Axon fasciculation in the developing olfactory nerve.
Olfactory sensory neuron (OSN) axons exit the olfactory epithelium (OE) and extend toward the olfactory bulb (OB) where they coalesce into glomeruli. Each OSN expresses only 1 of approximately 1,200 odor receptors (ORs). OSNs expressing the same OR are distributed in restricted zones of the OE. However, within a zone, the OSNs expressing a specific OR are not contiguous - distribution appears stochastic. Upon reaching the OB the OSN axons expressing the same OR reproducibly coalesce into two to three glomeruli. While ORs appear necessary for appropriate convergence of axons, a variety of adhesion associated molecules and activity-dependent mechanisms are also implicated. Recent data suggest pre-target OSN axon sorting may influence glomerular convergence. Here, using regional and OR-specific markers, we addressed the spatio-temporal properties associated with the onset of homotypic fasciculation in embryonic mice and assessed the degree to which subpopulations of axons remain segregated as they extend toward the nascent OB. We show that immediately upon crossing the basal lamina, axons uniformly turn sharply, usually at an approximately 90° angle toward the OB. Molecularly defined subpopulations of axons show evidence of spatial segregation within the nascent nerve by embryonic day 12, within 48 hours of the first OSN axons crossing the basal lamina, but at least 72 hours before synapse formation in the developing OB. Homotypic fasciculation of OSN axons expressing the same OR appears to be a hierarchical process. While regional segregation occurs in the mesenchyme, the final convergence of OR-specific subpopulations does not occur until the axons reach the inner nerve layer of the OB.


Bicycle safety programs: targeting injury prevention through education.
Children especially are prone to bicycle injuries, many of which are preventable. Data from an assessment of pediatric bicycle-related injuries at a major Southeastern Tennessee trauma center were used to support the need for a public awareness program about children's bicycle safety. Results of the assessment are reviewed and program planning, implementation, and evaluation are described.


Effects of Substance Use Disorder Criminalization on American Indian Pregnant Individuals.
Individuals with substance use disorders (SUDs) are at markedly elevated risk of involvement in the criminal legal system. Over the past 30 years, substance use during pregnancy has been criminalized through laws on the federal, state, and tribal level. American Indian (AI) individuals are disproportionately affected by these laws due to their race, socioeconomic status, and limited access to SUD treatment. This article aims to educate readers on laws criminalizing substance use during pregnancy and on how AI individuals are disproportionately affected by these laws. It also discusses how these laws conflict with the ethical principles of autonomy, nonmaleficence, and justice. Finally, this article recommends that clinicians advocate for the decriminalization of SUDs during pregnancy and for improvement in access to comprehensive, evidence-based SUDs care.


[What is new in pediatric nephrology?].
Recent advances in the knowledge of physiology, genetics, imaging, and therapeutics have lead to novel practical approaches in paediatric nephrology. Many inherited syndromes have been revisited in order to identify precise renal diseases at the molecular level. In addition, a large number of epidemiological studies and clinical trials have allowed guidelines and recommendations to be provided for chronic and end-stage renal failure, urinary tract infection, glomerular diseases, etc.


Risk factors for pelvic organ prolapse repair after hysterectomy.
To estimate the incidence and identify the risk factors for pelvic organ prolapse repair after hysterectomy. We conducted a case-control study. We identified 6,214 women who underwent hysterectomy in our gynecology department from 1982 to 2002. Cases (n=114) were women who required pelvic organ prolapse surgery after hysterectomy from January 1982 through December 2005. Controls (n=236) were women randomly selected from the same cohort who did not require pelvic organ surgery during the same period. We performed a univariable and a multivariable analysis among 104 cases and 190 controls to identify the variables associated with prolapse repair after hysterectomy. The incidence of pelvic organ prolapse that required surgical correction after hysterectomy was 1.3 per 1,000 women-years. The risk of prolapse repair was 4.7 times higher in women whose initial hysterectomy was indicated by prolapse and 8.0 times higher if preoperative prolapse grade 2 or more was present. Risk factors included preoperative prolapse grade 2 or more (adjusted odds ratio [OR] 12.6, 95% confidence interval [CI] 4.6-34.7), previous pelvic organ prolapse or urinary incontinence surgery (adjusted OR 7.9, 95% CI 1.3-48.2), history of vaginal delivery (adjusted OR 5.0, 95% CI 1.3-19.7), and sexual activity (adjusted OR 6.2, 95% CI 2.7-14.5). Vaginal hysterectomy was not a risk factor when preoperative prolapse was taken into account (adjusted OR 0.7, 95% CI 0.4-1.1). Preoperative pelvic organ prolapse and other factors related to pelvic floor weakness were significantly associated with subsequent pelvic floor repair after hysterectomy. Vaginal hysterectomy was not a risk factor. II.


Three-dimensional facial analysis using a video imaging system.
The purpose of this article was twofold: (1) to provide an estimate of error in the digitization of various soft tissue landmarks using a video imaging system, and (2) to evaluate the relationships of various soft tissue measurements in balanced young adult faces. A video imaging system was used to digitize frontal and lateral soft tissue landmarks on 25 male and 25 female Caucasian young adults with Class I occlusion and esthetically pleasing and balanced soft-tissue profiles. Twenty subjects were redigitized and only two measurements showed a statistically significant error. Large variabilities were found for several measurements. Males, in general, had greater soft tissue thickness, facial depth and width, and lip length than females. The measurements were found to compare favorably with previous reports. Imaging systems were seen to have the advantage of providing reliable measurements in all three dimensions without the potential hazards of ionizing radiation.


Loci discovery, network-guided approach, and genomic prediction for drought tolerance index in a multi-parent advanced generation intercross (MAGIC) cowpea population.
Cowpea is a nutrient-dense legume that significantly contributes to the population's diet in sub-Saharan Africa and other regions of the world. Improving cowpea cultivars to be more resilient to abiotic stress such as drought would be of great importance. The use of a multi-parent advanced generation intercross (MAGIC) population has been shown to be efficient in increasing the frequency of rare alleles that could be associated with important agricultural traits. In addition, drought tolerance index has been reported to be a reliable parameter for assessing crop tolerance to water-deficit conditions. Therefore, the objectives of this study were to evaluate the drought tolerance index for plant growth habit, plant maturity, flowering time, 100-seed weight, and grain yield in a MAGIC cowpea population, to conduct genome-wide association study (GWAS) and identify single nucleotide polymorphism (SNP) markers associated with the drought tolerance indices, to investigate the potential relationship existing between the significant loci associated with the drought tolerance indices, and to conduct genomic selection (GS). These analyses were performed using the existing phenotypic and genotypic data published for the MAGIC population which consisted of 305 F8 recombinant inbred lines (RILs) developed at University of California, Riverside. The results indicated that: (1) large variation in drought tolerance indices existed among the cowpea genotypes, (2) a total of 14, 18, 5, 5, and 35 SNPs were associated with plant growth habit change due to drought stress, and drought tolerance indices for maturity, flowering time, 100-seed weight, and grain yield, respectively, (3) the network-guided approach revealed clear interactions between the loci associated with the drought tolerance traits, and (4) the GS accuracy varied from low to moderate. These results could be applied to improve drought tolerance in cowpea through marker-assisted selection (MAS) and genomic selection (GS). To the best of our knowledge, this is the first report on marker loci associated with drought tolerance indices in cowpea.


[Vertebral trabecular bone in various age groups and in osteoporosis-- morphometry and bone matrix biochemistry].
Vertebral trabecular bone was analysed by morphometry and bone matrix biochemistry. Trabecular bone volume (TBV) and mean trabecular plate thickness (MTPT) decreased with age. TBV was significantly correlated with MTPT and mean trabecular plate density (MTPD). The individual structure of trabecular bone could be described by both MTPT and MTPD together, but changes of these parameters, that were pathognomonic for osteopenia, were not found. By measuring TBV 3 cases of severe osteopenia were identified (TBV less than 2s of controls); 2 of them showed matrix abnormalities so far not described. In one case (a 67 year old woman without risk factors for osteoporosis) an abnormal high content of type III collagen was found, in the other case (a 44 year old woman with acromegaly) bone matrix analysis atypically revealed a significant fraction of type II collagen. Further studies will be needed to assess the pathogenetic or diagnostic importance of these new findings.


Characterization and functional analysis of atl, a novel gene encoding autolysin in Streptococcus suis.
Streptococcus suis serotype 2 (S. suis 2) is an important swine and human pathogen responsible for septicemia and meningitis. A novel gene, designated atl and encoding a major autolysin of S. suis 2 virulent strain HA9801, was identified and characterized in this study. The Atl protein contains 1,025 amino acids with a predicted molecular mass of 113 kDa and has a conserved N-acetylmuramoyl-l-alanine amidase domain. Recombinant Atl was expressed in Escherichia coli, and its bacteriolytic and fibronectin-binding activities were confirmed by zymography and Western affinity blotting. Two bacteriolytic bands were shown in the sodium dodecyl sulfate extracts of HA9801, while both were absent from the atl inactivated mutant. Cell chains of the mutant strain became longer than that of the parental strain. In the autolysis assay, HA9801 decreased to 20% of the initial optical density (OD) value, while the mutant strain had almost no autolytic activity. The biofilm capacity of the atl mutant was reduced ∼30% compared to the parental strain. In the zebrafish infection model, the 50% lethal dose of the mutant strain was increased up to 5-fold. Furthermore, the adherence to HEp-2 cells of the atl mutant was 50% less than that of the parental strain. Based on the functional analysis of the recombinant Atl and observed effects of atl inactivation on HA9801, we conclude that Atl is a major autolysin of HA9801. It takes part in cell autolysis, separation of daughter cells, biofilm formation, fibronectin-binding activity, cell adhesion, and pathogenesis of HA9801.


