGD-R, and ephrin-A1 treatment. More importantly, magnolol could obviously inhibit phosphorylation of EphA2 (p-EphA2) not only in ephrin-A1-treated BMECs but also in cerebral I-R model of mice. In contrast to p-EphA2, magnolol significantly increased ZO-1 and occludin levels in BMECs subjected to OGD. Taken together, magnolol can protect neural damage from cerebral ischemia- and OGD-reperfusion, which may be associated with suppressing cerebral inflammation and improving BBB function.


Prognostic value of aerobic capacity and exercise oxygen pulse in postaortic dissection patients.
Although recommendations encourage daily moderate activities in post aortic dissection, very little data exists regarding cardiopulmonary exercise testing (CPET) to personalize those patient's physical rehabilitation and assess their cardiovascular prognosis. We aimed at testing the prognostic insight of CPET regarding aortic and cardiovascular events by exploring a prospective cohort of patients followed-up after acute aortic dissection. Patients referred to our department after an acute (type A or B) aortic dissection were prospectively included in a cohort between September 2012 and October 2017. CPET was performed once optimal blood pressure control was obtained. Clinical follow-up was done after CPET for new aortic event and major cardio-vascular events (MCE) not directly related to the aorta. Among the 165 patients who underwent CPET, no adverse event was observed during exercise testing. Peak oxygen pulse was 1.46(1.22-1.84) mlO2/beat, that is, 97 (83-113) % of its predicted value, suggesting cardiac exercise limitation in a population under beta blockers (92% of the population). During a follow-up of 39(20-51) months from CPET, 42 aortic event recurrences and 22 MCE not related to aorta occurred. Low peak oxygen pulse (<85% of predicted value) was independently predictive of aortic event recurrence, while low peak oxygen uptake (<70% of predicted value) was an independent predictor of MCE occurrence. CPET is safe in postaortic dissection patients should be used to not only to personalize exercise rehabilitation, but also to identify those patients with the highest risk for new aortic events and MCE not directly related to aorta.


Identification of residues contributing to the ATP binding site of Kir6.2.
The ATP-sensitive potassium (K(ATP)) channel links cell metabolism to membrane excitability. Intracellular ATP inhibits channel activity by binding to the Kir6.2 subunit of the channel, but the ATP binding site is unknown. Using cysteine-scanning mutagenesis and charged thiol-modifying reagents, we identified two amino acids in Kir6.2 that appear to interact directly with ATP: R50 in the N-terminus, and K185 in the C-terminus. The ATP sensitivity of the R50C and K185C mutant channels was increased by a positively charged thiol reagent (MTSEA), and was reduced by the negatively charged reagent MTSES. Comparison of the inhibitory effects of ATP, ADP and AMP after thiol modification suggests that K185 interacts primarily with the beta-phosphate, and R50 with the gamma-phosphate, of ATP. A molecular model of the C-terminus of Kir6.2 (based on the crystal structure of Kir3.1) was constructed and automated docking was used to identify residues interacting with ATP. These results support the idea that K185 interacts with the beta-phosphate of ATP. Thus both N- and C-termini may contribute to the ATP binding site.


Comparing brain networks of different size and connectivity density using graph theory.
Graph theory is a valuable framework to study the organization of functional and anatomical connections in the brain. Its use for comparing network topologies, however, is not without difficulties. Graph measures may be influenced by the number of nodes (N) and the average degree (k) of the network. The explicit form of that influence depends on the type of network topology, which is usually unknown for experimental data. Direct comparisons of graph measures between empirical networks with different N and/or k can therefore yield spurious results. We list benefits and pitfalls of various approaches that intend to overcome these difficulties. We discuss the initial graph definition of unweighted graphs via fixed thresholds, average degrees or edge densities, and the use of weighted graphs. For instance, choosing a threshold to fix N and k does eliminate size and density effects but may lead to modifications of the network by enforcing (ignoring) non-significant (significant) connections. Opposed to fixing N and k, graph measures are often normalized via random surrogates but, in fact, this may even increase the sensitivity to differences in N and k for the commonly used clustering coefficient and small-world index. To avoid such a bias we tried to estimate the N,k-dependence for empirical networks, which can serve to correct for size effects, if successful. We also add a number of methods used in social sciences that build on statistics of local network structures including exponential random graph models and motif counting. We show that none of the here-investigated methods allows for a reliable and fully unbiased comparison, but some perform better than others.


Tigecycline: a glycylcycline antimicrobial agent.
Tigecycline, the first glycylcycline to be approved by the US Food and Drug Administration, is a structural analogue of minocycline that was designed to avoid tetracycline resistance mediated by ribosomal protection and drug efflux. It is indicated for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections and is available for intravenous administration only. This article summarizes the in vitro and in vivo activities and pharmacologic and pharmacokinetic properties of tigecycline, and reviews its clinical efficacy and tolerability profile. Relevant information was identified through a search of MEDLINE (1966-April 2006), Iowa Drug Information Service (1966-April 2006), and International Pharmaceutical Abstracts (1970-April 2006) using the terms tigecycline, GAR-936, and glycylcycline. Also consulted were abstracts and posters from meetings of the Infectious Diseases Society of America and the Interscience Conference on Antimicrobial Agents and Chemotherapy (1999-2006) and documents provided for formulary consideration by the US manufacturer of tigecycline. Like the tetracyclines, tigecycline binds to the 30S subunit of bacterial ribosomes and inhibits protein synthesis by preventing the incorporation of amino acid residues into elongating peptide chains. In vitro, tigecycline exhibits activity against a wide range of clinically significant gram-positive and gram-negative bacteria, including multidrug-resistant strains (eg, oxacillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, extended-spectrum beta-lactamase-producing Enterobacteriaceae), and anaerobes (eg, Bacteroides spp). In pharmacokinetic studies in human adults, tigecycline had a large Vd (7-9 L/kg), was moderately bound to plasma protein (71%-89%), had an elimination t(1/2) of 42.4 hours, and was eliminated primarily by biliary/fecal (59%) and renal (33%) excretion. Dose adjustment did not appear to be necessary based on age, sex, renal function, or mild to moderate hepatic impairment (Child-Pugh class A-B). In patients with severe hepatic impairment (Child-Pugh class C), the maintenance dose should be reduced by 50%. In 4 Phase III clinical trials in patients with complicated skin and skin-structure infections and complicated intra-abdominal infections, tigecycline was reported to be noninferior to its comparators (vancomycin + aztreonam in 2 studies and imipenem/cilastatin in 2 studies), with clinical cure rates among clinically evaluable patients of >80% (P < 0.001 for noninferiority). The most frequently reported (> or =5 %) adverse events with tigecycline were nausea (28.5%), vomiting (19.4%), diarrhea (11.6%), local IV-site reaction (8.2%), infection (6.7%), fever (6.3%), abdominal pain (6.0%), and headache (5.6%). The recommended dosage of tigecycline is 100 mg IV given as a loading dose, followed by 50 mg IV g12h for 5 to 14 days. In clinical trials, tigecycline was effective for the treatment of complicated skin and skin-structure infections and complicated intra-abdominal infections. With the exception of gastrointestinal adverse events, tigecycline was generally well tolerated. With a broad spectrum of activity that includes multidrug-resistant gram-positive and gram-negative pathogens, tigecycline may be useful in the treatment of conditions caused by these pathogens.


Relationship between cows' milk consumption and incidence of IDDM in childhood.
To compare age-standardized incidence rates of diabetes in children 0-14 yr of age and cows' milk consumption in various countries. Ecological correlation study. Only incidence rates from diabetes registries carefully validated by the Diabetes Epidemiology Research International Study Group were used-Finland, Sweden, Norway, Great Britain, Denmark, United States, New Zealand, Netherlands, Canada, France, Israel, and Japan. Data on fluid cows' milk consumption in corresponding countries were obtained from the International Dairy Federation. Correlation between milk consumption and incidence of insulin-dependent diabetes mellitus (IDDM) was 0.96. The data fit a linear regression model, and analysis showed that 94% of the geographic variation in incidence might be explained by differences in milk consumption. The results support the hypothesis that cows' milk may contain a triggering factor for the development of IDDM.


Spatial scaling laws yield a synthetic theory of biodiversity.
Ecologists still search for common principles that predict well-known responses of biological diversity to different factors. Such factors include the number of available niches in space, productivity, area, species' body size and habitat fragmentation. Here we show that all these patterns can arise from simple constraints on how organisms acquire resources in space. We use spatial scaling laws to describe how species of different sizes find food in patches of varying size and resource concentration. We then derive a mathematical rule for the minimum similarity in size of species that share these resources. This packing rule yields a theory of species diversity that predicts relations between diversity and productivity more effectively than previous models. Size and diversity patterns for locally coexisting East African grazing mammals and North American savanna plants strongly support these predictions. The theory also predicts relations between diversity and area and between diversity and habitat fragmentation. Thus, spatial scaling laws provide potentially unifying first principles that may explain many important patterns of species diversity.