Trichoblastic carcinosarcoma in a 34-year-old woman with histopathologic and molecular analysis, including re-demonstration of a CDKN2A p.(R58*) mutation.
Trichoblastic carcinosarcomas are rare, adnexal-type cutaneous carcinosarcomas that are thought to be related histogenetically to trichoblastomas, yet in which both the epithelial and stromal components show features of malignancy. Ten cases have been described in the literature thus far, with a predilection for the head and neck of older males. We present a case of cutaneous carcinosarcoma in sun-damaged skin of a 34-year-old woman showing features of a trichoblastic carcinosarcoma, with histopathologic analysis along with targeted next-generation sequencing of 50 cancer-associated genes. Two pathogenic variants in TP53 were identified, p.(R158C), p.(R273P), along with a likely pathogenic variant CDKN2A, p.(R58*). In particular, it is noted that the CDKN2A p.(R58*) missense mutation has been described in two previous cases of cutaneous carcinosarcomas, including a case of trichoblastic carcinosarcoma.


Metallic implants and CT artefacts in the CTV area: Where are we in 2020?
Radiation therapy (RT) is one of the main modalities of cancer treatment worldwide with computed tomography (CT), as the most commonly used imaging method for treatment planning system (TPS). Image reconstruction errors may greatly affect all the radiation therapy planning process, such as target delineation, dose calculation and delivery, particularly with particle therapy. Metallic implants, such as hip and spinal implants, and dental filling significantly deteriorate image quality. These hardware structures are often very complex in geometry leading to geometric complex artefacts in the clinical target volume (CTV) area, rendering the delineation of CTV challenging. In our review, we focus on the methods to overcome artefact consequences on CTV delineation: 1- medical approaches anticipating issues associated with imaging artefacts during preoperative multidisciplinary discussions while following standard recommendations; 2- common metal artefact reduction (MAR) methods such as manually override artefact regions, ballistics avoiding beam paths through implanted materials, megavoltage-CT (MVCT); 3- prospects with radiolucent implants, MAR algorithms and various methods of dual energy computed tomography (DECT). Despite substantial and broad evidence for their benefits, there is still no universal solution for cases involving implanted metallic devices. There is still a high need for research efforts to adapt technologies to our issue: "how do I accurately delineate the ideal CTV in a metal artefact area?"


Unique Effect of Aspirin Therapy on Biomarkers in Aspirin-exacerbated Respiratory Disease. A Prospective Trial.
Rationale: Daily high-dose aspirin therapy benefits many patients with aspirin-exacerbated respiratory disease but provides no benefit for aspirin-tolerant patients with asthma. Type 2 inflammation characterizes aspirin-exacerbated respiratory disease.Objectives: To determine whether high-dose aspirin therapy changes biomarkers of type 2 inflammation in aspirin-exacerbated respiratory disease.Methods: Forty-two subjects with aspirin-exacerbated respiratory disease underwent an aspirin desensitization and were placed on high-dose aspirin (1,300 mg daily). Fifteen aspirin-tolerant subjects with asthma were also placed on high-dose aspirin. Biologic specimens and clinical parameters were collected at baseline and after 8 weeks on aspirin. Urinary eicosanoids, plasma tryptase and cytokine levels, platelet-leukocyte aggregates, and granulocyte transcripts were assessed.Measurements and Main Results: Eight weeks of high-dose aspirin decreased nasal symptoms and urinary prostaglandin E metabolite (P < 0.05) and increased urinary leukotriene E4 (P < 0.01) levels in subjects with aspirin-exacerbated respiratory disease, but not in those with aspirin-tolerant asthma. Urinary prostaglandin D2 and thromboxane metabolites decreased in both groups. Only in subjects with aspirin-exacerbated respiratory disease, exhaled nitric oxide (P < 0.05), plasma tryptase (P < 0.01), and blood eosinophil (P < 0.01) and basophil (P < 0.01) counts increased and plasma tryptase correlated with eosinophil counts (Pearson r = 0.514; P < 0.01) on aspirin. After correction for eosinophil counts, aspirin-induced changes in blood granulocyte transcripts did not differ between groups. Aspirin had no effect on platelet-leukocyte aggregates, platelet activation markers, or plasma cytokines in either group.Conclusions: High-dose aspirin therapy for 8 weeks paradoxically increases markers of type 2 inflammation in subjects with aspirin-exacerbated respiratory disease, despite reducing nasal symptoms. This effect of aspirin is unique to aspirin-exacerbated respiratory disease and not observed in subjects with aspirin-tolerant asthma.


Factors associated with perceived unmet dental care needs of older adults.
Although older adults have high dental care needs as a result of prevalent oral health problems, they have high unmet needs. The purpose of the present study was to examine factors associated with unmet dental care needs among older adults living in the community. This study analyzed 1419 adults aged 65 years and older who participated in both the health interview survey and oral examination of the Fifth Korea National Health and Nutrition Examination Survey carried out in 2010. Predisposing (age, sex, education, marital status), enabling (place of residence, work status, income, health insurance) and need (self-rated oral health, difficulty chewing, toothache, number of teeth, dental caries, periodontal disease) factors associated with self-perceived unmet dental care needs were analyzed through multiple logistic regression analysis. Unmet dental care needs accounted for 27.9% in older adults. Age, income, difficulty chewing and the presence of permanent tooth caries were significantly associated with unmet dental care needs, adjusting for covariates. Compared with those aged 75 years and older, the 65-69 years age group showed 1.86-fold higher odds of unmet dental care needs. Lower household income was associated with a higher likelihood of not receiving dental care when required. Unmet dental care needs were significantly higher among those with chewing difficulty (OR 2.14, 95% CI 1.55, 2.95) and permanent tooth caries (OR 1.86, 95% CI 1.28-2.70). Unmet dental care needs are prevalent in older people who are socioeconomically disadvantaged and vulnerable in oral health. Geriatr Gerontol Int 2017; 17: 1936-1942.


Hypersensitivity pneumonitis: whole Micropolyspora faeni or antigens thereof stimulate the release of proinflammatory cytokines from macrophages.
Hypersensitivity pneumonitis (HP) is an allergic granulomatous interstitial lung disease resulting from a reaction of selected individuals to repeated inhalations of certain antigens. HP is characterized by chronic inflammation, and the development of the disease seems to be immunologically mediated. In farmer's lung, the source of provoking antigen has been found to be actinomycetes such as Micropolyspora faeni. In this study, we show that M. faeni, or antigens thereof, stimulate strong release of proinflammatory cytokines from blood monocytes and alveolar macrophages obtained from nonfarmer volunteers and naive mouse peritoneal macrophages. Interleukin-1 (IL-1) was produced by human alveolar macrophages and murine peritoneal macrophages in response to whole M. faeni and antigens thereof. IL-1 activity was detected in the supernatants at 12 h of incubation and was maximal by 24 to 36 h (200 to 400 U/ml of IL-1). A rabbit antiserum to IL-1 alpha and IL-1 beta neutralized the thymocyte-stimulating activity of the supernatants. Moreover, M. faeni (1 to 100 micrograms of antigen) elicited a strong secretion of tumor necrosis factor-alpha (TNF-alpha) from human alveolar macrophages and monocytes as well as mouse peritoneal macrophages, where 1 micrograms of M. faeni elicited the secretion of approximately 100 U of TNF-alpha from 2 x 10(5) macrophages, and 100 micrograms stimulated the release of approximately 1,000 U of bioactive TNF-alpha. One particle of whole M. faeni per cell was sufficient to induce copious release of TNF-alpha from macrophages or monocytes (100 U of bioactive TNF-alpha; 1,000 pg/ml of antigenic TNF-alpha as seen by radioimmunoassay). Both IL-1 and TNF-alpha productions stimulated by M. faeni were not abrogated by inclusion of polymyxin B. We propose that the direct stimulation of cytokines by M. faeni or antigens thereof may play an important role in HP.


Utilization and expenditures for ambulatory medical care by people hospitalized: United States, 1980.
The National Medical Care Utilization and Expenditure Survey was conducted throughout 1980 to collect information on health, access to and use of medical services, associated charges and sources of payment, and health insurance coverage. The survey was based on a probability sample of about 6,600 households and 17,123 people representative of the civilian noninstitutionalized population of the United States. This report is one of a series of descriptive reports based on data from the National Medical Care Utilization and Expenditure Survey. It characterizes the population by hospital utilization and certain sociodemographic and health variables, and shows how hospitalization effects the use and cost of ambulatory medical care. The following are some of the highlights of the report. Almost everyone was covered by some form of health insurance at some time during 1980. Only 7.6 percent were not covered at all, and 10 percent had insurance only part of the year. The proportion not covered at all varied according to the number of times hospitalized, ranging from 8.2 percent for people not hospitalized during the year to 1.8 percent for people hospitalized three or more times. People with one or more hospital stays during 1980 had a physician visit rate greater than three times that for people not hospitalized. Similarly, the expenditures for ambulatory medical care for people experiencing hospitalizations was almost nine times that for people were not hospitalized during the year. The rate of physician visits is much larger immediately prior to hospital admission or immediately after discharge than it is at other times. About 40 percent of all physician visits during the year occurred within a month before admission and after discharge. within a month before admission and after discharge.


[Reversal effect of 5-Aza-dc on cisplatin-resistance in human NSCLC cells in vitro].
The aim of this study was to investigate the effect of 5-aza-2'-deoxycytidine (5-Aza-dc), a methylation inhibitor, on cisplatin-resistance in non-small cell lung cancer cell line A549/DDP and to explore its possible mechanism. MTT assay was used to test the cytotoxicity of 5-Aza-dc on A549/DDP cells, and the IC(50) and cisplatin resistance index of A540/DDP cells at 48 hours after 5-Aza-dc (0 µmol/L, 20 µmol/L, 40 µmol/L) treatment at different concentrations. MSP, fluorescence quantitative RT-PCR (real-time RT-PCR) and Western blot were used to detect the hMLH1 methylation status, mRNA and protein expressions, respectively. The IC(50) value of cisplatin in A549/DDP cells was 30.15 ± 0.76 µmol/L. The MTT assay results demonstrated that during the 5-Aza-dc treatment for 48 hours, the dose of 20 µmol/L was non-toxic and 40 µmol/L was low-toxic. 5-Aza-dc at those two doses reduced IC(50) value of cisplatin to 16.54 ± 0.35 µmol/L (RI = 1.82) and 6.82 ± 0.16 µmol/L (RI = 4.42), respectively. MSP, real-time RT-PCR and Western blot showed that 5-Aza-dc at non-toxic and low-toxic doses removed the partial hMLH1-hypermethylation, and up-regulated hMLH1 mRNA and protein expressions. Low dose 5-Aza-dc can partially reverse the cisplatin-resistance in A549/DDP cells, which may be achieved through removal of hMLH1 hypermethylation and increased expression of hMLH1 gene. 5-Aza-dc may have a role in increasing the efficacy of chemotherapy for patients whose tumors are lack of hMLH1 expression because of hMLH1 promoter hypermethylation.


Changes of paired-pulse evoked responses during the development of epileptic activity in the hippocampus.
Dysfunction of inhibitory synaptic transmission can destroy the balance between excitatory and inhibitory synaptic inputs in neurons, thereby inducing epileptic activity. The aim of the paper is to investigate the effects of successive excitatory inputs on the epileptic activity induced in the absence of inhibitions. Paired-pulse orthodromic and antidromic stimulations were used to test the changes in the evoked responses in the hippocampus. Picrotoxin (PTX), γ-aminobutyric acid (GABA) type A (GABA(A)) receptor antagonist, was added to block the inhibitory synaptic transmission and to establish the epileptic model. Extracellular evoked population spike (PS) was recorded in the CA1 region of the hippocampus. The results showed that the application of PTX induced a biphasic change in the paired-pulse ratio of PS amplitude. A short latency increase of the second PS (PS2) was later followed by a reappearance of PS2 depression. This type of depression was observed in both orthodromic and antidromic paired-pulse responses, whereas the GABAergic PS2 depression [called paired-pulse depression (PPD)] during baseline recordings only appeared in orthodromic-evoked responses. In addition, the depression duration at approximately 100 ms was consistent with a relative silent period observed within spontaneous burst discharges induced by prolonged application of PTX. In conclusion, the neurons may ignore the excitatory inputs and intrinsically generate bursts during epileptic activity. The depolarization block could be the mechanisms underlying the PPD in the absence of GABA(A) inhibitions. The distinct neuronal responses to stimulations during different epileptic stages may implicate the different antiepileptic effects of electrical stimulation.


How I treat paroxysmal nocturnal hemoglobinuria.
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, clonal, complement-mediated hemolytic anemia with protean manifestations. PNH can present as a hemolytic anemia, a form of bone marrow failure, a thrombophilia, or any combination of the above. Terminal complement inhibition is highly effective for treating intravascular hemolysis from PNH and virtually eliminates the risk of thrombosis, but is not effective for treating bone marrow failure. Here, I present a variety of clinical vignettes that highlight the clinical heterogeneity of PNH and the attributes and limitations of the 2 US Food and Drug Administration-approved C5 inhibitors (eculizumab and ravulizumab) to treat PNH. I review the concept of pharmacokinetic and pharmacodynamic breakthrough hemolysis and briefly discuss new complement inhibitors upstream of C5 that are in clinical development. Last, I discuss the rare indications for bone marrow transplantation in patients with PNH.


Evolutionary relationships among large double-stranded DNA viruses that infect microalgae and other organisms as inferred from DNA polymerase genes.
In order to examine genetic relatedness among viruses that infect microalgae, DNA polymerase gene (DNA pol) fragments were amplified and sequenced from 13 virus clones that infect three genera of distantly related microalgae (Chlorella strains NC64A and Pbi, Micromonas pusilla and Chrysochromulina spp.). Phylogenetic trees based on DNA pol sequences and hybridization of total genomic DNA showed similar branching patterns. Genetic relatedness calculated from the hybridization and sequence data showed good concordance (r=0.90), indicating that DNA pol sequences can be used to determine genetic relatedness and infer phylogenetic relationships among these viruses. The phylogenetic tree inferred from the deduced amino acid sequences of DNA pol from 24 dsDNA viruses, including phycodnaviruses, herpesviruses, poxviruses, baculoviruses, and African swine fever virus corresponded well with groupings based on the International Committee on Taxonomy of Viruses. Microalgal viruses are more closely related to each other than to the other dsDNA viruses and form a distinct phyletic group, suggesting that they share a common ancestor and belong to the Phycodnaviridae. Moreover, the Phycodnaviridae are more closely related to the Herpesviridae than to other virus families for which DNA pol sequences are available.


Effect of radiation on age at menopause among atomic bomb survivors.
Exposure to ionizing radiation has been thought to induce ovarian failure and premature menopause. Proximally exposed female atomic bomb survivors were reported to experience menopause immediately after the exposure more often than those who were distally exposed. However, it remains unclear whether such effects were caused by physical injury and psychological trauma or by direct effects of radiation on the ovaries. The objective of this study was to see if there are any late health effects associated with the exposure to atomic bomb radiation in terms of age at menopause in a cohort of 21,259 Life Span Study female A-bomb survivors. Excess absolute rates (EAR) of natural and artificial menopause were estimated using Poisson regression. A linear threshold model with a knot at 0.40 Gy [95% confidence interval (CI): 0.13, 0.62] was the best fit for a dose response of natural menopause (EAR at 1 Gy at age of 50 years = 19.4/1,000 person-years, 95% CI: 10.4, 30.8) and a linear threshold model with a knot at 0.22 Gy (95% CI: 0.14, 0.34) was the best fit for artificial menopause (EAR at 1 Gy at age of 50 years for females who were exposed at age of 20 years = 14.5/1,000 person-years, 95% CI: 10.2, 20.1). Effect modification by attained age indicated that EARs peaked around 50 years of age for both natural and artificial menopause. Although effect modification by age at exposure was not significant for natural menopause, the EAR for artificial menopause tended to be larger in females exposed at young ages. On the cumulative incidence curve of natural menopause, the median age at menopause was 0.3 years younger in females exposed to radiation of 1 Gy compared with unexposed females. The median age was 1 year younger for combined natural and artificial menopause in the same comparison. In conclusion, age at menopause was thought to decrease with increasing radiation dose for both natural and artificial menopause occurring at least 5 years after the exposure.


Exponentially weighed moving average charts for monitoring zero-inflated proportions with applications in health care.
In the context of public health surveillance, the aim is to monitor the occurrence of health-related events. Among them, statistical process monitoring focuses very often on the monitoring of rates and proportions (i.e. values in (0,1)) such as the proportion of patients with a specific disease. A popular control chart that is able to detect quickly small to moderate shifts in process parameters is the exponentially weighed moving average control chart. There are various models that are used to describe values in (0,1). However, especially in the case of rare health events, zero values occur very frequently which, for example, denote the absence of the disease. In this paper, we study the performance and the statistical design of exponentially weighed moving average control charts for monitoring proportions that arise in a health-related framework. The proposed chart is based on the zero-inflated Beta distribution, a mixed (discrete-continuous) distribution, suitable for modelling data in [0,1). We use a Markov chain method to study the run length distribution of the exponentially weighed moving average chart. Also, we investigate the statistical design as well as the performance of the proposed charts. Comparisons with a Shewhart-type chart are also given. Finally, we provide an example for the practical implementation of the proposed charts.


Effects of circumferential ankle pressure on ankle proprioception, stiffness, and postural stability: a preliminary investigation.
Cross-sectional repeated-measures design. Determine the effects of circumferential ankle pressure (CAP) intervention on proprioceptive acuity, ankle stiffness, and postural stability. The application of CAP using braces, taping, and adaptive shoes or military boots is widely used to address chronic ankle instability (CAI). An underlying assumption is that the CAP intervention might improve ankle stability through increased proprioceptive acuity and stiffness in the ankle. METHOD AND MEASURES: A convenience sample of 10 subjects was recruited from the local university community and categorized according to proprioceptive acuity (high, low) and ankle stability (normal, CAI). Proprioceptive acuity was measured when blindfolded subjects were asked to accurately reproduce a self-selected target ankle position before and after the application of CAP. Proprioceptive acuity was determined in 5 different ankle joint position sense tests: neutral, inversion, eversion, plantar flexion, and dorsiflexion. Joint position angles were recorded electromechanically using a potentiometer. Passive ankle stiffness was computed from the ratio of applied static moment versus angular displacement. Active ankle stiffness was determined from biomechanical analyses of ankle motion following a mediolateral perturbation. Postural stability was quantified from the center of pressure displacement in the mediolateral and the anteroposterior directions in unipedal stance. All measurements were recorded with and without CAP applied by a pediatric blood pressure cuff. Data were analyzed using a separate mixed-model analysis of variance (ANOVA) for each dependent variable. Post hoc comparison using Tukey's honestly significant difference (HSD) test was performed if significant interactions were obtained. Significance level was set at P<.05 for all analyses. Significant group (high versus low proprioceptive acuity) x CAP interactions were identified for postural stability. Passive ankle stiffness was not increased by an application of CAP. Active ankle stiffness was significantly different between the high and low proprioceptive acuity groups and was not affected by an application of CAP. Significant group (normal versus CAI) x CAP interactions were observed for mediolateral center-of-pressure displacement with a main effect of group on neutral joint position sense. Application of CAP increased proprioceptive acuity and demonstrated trends toward increased active stiffness in the ankle, hence improved postural stability. The effects tend to be limited to individuals with low proprioceptive acuity.