Is aspirin intake associated with early age-related macular degeneration? The Singapore Indian Eye Study.
To examine the relationship between aspirin intake and early age-related macular degeneration (AMD) among an Asian population. A population based cross sectional study of 3207 ethnic Indians aged 40 years or older residing in Singapore. AMD signs were graded from retinal images following the modified Wisconsin grading system. Information on aspirin intake was obtained from a standardised questionnaire. The prevalence of early AMD was 5.6%. Aspirin use was reported by 11.4% of participants. Early AMD signs were present among 10.9% of aspirin users and 4.9% of non-aspirin users (p<0.001). After adjusting for potential confounders, including age, smoking and previous cataract surgery, aspirin use was associated with early AMD (OR 1.50; 95% CI: 1.01 to 2.22). The association weakened and was not significant after additional adjustment for cardiovascular disease (OR 1.38; 95% CI 0.89 to 2.14). In stratified analysis, aspirin use was significantly associated with early AMD in participants with (adjusted OR 2.64, 95% CI 1.31 to 5.36) but not without (OR 0.73; 95% CI 0.36 to 1.51) a history of cardiovascular disease (interaction term, p=0.011). Aspirin intake overall was not associated with early AMD in this sample of Asian Indians, but in those with a history of cardiovascular disease the association between aspirin intake and early AMD might warrant further investigation.


Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD.
It is known that non-cachectic patients with chronic obstructive pulmonary disease (COPD) respond well to pulmonary rehabilitation, but whether cachectic COPD patients are capable of adaptive responses is both important and unknown. 10 cachectic and 19 non-cachectic COPD patients undertook high-intensity cycling training, at the same relative intensity, for 45 min x day(-1), 3 days x week(-1) for 10 weeks. Before and after rehabilitation vastus lateralis muscle biopsies were analysed morphologically and for the expression of muscle remodelling factors (insulin-like growth factor (IGF)-I, myogenic differentiation factor D (MyoD), tumour necrosis factor (TNF)-alpha, nuclear factor (NF)-kappaB and myostatin) and key components of ubiquitin-mediated proteolytic systems (muscle ring finger protein (MURF)-1 and Atrogin-1). Rehabilitation improved peak work-rate and the 6-min walk distance similarly in non-cachectic (18+/-3% and 42+/-13 m, respectively) and cachectic (16+/-2% and 53+/-16 m, respectively) patients, but quality of life only improved in non-cachectic COPD. Mean muscle fibre cross-sectional area increased in both groups, but significantly less in cachectic (7+/-2%) than in non-cachectic (11+/-2%) patients. Both groups equally decreased the proportion of type IIb fibres and increased muscle capillary/fibre ratio. IGF-I mRNA expression increased in both groups, but IGF-I protein levels increased more in non-cachectic COPD. MyoD was upregulated, whereas myostatin was downregulated at the mRNA and protein level only in non-cachectic patients. Whilst rehabilitation had no effect on TNF-alpha expression, it decreased the activation of the transcription factor NF-kappaB in both groups by the same amount. Atrogin-1 and MURF-1 expression were increased in cachectic COPD, but it was decreased in non-cachectic patients. Cachectic COPD patients partially retain the capacity for peripheral muscle remodelling in response to rehabilitation and are able to increase exercise capacity as much as those without cachexia, even if they exhibit both quantitative and qualitative differences in the type of muscle fibre remodelling in response to exercise training.