Stratified initial values and change scores.
A common question that is encountered in many studies is relating a change in a variable to the variable's initial value. It is well known that regressing the change on the initial value creates a spurious association and misleads the unwary. One attempt to cope with this problem has been to stratify that data based on the initial value. We show that this approach does not solve the problem. Theoretical and simulation results for independent normal and independent exponential random variables are provided.


Acute intestinal ischemia. A 14-year retrospective investigation.
The records of 60 patients with acute intestinal ischemia treated between 1969 and 1982 were studied retrospectively. Fifty-three patients (88%) had thrombosis or embolus of the superior mesenteric artery and 7 patients (12%) occlusion of the superior mesenteric vein. Initial symptoms were obscure, although 25% presented with signs of peritonitis. The most frequently used investigation was plain abdominal X-ray with a positive finding in only 1/3. Forty-three patients (72%) were operated on. In 18 patients irreversible changes were found. Total mortality rate was 82%, in SMA-thromboembolism 85% and in SMV-thrombosis 57%. To improve the prognosis clinical awareness of the problem and attempts towards early diagnosis should be raised.


Influence of three coccidiostats on the pharmacokinetics of florfenicol in rabbits.
In-feed Medication has been used for a long time to prevent coccidiosis, a worldwide protozoal disease in rabbits. Florfenicol (FFC) has been widely used in veterinary clinics for bacterial diseases treatment. Therefore, the use of combinations of coccidiostats with FFC in rabbits is common. In the present study, we aimed to evaluate the effect of three coccidiostats, sulfaquinoxaline (SUL), robenidine (ROB), and toltrazuril (TOL), as feed additives on the pharmacokinetic profile of FFC in rabbits. The disposition kinetics of FFC in rabbits were investigated after a single intravenous injection (25 mg/kg) in rabbits fed anticoccidial-free diets or feeds containing SUL (250 ppm), ROB (66 ppm), or TOL (2 ppm), respectively, for 20 days. Plasma FFC concentrations were determined by the high performance liquid chromatography (HPLC) method. The pharmacokinetic parameters of FFC were analyzed using a non-compartmental analysis based on the statistical moment theory. The results demonstrated that ROB feeding resulted in an obvious decrease in plasma FFC level as compared with anticoccidial-free feeding. The terminal elimination half-life (t1/2z), area under the concentration-time curve (AUC), area under the first moment curve (AUMC), and mean residence time (MRT) significantly decreased, whereas the elimination rate constant (λz) and total body clearance (CLz) obviously increased in rabbits pretreated with ROB. However, we did not find that SUL or TOL feeding had any effect on the pharmacokinetic profile of FFC. Our findings suggested that more attention should be paid to the use of FFC in rabbits supplemented with ROB.


Atypical antidepressants versus imipramine in the treatment of major depression: a meta-analysis.
Our investigation involved a quantitative literature review technique known as meta-analysis to compare the efficacy of three newer antidepressants and imipramine. We examined seven major journals in psychiatry from 1980 through 1990, inclusive, and selected those investigations of imipramine, trazodone, bupropion, and fluoxetine that met our minimal criteria for interpretability. These criteria included: (1) the presence of a placebo control, (2) double-blind status, (3) the use of the Hamilton Rating Scale for Depression as a dependent variable measure, (4) the use of nongeriatric adults with a diagnosis of major depression by DSM or RDC standards, and (5) the presence of reported means and standard deviations in the investigation, or sufficient data that allowed such to be computed. Each study of four antidepressants was analyzed for an effect size of the drug investigated. The effect size allows for a determination of the efficacy of a particular drug as compared with placebo, measured in standard deviation units. The data indicated that all four agents are effective as compared with placebo. Furthermore, there is no evidence that the newer heterocyclic agents are less effective than imipramine, as an ANOVA showed no statistically significant difference between the effect sizes of the four antidepressants. These data are discussed in terms of characteristics of the various investigations and the need for further research comparing the efficacy of psychopharmacologic agents.


Milk-Derived Exosomes as Nanocarriers to Deliver Curcumin and Resveratrol in Breast Tissue and Enhance Their Anticancer Activity.
Dietary (poly)phenols are extensively metabolized, limiting their anticancer activity. Exosomes (EXOs) are extracellular vesicles that could protect polyphenols from metabolism. Our objective was to compare the delivery to breast tissue and anticancer activity in breast cancer cell lines of free curcumin (CUR) and resveratrol (RSV) vs. their encapsulation in milk-derived EXOs (EXO-CUR and EXO-RSV). A kinetic breast tissue disposition was performed in rats. CUR and RSV were analyzed using UPLC-QTOF-MS and GC-MS, respectively. Antiproliferative activity was tested in MCF-7 and MDA-MB-231 breast cancer and MCF-10A non-tumorigenic cells. Cell cycle distribution, apoptosis, caspases activation, and endocytosis pathways were determined. CUR and RSV peaked in the mammary tissue (41 ± 15 and 300 ± 80 nM, respectively) 6 min after intravenous administration of EXO-CUR and EXO-RSV, but not with equivalent free polyphenol concentrations. Nanomolar EXO-CUR or EXO-RSV concentrations, but not free CUR or RSV, exerted a potent antiproliferative effect on cancer cells with no effect on normal cells. Significant (p < 0.05) cell cycle alteration and pro-apoptotic activity (via the mitochondrial pathway) were observed. EXO-CUR and EXO-RSV entered the cells primarily via clathrin-mediated endocytosis, avoiding ATP-binding cassette transporters (ABC). Milk EXOs protected CUR and RSV from metabolism and delivered both polyphenols to the mammary tissue at concentrations compatible with the fast and potent anticancer effects exerted in model cells. Milk EXOs enhanced the bioavailability and anticancer activity of CUR and RSV by acting as Trojan horses that escape from cancer cells' ABC-mediated chemoresistance.


Characterization of toxin-antitoxin systems from public sequencing data: A case study in Pseudomonas aeruginosa.
The toxin-antitoxin (TA) system is a widely distributed group of genetic modules that play important roles in the life of prokaryotes, with mobile genetic elements (MGEs) contributing to the dissemination of antibiotic resistance gene (ARG). The diversity and richness of TA systems in Pseudomonas aeruginosa, as one of the bacterial species with ARGs, have not yet been completely demonstrated. In this study, we explored the TA systems from the public genomic sequencing data and genome sequences. A small scale of genomic sequencing data in 281 isolates was selected from the NCBI SRA database, reassembling the genomes of these isolates led to the findings of abundant TA homologs. Furthermore, remapping these identified TA modules on 5,437 genome/draft genomes uncovers a great diversity of TA modules in P. aeruginosa. Moreover, manual inspection revealed several TA systems that were not yet reported in P. aeruginosa including the hok-sok, cptA-cptB, cbeA-cbtA, tomB-hha, and ryeA-sdsR. Additional annotation revealed that a large number of MGEs were closely distributed with TA. Also, 16% of ARGs are located relatively close to TA. Our work confirmed a wealth of TA genes in the unexplored P. aeruginosa pan-genomes, expanded the knowledge on P. aeruginosa, and provided methodological tips on large-scale data mining for future studies. The co-occurrence of MGE, ARG, and TA may indicate a potential interaction in their dissemination.


Celiac Neuropathy: A Case Report from Kashmir (India).
Celiac disease is considered to be rare in parts of the world where rice is a staple cereal. Kashmir is one of such places. We present an adult Kashmiri man, who had peripheral neuropathy, which turned out to be associated with celiac disease and improved remarkably with total elimination of gluten containing foods. This is probably the first case of celiac neuropathy reported from India.


Determination of the Geographical Origin of Asparagus officinalis L. by 1H NMR Spectroscopy.
Food authenticity concerning the geographical origin becomes increasingly important for consumers, food industries, and food authorities. In this study, nontargeted 1H NMR metabolomics combined with machine learning methodologies was applied to successfully distinguish the geographical origin of 237 samples of white asparagus from Germany, Poland, The Netherlands, Spain, Greece, and Peru. Support vector classification of the geographical origin achieved an accuracy of 91.5% for the entire sample set and 87.8% after undersampling the majority class. Important regions of the spectra could be identified and assigned to potential chemical markers. A subset of samples was compared to isotope-ratio mass spectrometry (IRMS), an established method for the determination of origin of white asparagus in Germany. Here, SVM classification led to accuracies of 79.4% for NMR and 70.9% for IRMS. Finally, the classification of asparagus from different German regions was evaluated, and the influence of year and variety was analyzed.


Coparenting Intervention for Expectant Parents Affects Relationship Quality: A Pilot Study.
Research has shown that the transition to parenthood is a particularly challenging period of life which is often associated with a decline in relationship quality and an increase in mental health problems. Emerging parents often experience difficulties in coping with new tasks and challenges in the relationship, resulting in inadequate mutual support, stress, conflicts and even depressive symptoms. To support expectant parents in establishing an effective and strong coparenting alliance, we have employed an educational coparenting intervention to teach important coparenting skills. The intervention was a non-randomized case-control study with 126 expectant parents. The intervention group participated in a five-session intervention, whereas the control group received an information booklet and had an optional meeting postpartum. The purpose of this study was to ease the transition to parenthood in order to prevent postpartum conflict and depression. Parents in the intervention group (n = 34 couples) showed significantly fewer conflicts postpartum than before (Z = -3.28, p = 0.00), and scored better in postnatal delegated dyadic coping (β = 0.25, p = 0.00, R2 = 0.32), a form of mutual support. Neither the intervention group (Z = -0.83, p = 0.40) nor the control group (Z = -0.86, p = 0.38) showed a significant increase in depression scores after childbirth. Although conflicts during the transition to parenthood declined and postnatal delegated dyadic coping strengthened, the study design does not allow to draw conclusion on group effects. Nevertheless, the promising results of this pilot intervention are a base for future studies.


Abnormal effect of thiol groups on erythrocyte Na/Li countertransport kinetics in adult polycystic kidney disease.
Evidence suggests that in adult polycystic kidney disease (APCKD) there is abnormal membrane organisation that involves cytoskeletal proteins and affects ion-transport proteins. The possibility of detecting a membrane organisation defect in erythrocytes from APCKD patients was investigated. Na/Li countertransport (CT) kinetics were measured in erythrocytes from APCKD patients compared with normal controls. The modulation of Na/Li CT kinetics by key membrane thiol groups and by dissociation of spectrin by heating was studied. In erythrocytes from APCKD compared to normal subjects the Km of Na/Li CT was lower (64 SEM 3v 90 SEM 3 mmol Na/l, P < 0.001) and Vmax/Km was higher (6.8 SEM 0.6v 5.3 SEM 0.4 (x 19(-3)), P < 0.05). In erythrocytes from normal subjects, after N-ethylmaleimide (NEM) treatment in choline medium, Km of Na/Li CT was reduced and Vmax/Km increased (59 SEM 5, 8.2 SEM 0.4 (x 10(-3)), P < 0.001) but there was no effect on these kinetic parameters in erythrocytes from APCKD. The effect of heating was similar to that of NEM in choline medium. In normal controls after NEM treatment in sodium medium both Km and Vmax were reduced whereas in APCKD Vmax was reduced but Km was unchanged. In APCKD the effect of a key membrane thiol group on Na association with Na/Li CT was absent and the effect of spectrin dissociation was similarily abnormal. A second thiol group effect on the Vmax of Na/Li CT was normal. The results are consistent with a thiol-protein linked to the spectrin cytoskeleton that modulates Na/Li CT and is abnormal in APCKD.


Interventional Treatment Options in Children with Extracranial Vascular Malformations.
Extracranial vascular malformations vary greatly and belong to the complex field of orphan diseases and can involve all segments of the vascular tree: arteries, capillaries, and veins, and similarly the lymphatic system. The classification according to the International Society for the Study of Vascular Anomalies (ISSVA) represents an important guidance for selecting appropriate therapy. Although many of the principles of endovascular treatment, including image-guided sclerotherapy and embolization, are similar in adult and pediatric practice, there are some distinct differences regarding the treatment of vascular malformations of children. Thus, it is crucial to involve longer-term plan about managing these chronic diseases and their impact on a growing child. This review provides a detailed overview over the clinical presentation of venous, lymphatic, and arteriovenous malformations in children and emphasizes the specifics of their interventional treatment options, including distinct pediatric dose limitations and procedure-related side effects.


Structure-Property Relations of Methylamine Vapor Treated Hybrid Perovskite CH3NH3PbI3 Films and Solar Cells.
The power conversion efficiency of halide perovskite solar cells is heavily dependent on the perovskite layer being sufficiently smooth and pinhole-free. It has been shown that these features can be obtained even when starting out from rough and discontinuous perovskite film by briefly exposing the film to methylamine (MA) vapor. The exact underlying physical mechanisms of this phenomenon are, however, still unclear. By investigating smooth, MA treated films based on very rough and discontinuous reference films of methylammonium triiode (MAPbI3) and considering their morphology, crystalline features, local conductive properties, and charge carrier lifetime, we unraveled the relation between their characteristic physical qualities and their performance in corresponding solar cells. We discovered that the extensive improvement in photovoltaic performance upon MA treatment is a consequence of the induced morphological enhancement of the perovskite layer together with improved electron injection into TiO2, which in fact compensates for an otherwise compromised bulk electronic quality simultaneously caused by the MA treatment.


Coexisting rogue waves within the (2+1)-component long-wave-short-wave resonance.
The coexistence of two different types of fundamental rogue waves is unveiled, based on the coupled equations describing the (2+1)-component long-wave-short-wave resonance. For a wide range of asymptotic background fields, each family of three rogue wave components can be triggered by using a slight deterministic alteration to the otherwise identical background field. The ability to trigger markedly different rogue wave profiles from similar initial conditions is confirmed by numerical simulations. This remarkable feature, which is absent in the scalar nonlinear Schrödinger equation, is attributed to the specific three-wave interaction process and may be universal for a variety of multicomponent wave dynamics spanning from oceanography to nonlinear optics.


Thermal conductivity of diamond nanorods: Molecular simulation and scaling relations.
Thermal conductivities of diamond nanorods are estimated from molecular simulations as a function of radius, length, and degree of surface functionalization. While thermal conductivity is predicted to be lower than carbon nanotubes, their thermal properties are less influenced by surface functionalization, making them prime candidates for thermal management where heat transfer is facilitated by cross-links. A scaling relation based on phonon surface scattering is developed that reproduces the simulation results and experimental measurements on silicon nanowires.


Farnesoid X receptor agonist CDCA reduces blood pressure and regulates vascular tone in spontaneously hypertensive rats.
The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, which plays an essential role in lipid homeostasis and glucose metabolism. However, whether or not FXR can prevent rise in blood pressure remains unknown. Here, we investigate the possibility of using chenodeoxycholic acid (CDCA), a natural ligand of FXR, to attenuate elevated blood pressure in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto rats (WKY) were treated with CDCA (30 mg/kg) for 8 weeks. Compared with vehicle control, CDCA attenuated rise in blood pressure in SHR. In addition, CDCA improved vasorelaxation and diminished the contractile response to endothelin-1 (ET-1) in mesenteric arteries from SHR. CDCA also stimulated endothelial nitric oxide synthase (eNOS) expression, repressed ET-1 levels, and inhibited NF-κB activities in mesenteric arteries of the SHR. Overall, we showed that CDCA treatment reduces systolic blood pressure, improves vascular relaxation, and inhibits vasoconstriction activity in SHR. The repressed ET-1 level, the raised eNOS expression, and the ameliorated inflammation in mesenteric arteries could be responsible for the vasorelaxant and hypotensive effect of CDCA. These findings support a potential role for FXR as a regulator in vascular activities and in the development of treatment for hypertension.


Sirolimus-FKBP12.6 impairs endothelial barrier function through protein kinase C-α activation and disruption of the p120-vascular endothelial cadherin interaction.
Sirolimus (SRL) is an immunosuppressant drug used to prevent rejection in organ transplantation and neointimal hyperplasia when delivered from drug-eluting stents. Major side effects of SRL include edema and local collection of intimal lipid deposits at drug-eluting stent sites, suggesting that SRL impairs endothelial barrier function (EBF). The aim of this study was to address the role of SRL on impaired EBF and the potential mechanisms involved. Cultured human aortic endothelial cells (HAECs) and intact human and mouse endothelium was examined to determine the effect of SRL, which binds FKBP12.6 to inhibit the mammalian target of rapamycin, on EBF. EBF, measured by transendothelial electrical resistance, was impaired in HAECs when treated with SRL or small interfering RNA for FKBP12.6 and reversed when pretreated with ryanodine, a stabilizer of ryanodine receptor 2 intracellular calcium release channels. Intracellular calcium increased in HAECs treated with SRL and normalized with ryanodine pretreatment. SRL-treated HAECs demonstrated increases in protein kinase C-α phosphorylation, a calcium sensitive serine/threonine kinase important in vascular endothelial (VE) cadherin barrier function through its interaction with p120-catenin (p120). Immunostaining of HAECs, human coronary and mouse aortic endothelium treated with SRL showed disruption of p120-VE cadherin interaction treated with SRL. SRL impairment of HAEC EBF was reduced with protein kinase C-α small interfering RNA. Mice treated with SRL demonstrated increased vascular permeability by Evans blue albumin extravasation in the lungs, heart, and aorta. SRL-FKBP12.6 impairs EBF by activation of protein kinase C-α and downstream disruption of the p120-VE cadherin interaction in vascular endothelium. These data suggest this mechanism may be an important contributor of SRL side effects related to impaired EBF.


α,β-Unsaturated imines via Ru-catalyzed coupling of allylic alcohols and amines.
A convenient synthesis of α,β-unsaturated imines requiring only an allylic alcohol, an amine and a Ru catalyst has been developed. The use of large excesses of oxidant and the purification of sensitive intermediates can be avoided.


Liquid biopsy in biliary tract cancer from blood and bile samples: current knowledge and future perspectives.
Biliary tract cancer (BTC) is an aggressive tumor characterized by a poor prognosis. In the latest years, targetable genetic alterations have been discovered in BTC patients, leading to the approval of new targeted therapies. Liquid biopsy, which is a non-invasive method for detecting tumor biomarkers from fluid samples, is a useful tool for diagnosis and molecular characterization, but also for prognosis assessment and monitoring of treatment response. In this review, recent works on liquid biopsy in BTC patients were analyzed, focusing on some relevant aspects for clinical use and trying to depict the future role of this technique. Moreover, differences between plasma and bile samples were pointed out, in light of the peculiar biology of BTC and the possibility of using bile as an alternative source of cell-free DNA (cfDNA) for genomic analysis. In the era of precision oncology, the increasing adoption of liquid biopsy in BTC patients will certainly improve the management of this disease.


Cholinesterase inhibiting withanolides from Withania somnifera.
A total of two new (1, 2) and four known (3-6) withanolides were isolated from the whole plant of Withania somnifera. Their structures were elucidated on the basis of spectroscopic techniques and were characterized as 6alpha,7alpha-epoxy-3beta,5alpha,20beta-trihydroxy-1-oxowitha-24-enolide (1), 5beta,6beta-epoxy-4beta,17alpha,27-trihydroxy-1-oxowitha-2,24-dienolide (2), withaferin-A (3), 2,3-dihydrowithaferin-A (4), 6alpha,7alpha-epoxy-5alpha,20beta-dihydroxy-1-oxowitha-2,24-dienolide (5), and 5beta,6beta-epoxy-4beta-hydroxy-1-oxowitha-2,14,24-trienolide (6), respectively. Compounds 2, 3, 5, and 6 displayed inhibitory potential against butyrylcholinesterase, but only compounds 3, 4, and 6 were found to be active against acetylcholinesterase.