Adjuvant sclerotherapy after ligation for the treatment of esophageal varices: a prospective, randomized long-term study.
To assess the efficacy of adjuvant sclerotherapy after banding for the treatment of esophageal varices, a randomized trial was carried out of endoscopic variceal ligation (EVL) alone with sequential sclerotherapy versus sequential ligation-sclerotherapy (SLS) after banding with respect to variceal eradication, associated complications, and recurrence of varices. One hundred patients qualified for this study. Fourteen patients were not included for the following reasons: 6 chose not to participate, 4 had fundal varices, and 4 had some form of cancer. Of the remaining 86 patients in the study, 42 underwent EVL alone and the other 44 SLS. Variceal ligation was begun in the region of the gastroesophageal junction, with subsequent ligatures applied cephalad 3 to 5 cm; ligation was repeated every 2 weeks until variceal obliteration. For SLS, ligation was also begun in the region of the gastroesophageal junction and repeated until varices were reduced to F1 size. Subsequently, these patients underwent sclerotherapy with between 6 and 8 mL of sodium tetradecyl sulfate (free hand technique). No significant differences were found between EVL alone and SLS with regard to variceal eradication, development of associated complications, and recurrent bleeding during a follow-up of 2 years. The probability of variceal recurrence requiring further treatment after 1 year was 14% for the SLS group and 26% for EVL group patients. Another year later, the probability of variceal recurrence was 24% and 45%, respectively, for the SLS and EVL groups. Because a significantly lower rate of variceal recurrence was found for SLS patients, sequential sclerotherapy followed by ligation to eradicate those varices too small to easily band may be a better procedure.


Control of skeletal patterning by ephrinB1-EphB interactions.
We report that targeted inactivation of the Eph receptor ligand ephrinB1 in mouse caused perinatal lethality, edema, defective body wall closure, and skeletal abnormalities. In the thorax, sternocostal connections were arranged asymmetrically and sternebrae were fused, defects that were phenocopied in EphB2/EphB3 receptor mutants. In the wrist, loss of ephrinB1 led to abnormal cartilage segmentation and the formation of additional skeletal elements. We conclude that ephrinB1 and B class Eph receptors provide positional cues required for the normal morphogenesis of skeletal elements. Another malformation, preaxial polydactyly, was exclusively seen in heterozygous females in which expression of the X-linked ephrinB1 gene was mosaic, so that ectopic EphB-ephrinB1 interactions led to restricted cell movements and the bifurcation of digital rays. Our findings suggest that differential cell adhesion and sorting might be relevant for an unusual class of X-linked human genetic disorders, in which heterozygous females show more severe phenotypes than hemizygous males.


Trends in kidney function testing in UK primary care since the introduction of the quality and outcomes framework: a retrospective cohort study using CPRD.
To characterise serum creatinine and urinary protein testing in UK general practices from 2005 to 2013 and to examine how the frequency of testing varies across demographic factors, with the presence of chronic conditions and with the prescribing of drugs for which kidney function monitoring is recommended. Retrospective open cohort study. Routinely collected data from 630 UK general practices contributing to the Clinical Practice Research Datalink. 4 573 275 patients aged over 18 years registered at up-to-standard practices between 1 April 2005 and 31 March 2013. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. The rate of serum creatinine and urinary protein testing per year and the percentage of patients with isolated and repeated testing per year. The rate of serum creatinine testing increased linearly across all age groups. The rate of proteinuria testing increased sharply in the 2009-2010 financial year but only for patients aged 60 years or over. For patients with established chronic kidney disease (CKD), creatinine testing increased rapidly in 2006-2007 and 2007-2008, and proteinuria testing in 2009-2010, reflecting the introduction of Quality and Outcomes Framework indicators. In adjusted analyses, CKD Read codes were associated with up to a twofold increase in the rate of serum creatinine testing, while other chronic conditions and potentially nephrotoxic drugs were associated with up to a sixfold increase. Regional variation in serum creatinine testing reflected country boundaries. Over a nine-year period, there have been increases in the numbers of patients having kidney function tests annually and in the frequency of testing. Changes in the recommended management of CKD in primary care were the primary determinant, and increases persist even after controlling for demographic and patient-level factors. Future studies should address whether increased testing has led to better outcomes.


Cell type-specific protein-DNA interactions in the human zeta-globin upstream promoter region: displacement of Sp1 by the erythroid cell-specific factor NF-E1.
The protein-DNA interactions of the upstream promoter region of the human embryonic zeta-globin gene in nuclear extracts of erythroid K562 cells and nonerythroid HeLa cells were analyzed by DNase I footprinting, gel mobility shift assay, methylation interference, and oligonucleotide competition experiments. There are mainly two clusters of nuclear factor-binding sites in the zeta promoter. The proximal cluster spans the DNA sequence from -110 to -60 and consists of binding sites for CP2, Sp1, and NF-E1. NF-E1 binding is K562 specific, whereas CP2 binding is common to both types of cells. Overlapping the NF-E1- and CP2-binding sites is a hidden Sp1-binding site or CAC box, as demonstrated by binding studies of affinity-purified Sp1. In the distal promoter region at -250 to -220, another NF-E1-binding site overlaps a CAC box or Sp1-binding site. Extract-mixing experiments demonstrated that the higher affinity of NF-E1 binding excluded the binding of Sp1 in the K562 extract. NF-E1 factors could also displace prebound Sp1 molecules. Between the two clusters of multiple-factor-binding sites are sequences recognized by other factors, including zeta-globin factors 1 and 2, that are present in both HeLa and K562 extracts. We discuss the cell type-specific, competitive binding of multiple nuclear factors in terms of functional implications in transcriptional regulation of the zeta-globin gene.