Antioxidant and antihyperlipidemic activity of Hibiscus sabdariffa Linn. leaves and calyces extracts in rats.
Antioxidant and antihyperlipidemic activities of the extracts of leaves and calyces of Hibiscus sabdariffa were investigated by studying their in vitro inhibitory activity on lipid peroxidation and in vivo effects on cholesterol induced hyperlipidemia. Highest antioxidant activity was exhibited by ethanolic extract of calyces followed by ethanolic extract of leaves followed by aqueous extract of leaves of H. sabdariffa. In cholesterol induced hyperlipidemic model, groups of rats treated with extracts of calyces and leaves of H. sabdariffa showed a significant decrease in the serum TC, LDL-C, VLDL-C, TAG values alongwith an increase in serum HDL-C levels. The treated groups also showed significant decrease in the atherogenic index, LDL-C: HDL-C risk ratios, and in the levels of SGOT, SGPT and ALP activities compared to cholesterol induced hyperlipidemic control group. Significant antihyperlipidemic activity was shown by ethanolic extract of calyces, followed by ethanolic extract of leaves. It was observed from the histopathological findings that rats fed with H. sabdariffa extracts showed decrease in granular degeneration caused by cholesterol feedings. Results suggest that the ethanolic extracts of calyces and leaves of H. sabdarifa containing polyphenols and flavanols possess significant antioxidant and antihyperlipidemic activities.


How effective are injection treatments for lateral epicondylitis?
To compare the effectiveness, after 3 months, of a single injection of platelet-rich plasma (PRP), glucocorticoid (GC), or saline in reducing pain in lateral epicondylitis. Randomized, controlled, 3-group trial (RCT). Patients and outcome assessors were blinded to intervention group. Sample size was calculated to show a clinically important difference in patient-reported pain intensity at 12 months with 17 patients per group. Tertiary study at the Rheumatology Unit at the Diagnostic Centre of the Region Hospital Silkeborg, Denmark. Patients were referred to the Rheumatology Unit by general practitioners or other rheumatology or orthopedic departments. Inclusion criteria (verified by 1 physician) were lateral epicondylitis symptoms for ≥3 months (pain on the lateral side of the elbow and at the lateral epicondyle on palpation and during resisted dorsiflexion of the wrist), an ultrasound (US) color Doppler flow of ≥ grade 2 (range, 0-4). Exclusion criteria were age <18 years, treatment with GC injection within 3 months, inflammatory diseases, and conditions causing chronic pain. The 60 included patients had a mean age of 45 years, 52% were women, 58% had ≥1 previous injection, and 58% used analgesics. The patients were randomized to a single US-guided injection of PRP, GC, or saline, administered by the 1 physician who had made the diagnosis. All patients were blindfolded during blood collection and injection. They all received an injection of 10 to 15 mL of lidocaine into the peritendon before the procedure. The PRP injection was of approximately 3.5 mL of autologous platelets (collected and centrifuged for 15 minutes from 27 mL of whole blood) buffered with 8.4% sodium bicarbonate, and immediately peppered into the common tendon origin. The GC injection (1 mL triamcinolon, 40 mg/mL + 2 mL lidocaine, 10 mg/mL) was delivered through 1 site. The saline injection (3 mL saline, 0.9%) was peppered in the same manner as the PRP injection. After treatment, the patients were asked to use the arm minimally for 3 days and then gradually to return to normal use. The pain intensity scale of the Patient-Rated Tennis Elbow Evaluation (PRTEE) questionnaire was the main outcome measure (least to most pain = 0-50 points). The secondary end points included changes in functional disability using the functional section of the PRTEE, (least to most disability = 0-100 points), US changes in color Doppler signal and tendon thickness, and adverse events, which included pain after the injection. After 3 months, if the patient was unsatisfied with the result of treatment, he or she could be released from the study to seek other management. Ten, 11, and 13 patients (58% of the total) dropped out of the PRP, GC, and saline groups, respectively, at the 3-month follow-up, thus evaluations were only made at 1 and 3 months. At 1 month, the mean reduction in pain for the PRP group versus the saline group was 1.2 (95% confidence interval [CI], -5.0 to 7.3); for the GC group versus the saline group was -8.1 (95% CI, -14.3 to -1.9); and for the GC group versus the PRP group, -9.3 (95% CI, -15.4 to -3.2). At 3 months, the mean reduction in pain for no group was significantly greater than for others (PRP vs the saline group, -2.7; 95% CI, -8.8 to 3.5; GC vs the saline group, -3.8; 95% CI, -9.9 to 2.4; GC vs the PRP group, -1.1; 95% CI, -7.2 to 5.0). The PRTEE disability scores at 1 month also favored the GC group versus saline, but no differences were found between any groups at 3 months. The improvement in Doppler grades at 3 months favored the GC group versus the saline group and the PRP group (P<0.0001 for both comparisons). Mean reduction in tendon thickness was greater for the GC group versus the saline group (P<0.0001) and the PRP group (P=0.002). PRP injections were found to be more painful than GC and saline injections. No adverse events leading to hospitalization, and no reports of infections resulting from the injections, occurred. The dropout rate of 58% at 3 months showed that none of PRP, glucocorticoid, or saline injections adequately reduced the pain and disability of lateral epicondylitis.


Determination of antimicrobial effect, antioxidant activity and phenolic contents of desert truffle in Turkey.
Terfezia boudieri Chatin (Scop.) Pers., is a famous macrofungus in the world as well as in Turkey for its pleasant aroma and flavour. People believe that this mushroom has some medicinal properties. Therefore, it is consumed as food and for medicinal purposes. Chloroform, acetone and methanol extracts of T. boudieri were tested to reveal its antimicrobial activity against four Gram-positive and five Gram-negative bacteria, and one yeast using a micro dilution method. In this study, the highest minimum inhibitory concentration (MIC) value was observed with the acetone extract (MIC, 4.8 µg/mL) against Candida albicans. Maximum antimicrobial effect was also determined with the acetone extract (MIC, 39-78 µg/mL). The scavenging effect of T. boudieri on 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radicals was measured as 0.031 mg/mL at 5 mg/mL concentration, and its reducing power was 0.214 mg/mL at 0.4 mg/mL. In addition, the phenolic contents were determined as follows: the catechin was 20 mg/g, the ferulic acid was 15 mg/g, the p-coumaric acid was 10 mg/g, and the cinnamic acid was 6 mg/g. The results showed that T. boudieri has antimicrobial activity on the gram negative and positive bacteria as well as yeast, and it also has a high antioxidant capacity. Therefore, T. boudieri can be recommended as an important natural food source.


Comparison of circulating DNA in malignant neoplasia from diverse locations: Investigating a diagnostic role.
Circulating free DNA (cfDNA) analysis has emerged as novel noninvasive diagnostic biomarker in several solid tumors. Raised levels have been reported in several malignancies and may correlate with clinicopathological and treatment response. The current study was designed to assess the diagnostics of cfDNA in different tumor types of malignancies correlating with tumor (T), nodes (N), and metastases (M) stage. Serum samples were collected from treatment naïve cases with histologically diagnosed tumors including 23 brain tumors, 48 breasts, 50 gallbladder carcinoma (GBC), 13 lungs, 68 oral squamous cell carcinoma (OSCC), and 25 normal controls. CfDNA was quantified with real-time polymerase chain reaction (PCR), Invasive ductal carcinoma (IDC) using beta-globin gene amplification. Cut off values for diagnostics were calculated using receiver operating curve analysis. Contrary to other cfDNA studies where it was postulated that cfDNA would not cross the blood-brain barrier and reach the systemic circulation, we found detectable cfDNA in glioma with median (Q1-Q3) of 349.22 ng/ml (19.87-1276.58). Median cfDNA concentration in breast, gallbladder, lung, oral and normal controls was 328.72 (128.38-624.44), 778.50 (589.88-1864.35), 348.73 (194.67-483.61), 386.27 (47.88-959.67), and 74.12 (49.66-120.00), respectively. Grades I and II glioma had significantly lower levels compared to Grades III and IV (P = 0.0001). Significant difference in median cfDNA values in IDC and GBC was observed with increasing tumor grades, stage, T stage, nodal stage and metastasis and with stage of OSCC cases. CfDNA levels showed good diagnostic discrimination in glioma, GBC, breast, lung carcinoma, and OSCC. Significant increase in titers was evident with increase in cancer stage from I to IV in breast, GBC and OSCC.


Thermochemical properties and electronic structure of boron oxides BnOm (n = 5-10, m = 1-2) and their anions.
The molecular and electronic structures of a series of small boron monoxide and dioxide clusters B(n)O(m) (n = 5-10, m = 1, 2) plus their anions were predicted. The enthalpies of formation (DeltaH(f)'s), electron affinities (EAs), vertical detachment energies, and energies of different fragmentation processes are predicted using the G3B3 method. The G3B3 results were benchmarked with respect to more accurate CCSD(T)/CBS values for n = 1-4 with average deviations of +/-1.5 kcal/mol for DeltaH(f)'s and +/-0.03 eV for EAs. The results extend previous observations on the growth mechanism for boron oxide clusters: (i) The low spin electronic state is consistently favored. (ii) The most stable structure of a neutral boron monoxide B(n)O is obtained either by condensing O on a BB edge of a B(n) cycle, or by binding one BO group to a B(n-1) ring. The balance between both factors is dependent on the inherent stability of the boron cycles. (iii) A boron dioxide is formed by incorporating the second O atom into the corresponding monoxide to form BO bonds. (iv) A B(n)O(m)(-) anion is constructed with BO groups bound to the B(n-1) or B(n-2) rings (yielding the B(n-2)(BO)(2)(-) species). This becomes the preferred geometry for the larger boron dioxides, even in the neutral state. The boronyl group mainly behaves as an electron-withdrawing substituent reducing the binding energy and resonance energy of the oxides. (v) The boron oxides conserve some of the properties of the parent boron clusters such as the planarity and multiple aromaticity.