Evolution of the Borrelia burgdorferi outer surface protein OspC.
The genes coding for outer surface protein OspC from 22 Borrelia burgdorferi strains isolated from patients with Lyme borreliosis were cloned and sequenced. For reference purposes, the 16S rRNA genes from 17 of these strains were sequenced after being cloned. The deduced OspC amino acid sequences were aligned with 12 published OspC sequences and revealed the presence of 48 conserved amino acids. On the basis of the alignment, OspC could be divided into an amino-terminal relatively conserved region and a relatively variable region in the central portion. The distance tree obtained divided the ospC sequences into three groups. The first group contained ospC alleles from all (n = 13) sensu stricto strains, the second group contained ospC alleles from seven Borrelia afzelii strains, and the third group contained ospC alleles from five B. afzelii and all (n = 9) Borrelia garinii strains. The ratio of the mean number of synonymous (dS) and nonsynonymous (dN) nucleotide substitutions per site calculated for B. burgdorferi sensu stricto, B. garinii, and B. afzelii ospC alleles suggested that the polymorphism of OspC is due to positive selection favoring diversity at the amino acid level in the relatively variable region. On the basis of the comparison of 16S rRNA gene sequences, Borrelia hermsii is more closely related to B. afzelii than to B. burgdorferi sensu stricto and B. garinii. In contrast, the phylogenetic tree obtained for the B. hermsii variable major protein, Vmp33, and 18 OspC amino acid sequences suggested that Vmp33 and OspC from B. burgdorferi sensu stricto strains share a common evolutionary origin.


A comparative study of in-gel digestions using microwave and pressure-accelerated technologies.
One of the most popular methods to prepare tryptic peptides for bottom-up proteomic analysis is in-gel digestion. To date, there have been few studies comparing various digestion methods. In this study, we compare the efficiency of several popular in-gel digestion methods, along with new technologies that may improve digestion efficiency, using a human epidermoid carcinoma cell lysate protein standard. The efficiency of each protocol was based on the average number of proteins identified and their respective sequence coverage and relative quantitation using spectral counting. The importance of this study lies in its comparison of pre-existing in-gel digestion methods with those that use newly developed technologies that may introduce the potential for a more cost-effective digestion, higher protein yield, and an overall reduction in processing time. The following four protocols were compared: an overnight in-gel digestion protocol; an overnight in-gel digestion protocol, in which we remove the vacuum centrifugation steps; in-gel digestion in a barometric pressure cycler; and in-gel digestion in a scientific microwave. Several variables were tested for increased digestion efficiency and decreased keratin contamination. Statistical analysis was performed on replicate samples to determine significant differences between protocols.


Mechanisms underlying encoding of short-lived versus durable episodic memories.
We continuously encounter and process novel events in the surrounding world, but only some episodes will leave detailed memory traces that can be recollected after weeks and months. Here, our aim was to monitor brain activity during encoding of events that eventually transforms into long-term stable memories. Previous functional magnetic resonance imaging (fMRI) studies have shown that the degree of activation of different brain regions during encoding is predictive of later recollection success. However, most of these studies tested participants' memories the same day as encoding occurred, whereas several lines of research suggest that extended post-encoding processing is of crucial importance for long-term consolidation. Using fMRI, we tested whether the same encoding mechanisms are predictive of recollection success after hours as after a retention interval of several weeks. Seventy-eight participants were scanned during an associative encoding task and given a source memory test the same day or after ∼6 weeks. We found a strong link between regional activity levels during encoding and recollection success over short time intervals. However, results further showed that durable source memories, i.e., events recollected after several weeks, were not simply the events associated with the highest activity levels at encoding. Rather, strong levels of connectivity between the right hippocampus and perceptual areas, as well as with parts of the self-referential default-mode network, seemed instrumental in establishing durable source memories. Thus, we argue that an initial intensity-based encoding is necessary for short-term encoding of events, whereas additional processes involving hippocampal-cortical communication aid transformation into stable long-term memories.