Directed ortho-lithiation of aminophosphazenes: an efficient route to the stereoselective synthesis of P-chiral compounds.
Ortho-directed lithiation of P,P-diphenylaminophosphazenes followed by electrophilic quench is described as an efficient process for synthesizing P-chiral ortho-functionalized derivatives in high yields and diastereoselectivities. The method allows the tunable preparation of structurally diverse enantiopure P-chiral compounds including phosphinic and phosphinothioic amides, phosphinic esters, phosphine oxides, and o-aminophosphines.


Concordant expression of proto-oncogene promyelocytic leukemia and major histocompatibility antigen HLA class I in human hepatocellular carcinoma.
Many malignant cancer cells downregulate human leukocyte antigen (HLA) class I antigen expression to evade T cell recognition. However, hepatocellular carcinoma (HCC) is exceptional to the general findings in cancer cells, and the mechanisms for its upregulation remain unclear. It has been reported that promyelocytic leukemia (PML) proto-oncogene controls the transcription of multiple class I antigen presentation genes in murine cancer cells. To find out the functional role of PML gene on the increased HLA class I antigen expression in HCC cells, we analyzed the expression of proto-oncogene PML and multiple class I antigen presentation genes in HCC specimens obtained in China. The results showed concordant changes of proto-oncogene PML and cell surface HLA-A expression in 44 paraffin-embedded HCC tissues. Furthermore, co-upregulated expression of PML genes and class I antigen presentation genes could be detected in 9 of 15 fresh HCC tissues by reverse transcription polymerase chain reaction (RT-PCR). In addition, studies using HCC cell lines showed that increased expression of HLA class I molecules paralleled with PML upregulation were detected in QGY-7701 HCC cell line with RT-PCR, western blot, and flow cytometry, and that the overexpression of exogenous PML in a low-expression class I cell line BEL-7405 could induce the expression of multiple class I antigen-presenting molecule genes and slightly but significantly increase the expression of cell surface HLA class I molecules. In conclusion, the expression of proto-oncogene PML and HLA class I molecules were concordantly upregulated and the expression of PML gene might be one of the mechanisms that leads to the increased expression of class I antigen in HCC.


Effects of receptor dimerization on the interaction between the class I major histocompatibility complex-related Fc receptor and IgG.
The neonatal Fc receptor (FcRn) transports maternal IgG from ingested milk in the gut to the bloodstream of newborn mammals. An FcRn dimer was observed in crystals of the receptor alone and of an FcRn-Fc complex, but its biological relevance was unknown. Here we use surface plasmon resonance-based biosensor assays to assess the role of FcRn dimerization in IgG binding. We find high-affinity IgG binding when FcRn is immobilized on a biosensor chip in an orientation facilitating dimerization but not when its orientation disrupts dimerization. This result supports a model in which IgG-induced dimerization of FcRn is relevant for signaling the cell to initiate endocytosis of the IgG-FcRn complex.


A pilot theory-based intervention to improve resilience, psychosocial well-being, and quality of life among people living with HIV in rural China.
This pilot study aimed at fostering resilience among people living with HIV and improving the HIV-negative participants' acceptance of people living with HIV. A group of 75 people living with HIV who were former blood/plasma donors and 36 HIV-negative fellow villagers in rural China participated in the intervention. The 8 sessions lasted for 4 months and were facilitated by trained local family-planning officers. Efficacy of the intervention was assessed using a pre- and postprogram study design; measurements were made at baseline, at completion, and 3 months afterward completion. The authors found that the HIV-positive participants increased their levels of resilience, social support, and quality of life and that they reported fewer symptoms of depression, anxiety, and stress at the completion of the intervention; most of these changes were sustained at the 3-month follow-up. Such participants also reported subjective improvements on problem-solving skills, self-confidence, and a feeling of being cared for by others. In addition, the HIV-negative participants' discriminatory attitudes toward people living with HIV were reduced after completing the intervention. The majority of the participants was satisfied with the intervention and would recommend it to others. The train-the-trainer approach was used effectively. Positive effects of the intervention have been revealed and future randomized controlled studies are warranted.


Oesophageal dysmotility in systemic sclerosis: comparison of HRCT and scintigraphy.
The aim of this study was to compare oesophageal abnormalities observed in high-resolution CT with radionuclide transit in patients with systemic sclerosis. 76 patients with systemic sclerosis were evaluated by high-resolution CT and oesophageal transit scintigraphy. Residual activity > or =20% (in relation to peak activity) at 15 s after the beginning of the swallow of the labelled liquid (in supine position) was considered indicative of oesophageal dysfunction. Supra-aortic and infra-aortic oesophageal coronal diameters were measured in high-resolution CT. Oesophageal dilatation was deemed present when the diameters exceeded 10 mm. 19 patients (25%) had supra-aortic oesophageal dilatation and 48 patients (63.1%) had infra-aortic dilatation. The prevalence of radionuclide transit delay was 77.6%. All patients (19/19) with supra-aortic dilatation had oesophageal dysfunction, compared with 70.2% (40/57) of the patients with no supra-aortic dilatation (p = 0.004). Oesophageal dysfunction was present in 97.9% (47/48) of patients with infra-aortic dilatation, compared with 42.9% (12/28) in patients without it (p < 0.001). Receiver operating characteristic (ROC) curves have demonstrated that the supra-aortic and infra-aortic diameters had good discriminatory capacity for oesophageal dysfunction in systemic sclerosis (area under the curve, 95% confidence interval: 0.80, 0.70-0.89 and 0.92, 0.86-0.98, respectively). There is a clinically significant association between oesophageal dysmotility and high-resolution CT findings of oesophageal coronal dilatation. The evaluation of infra-aortic oesophageal coronal diameter can provide additional useful information about the functional and anatomic conditions of the oesophagus in systemic sclerosis.


Mutual coherence in time-varying radiation fields and interferometric frequency discrimination.
The theory of partially coherent light is extended to cover time-varying fields observed by a detector with time constant T. The response of an interferometric optical discriminator is examined. The system uses a two-beam interferometer with transit time difference taur. The curves presented show discriminator response to step-function optical frequency shifts as a function of tau/T. They point to two conclusions, valid for tau/T > 10(-1): (i) initial and final states, and exponential detector response, neglecting mutual coherence theory, fail to explain dynamic behavior; (ii) multiple-fringe step-function frequency shifts are stretched over a period tau, permitting fringe counting.


Distance-based differential analysis of gene curves.
Time course gene expression experiments are performed to study time-varying changes in mRNA levels of thousands of genes. Statistical methods from functional data analysis (FDA) have recently gained popularity for modelling and exploring such time courses. Each temporal profile is treated as the realization of a smooth function of time, or curve, and the inferred curve becomes the basic unit of statistical analysis. The task of identifying genes with differential temporal profiles then consists of detecting statistically significant differences between curves, where such differences are commonly quantified by computing the area between the curves or the l₂ distance. We propose a general test statistic for detecting differences between gene curves, which only depends on a suitably chosen distance measure between them. The test makes use of a distance-based variance decomposition and generalizes traditional MANOVA tests commonly used for vectorial observations. We also introduce the visual l₂ distance, which is shown to capture shape-related differences in gene curves and is robust against time shifts, which would otherwise inflate the traditional l₂ distance. Other shape-related distances, such as the curvature, may carry biological significance. We have assessed the comparative performance of the test on realistically simulated datasets and applied it to human immune cell responses to bacterial infection over time.


Are coffee, tea, and total fluid consumption associated with bladder cancer risk? Results from the Netherlands Cohort Study.
Coffee, tea, and fluid consumption have been thought to influence bladder cancer incidence. In a large prospective study, these associations were investigated. In 1986, cohort members (55-69 years) completed a questionnaire on cancer risk factors. Follow-up was established by linkage to cancer registries until 1992. The multivariable case-cohort analysis was based on 569 bladder cancer cases and 3,123 subcohort members. The incidence rate ratios (RR) for men consuming <2 cups of coffee/day was 0.89 (95% CI 0.51-1.5) using the median consumption category (4-<5 cups/day) as reference. This RR increased to 1.3 (95% CI 0.94-1.9) for men consuming >7 cups/day, although no clear dose response association was found. The RRs decreased from 1.2 (95% CI 0.56-2.7) for women consuming <2 cups of coffee/day to 0.36 (95% CI 0.18-0.72) for women consuming >5 cups/day compared to the median consumption category (3-<4 cups/day). Men and women who abstained from drinking tea had a RR of 1.3 (95% Cl 0.97-1.8) compared to those consuming 2-<3 cups of tea per day (median consumption category). The RR for men and women comparing highest to lowest quintile of total fluid consumption was 0.87 (95% CI 0.63 1.2). The data suggest a possible positive association between coffee consumption and bladder cancer risk in men and a probable inverse association in women. Tea consumption was inversely associated with bladder cancer. Total fluid consumption did not appear to be associated with bladder cancer.