Induction in vivo and in vitro of terminal deoxynucleotidyl transferase by thymosin in bone marrow cells from athymic mice.
Terminal deoxynucleotidyl transferase (TdT) expression in bovine serum albumin (BSA) gradient-fractionated bone marrow cells was examined in NIH Swiss nu/nu and thymectomized C57BL/6 mice. In nude mice, TdT levels were approximately 10% of those of thymus-bearing littermates. In C57BL/6 mice, thymectomy caused a time-dependent loss of TdT activity in bone marrow cells. To determine whether or not not the apparent thymic requirement for TdT expression in bone marrow was mediated by thymic hormones, we examined the effects of thymosin fraction 5. Treatment of either NIH Swiss nu/nu or thymectomized C57BL/6 mice with thymosin fraction 5 restored the levels of TdT activity in BSA gradient-fractionated bone marrow cells to normal. Moreover, treatment of BSA gradient-fractionated bone marrow cells from NIH Swiss nu/nu or thymectomized C57BL/6 mice in tissue culture with thymosin fraction 5 induced TdT expression. In tissue culture, TdT induction was optimal with 25 ng/ml of thymosin fraction 5, it occurred within 6 h, and it was completely inhibited by actinomycin D. The effect was specific in that neither control nor spleen fraction 5-treated cells were induced to express TdT. These data demonstrate that TdT expression in bone marrow cells is under the direct control of thymic polypeptide hormones.


Dynamics of renal electrolyte excretion in growing mice.
Genetically modified mice represent important models for elucidating renal pathophysiology, but gene deletions frequently cause severe failure to thrive. In such cases, the analysis of the phenotype is often limited to the first weeks of life when renal excretory function undergoes dramatic physiological changes. Here, we investigated the postnatal dynamics of urinary ion excretion in mice. The profiles of urinary electrolyte excretion of mice were examined from birth until after weaning using an automated ion chromatography system. Postnatally, mice grew about 0.4 g/day, except during two phases with slower weight gain: (i) directly after birth during adaptation to extrauterine conditions (P0-P2) and (ii) during the weaning period (P15-P21), when nutrition changed from mother's milk to solid chow and water. During the first 3 days after birth, remarkable changes in urinary Na(+), Ca(2+), Mg(2+), and phosphate concentrations occurred, whereas K(+) and Cl(-) concentrations hardly changed. From days 4-14 after birth, Na(+), Ca(2+), Mg(2+), K(+), and Cl(-) concentrations remained relatively stable at low levels. Urinary concentrations of creatinine, NH4(+), phosphate, and sulfate constantly increased from birth until after weaning. Profiles of salt excretion in KCNJ10(-/-) mice exemplified the relevance of age-dependent analysis of urinary excretion. In conclusion, the most critical phases for analysis of renal ion excretion during the first weeks of life are directly after birth and during the weaning period. The age dependence of urinary excretion varies for the different ions. This should be taken into consideration when the renal phenotype of mice is investigated during the first weeks of life.


Genetic variation in base excision repair pathway genes, pesticide exposure, and prostate cancer risk.
Previous research indicates increased prostate cancer risk for pesticide applicators and pesticide manufacturing workers. Although underlying mechanisms are unknown, evidence suggests a role of oxidative DNA damage. Because base excision repair (BER) is the predominant pathway involved in repairing oxidative damage, we evaluated interactions between 39 pesticides and 394 tag single-nucleotide polymorphisms (SNPs) for 31 BER genes among 776 prostate cancer cases and 1,444 male controls in a nested case-control study of white Agricultural Health Study (AHS) pesticide applicators. We used likelihood ratio tests from logistic regression models to determine p-values for interactions between three-level pesticide exposure variables (none/low/high) and SNPs (assuming a dominant model), and the false discovery rate (FDR) multiple comparison adjustment approach. The interaction between fonofos and rs1983132 in NEIL3 [nei endonuclease VIII-like 3 (Escherichia coli)], which encodes a glycosylase that can initiate BER, was the most significant overall [interaction p-value (pinteract) = 9.3 × 10-6; FDR-adjusted p-value = 0.01]. Fonofos exposure was associated with a monotonic increase in prostate cancer risk among men with CT/TT genotypes for rs1983132 [odds ratios (95% confidence intervals) for low and high use compared with no use were 1.65 (0.91, 3.01) and 3.25 (1.78, 5.92), respectively], whereas fonofos was not associated with prostate cancer risk among men with the CC genotype. Carbofuran and S-ethyl dipropylthiocarbamate (EPTC) interacted similarly with rs1983132; however, these interactions did not meet an FDR < 0.2. Our significant finding regarding fonofos is consistent with previous AHS findings of increased prostate cancer risk with fonofos exposure among those with a family history of prostate cancer. Although requiring replication, our findings suggest a role of BER genetic variation in pesticide-associated prostate cancer risk.


Association of Age-Related Cataract With Skin Cancer in an Australian Population.
Ultraviolet radiation from sunlight contributes to age-related cataract and skin cancer. The EPHA2 gene is implicated in both these diseases. The purpose of this study was to determine whether age-related cataract and skin cancer are associated in a cohort of older Australians. A cross-sectional study was performed using the Historical Cohort of the Registry of Senior Australians. Individuals aged ≥65 years or aged ≥50 years and of Aboriginal or Torres Strait Islander descent, who had an aged care eligibility assessment between July 2005 and June 2015, and had a history of cataract surgery and/or skin cancer according to the Australian Government Medicare Benefits Schedule dataset, during the 3-year period prior, were evaluated (N = 599,316). A multivariable logistic regression model was used to determine association and multiple hypothesis correction was employed. Of the evaluated individuals, 87,097 (14.5%) had a history of cataract and 170,251 (28.4%) a history of skin cancer. Among those with a history of cataract, 20,497 (23.5%), 1127 (1.3%), and 14,730 (16.9%) individuals had a concurrent history of keratinocyte, melanoma, and premalignant/solar keratosis, respectively. Those with a history of cataract were 19% more likely to have a history of skin cancer (odds ratio [OR], 1.19; 95% confidence interval [CI], (1.17-1.21). Co-occurrence of keratinocyte skin cancer was 16% (OR, 1.16; 95% CI, 1.14-1.18), melanoma 21% (OR, 1.21; 95% CI, 1.13-1.29), and premalignant/solar keratosis 19% (OR, 1.19; 95% CI, 1.17-1.22) more in the presence than absence of history of cataract. Age-related cataract is positively associated with skin cancer and its subtypes, including premalignant lesions in an older Australian population.


Changing healthcare professionals' behaviors to eliminate disparities in healthcare: What do we know? How might we proceed?
The patient-healthcare provider communication process--particularly the provider's cultural competency--is increasingly recognized as a key to reducing racial/ethnic disparities in health and healthcare utilization. A working group was formed by the Office of Minority Health, Department of Health and Human Services to identify strategies for improving healthcare providers' cultural competency. This expert panel, one of several working groups called together to explore methods of reducing healthcare disparities, was comprised of individuals from academic medical centers and health professional organizations who were nationally recognized as having expertise in healthcare communication as it relates to diverse populations. During the 2-day conference, the panel identified, from personal experience and knowledge of the literature, key points of intervention and interventions most likely to improve the cross-cultural competency of healthcare providers. Proposed interventions included introduction of cultural competence education before, during, and after clinical training; implementation of certification and accreditation requirements in cross-cultural competence for practicing healthcare providers; use of culturally diverse governing boards for clinical practices; and active promotion of workforce cross-cultural diversity by healthcare organization administrators. For each intervention, methods for implementation were specified. On-going monitoring and evaluation of processes of care using race/ethnicity data were recommended to ensure the programs were functioning.


Dielectric effects on the ion distribution near a Janus colloid.
Spherical Janus colloids, particles with different surface properties on their two hemispheres, are generally heterogeneous in permittivity. This dielectric heterogeneity may affect their behavior in electrolytes and external electric fields, but is typically not taken into account in computational studies. We apply the iterative dielectric solver developed by Barros and Luijten [Phys. Rev. Lett., 2014, 113, 017801] in combination with preconditioning techniques that can accurately and efficiently compute the polarization of dielectrically anisotropic particles. Employing this approach, we systematically study the ion distribution around neutral and charged Janus particles with various permittivities, immersed in symmetric and asymmetric electrolytes. We demonstrate that neutral Janus colloids may carry a nonzero dipole moment in asymmetric salts. For charged Janus colloids, dielectric effects can substantially influence the electric double layer. These findings also have implications for other dielectrically anisotropic entities, such as proteins.