Segmental osteotomy in the treatment of obsolete orbitozygomatic fractures.
Different kinds of orbitozygomatic fractures lead to different levels of orbital structural destructions. Although the magnitude of the management of orbitozygomatic fractures varies considerably, an unsolved and important question remains regarding how to select the best surgical modality according to different kinds of fractures. Among 26 cases of unilateral noncomminuted orbitozygomatic fractures, a segmental osteotomy technique was used to repair the displaced orbitozygomatic complex. The fragment contributing to the orbital structure was mobilized and reduced, whereas the fragment without contribution to the orbital structure was not mobilized and left in situ. Next, the cuneate fragment was imbricated with the orbital osteotomy sites unilaterally or bilaterally. Miniplates and screws were used to span the osteotomy sites and provided fixation once the alignment of the orbit was achieved. The mean difference in volume between fractured orbits preoperatively and postoperatively was 2.47 mL. The mean difference in ocular globe projection was 2.76 mm. When postoperative results were compared with those of the preoperative site, statistically significant difference was noted. At follow-up 1 year postoperatively, the management of orbitozygomatic fractures using segmental osteotomy reduces complications and attains aesthetically satisfying results. Subjective assessment of the patients' globe position found that 88.5% of the patients were satisfied with the outcome, and 11.5% of the patients found it unacceptable. Compared with the traditional method, segmental osteotomy is a simple technique requiring less dissection and can reconstruct the orbital anatomic structure and restore globe position effectively.


Novel and selective DNA methyltransferase inhibitors: Docking-based virtual screening and experimental evaluation.
The DNA methyltransferase (DNMT) enzyme family consists of four members with diverse functions and represents one of the most promising targets for the development of novel anticancer drugs. However, the standard drugs for DNMT inhibition are non-selective cytosine analogues with considerable cytotoxic side-effects that have been developed several decades ago. In this work, we conducted a virtual screening of more than 65,000 lead-like compounds selected from the National Cancer Institute collection using a multistep docking approach with a previously validated homology model of the catalytic domain of human DNMT1. Experimental evaluation of top-ranked molecules led to the discovery of novel small molecule DNMT1 inhibitors. Virtual screening hits were further evaluated for DNMT3B inhibition revealing several compounds with selectivity towards DNMT1. These are the first small molecules reported with biochemical selectivity towards an individual DNMT enzyme capable of binding in the same pocket as the native substrate cytosine, and are promising candidates for further rational optimization and development as anticancer drugs. The availability of enzyme-selective inhibitors will also be of great significance for understanding the role of individual DNMT enzymes in epigenetic regulation.


[Fatal active rheumatic disease. Study of 13 necropsy cases].
To study the clinical features of a group of patients with fatal acute rheumatic fever (ARF). Thirteen patients with ARF, the ages ranged between 4.5 and 25 (mean 14) years. Eight patients were male. Patients were studied in two groups: group A of those 14 year-old or younger (8 cases), and group B of those older than 15 years (5 cases). Clinical presentation was fever and severe heart failure in all patients. In group A, it was the first attack of ARF in 5 patients. The time elapsed between beginning of symptoms and hospital admission ranged between 10 and 90 (mean 40) days. Mitral insufficiency occurred in all patients. The blood leukocyte count was greater than 10000 per mm3 in six cases. Atrioventricular block occurred in one case. Valvular vegetations were detected on echocardiogram in 4 cases. Two patients received antibiotic therapy. Surgical treatment of the valvular heart disease was carried on in one patient. In group B, it was the first ARF attack in 2 cases, the time elapsed between beginning of the symptoms and hospital admission ranged between 4 and 60 (mean 21) days. Leukocyte count greater than 10000 por mm3 occurred in 4 cases. Atrioventricular block was diagnosed in one case. Valvular vegetations on echocardiogram were detected in 2 patients. In two cases, the treatment was antibiotic therapy. Three patients were operated on. ARF may still be fatal, even in the first attack or in patients in the third decade of life. Other diagnoses are frequently considered, due to the intense clinical and laboratorial manifestations.


Does ethylene play a role in the release of lateral buds (tillers) from apical dominance in oats?
The growth of lateral buds (tillers), which are undergoing release from apical dominance, was measured in upright and gravistimulated intact Avena sativa L. cv. ;Victory' (oat) shoots as well as in isolated Avena stem segments treated with kinetin and sucrose. During release, the tiller bud initially shows a slow rate of elongation accompanied by swelling. It is followed by a more rapid rate of elongation. Ethylene (C(2)H(4)) production in shoot segments containing a tiller bud was found to occur at the onset of tiller swelling during gravistimulation as well as during inflorescence emergence. Exogenous application of indoleacetic acid or C(2)H(4) inhibits kinetin-induced tiller bud swelling and elongation. However, stem segments pulsed for 24 hours in C(2)H(4) or the C(2)H(4) biosynthesis precursor, 1-amino-cyclopropane-1-carboxylic acid (ACC) and then transferred to kinetin and sucrose, showed a significant increase in swelling elongation as compared with segments maintained under the same conditions but without C(2)H(4) or ACC in the pulse. Segments pulsed for 24 hours with kinetin and sucrose plus the ACC biosynthesis inhibitor, aminoethoxyvinylglycine, or the C(2)H(4) action inhibitor, CO(2), then transferred to kinetin and sucrose medium, showed inhibition of tiller swelling during the pulse and of subsequent elongation. These results indicate that C(2)H(4) plays a role in promoting tiller swelling during the onset of tiller release from apical dominance and may act as a modulator hormone in promoting tiller elongation in the presence of cytokinin.


[Pain intensity in patients treated by the external fixation].
One of the inherent features of the external fixation is pain occurring during the whole treatment process. The aim of this paper is evaluation of the level of pain intensity during particular stages of treatment and defining the correlation between pain intensity and type and also localization of fixator, etiology, type of treatment and patient's life activity. We analyzed 64 patients treated by external fixation of the lower limb in the age between 13 to 72 (mean 23.7). The pain intensity was evaluated four times by the NRS protocol (Numeric Rating Scale) in active and passive situation. It is stated that there is a different pain pattern in time depending on the type of treatment and personal life activity. Lengthened and patients in full time education are characterized by rapid increase in pain level in the first period of treatment. Patients with stabilization of non-union or fracture and professionally inactive had lower fluctuations of pain intensity. Localization of apparatus has influence on pain intensity level- greater pain was noted in the tibial group. Etiology influences on pain intensity. Increase of pain intensity in patients with non-union is lower in comparison to patients treated for the other indications.


The metabolism of 1-nitropyrene by human cytochromes P450.
The metabolism of [3H]1-nitropyrene by specific forms of human cytochrome P450 was investigated in vitro using Vaccinia virus expression of P450 cDNAs in HepG2 cells. Cell lysates were injected individually with recombinant Vaccinia virus containing human P450 cDNA (P450 IA2, IIA3, IIB7, IIC8, IIC9, IID6, IIE1, IIF1, IIIA3, IIIA4, IIIA5 AND IVB1). Only IIIA3 and IIIA4 demonstrated significant activity in the C-oxidation of 1-nitropyrene. The principal metabolite from both P450 forms was 1-nitropyren-3-ol, produced in at least 4-fold greater abundance than the mixture of 1-nitropyren-6-ol and 1-nitropyren-8-ol, or the K-region dihydrodiols. This is in contrast to the metabolism in many species where 6-ol and 8-ol formation predominate over 3-ol formation. In fact, in rats and rabbits, P450 forms quite distinct from the IIIA P450s catalyze the majority of the metabolism of this pollutant. This is the first demonstration of the role of individual human P450 forms in the metabolism of a representative chemical in this important class of environmental pollutants. The importance of these observations in the overall carcinogenic risk of humans to these chemicals remains to be established. These studies furthermore establish a marked species difference in the metabolism of nitrated polycyclic aromatic hydrocarbons.


Single-stage laparoscopic common bile duct exploration and cholecystectomy versus two-stage endoscopic stone extraction followed by laparoscopic cholecystectomy for patients with concomitant gallbladder stones and common bile duct stones: a randomized controlled trial.
The ideal method for managing concomitant gallbladder stones and common bile duct (CBD) stones is debatable. The currently preferred method is two-stage endoscopic stone extraction followed by laparoscopic cholecystectomy (LC). This prospective randomized trial compared the success and cost effectiveness of single- and two-stage management of patients with concomitant gallbladder and CBD stones. Consecutive patients with concomitant gallbladder and CBD stones were randomized to either single-stage laparoscopic CBD exploration and cholecystectomy (group 1) or endoscopic retrograde cholangiopancreatography (ERCP) for endoscopic extraction of CBD stones followed by LC (group 2). Success was defined as complete clearance of CBD and cholecystectomy by the intended method. Cost effectiveness was measured using the incremental cost-effectiveness ratio. Intention-to-treat analysis was performed to compare outcomes. From February 2009 to October 2012, 168 patients were randomized: 84 to the single-stage procedure (group 1) and 84 to the two-stage procedure (group 2). Both groups were matched with regard to demographic and clinical parameters. The success rates of laparoscopic CBD exploration and ERCP for clearance of CBD were similar (91.7 vs. 88.1 %). The overall success rate also was comparable: 88.1 % in group 1 and 79.8 % in group 2 (p = 0.20). Direct choledochotomy was performed in 83 of the 84 patients. The mean operative time was significantly longer in group 1 (135.7 ± 36.6 vs. 72.4 ± 27.6 min; p ≤ 0.001), but the overall hospital stay was significantly shorter (4.6 ± 2.4 vs. 5.3 ± 6.2 days; p = 0.03). Group 2 had a significantly greater number of procedures per patient (p < 0.001) and a higher cost (p = 0.002). The two groups did not differ significantly in terms of postoperative wound infection rates or major complications. Single- and two-stage management for uncomplicated concomitant gallbladder and CBD stones had similar success and complication rates, but the single-stage strategy was better in terms of shorter hospital stay, need for fewer procedures, and cost effectiveness.


The association between albumin and C-reactive protein in older adults.
Albumin had been found to be a marker of inflammation. The purpose of our study was to investigate the relationship between albumin and C-reactive protein (CRP) in 3579 participants aged 60 to 80 years from the National Health and Nutrition Examination Survey (NHANES). In order to evaluate the association between albumin and CRP, We downloaded the analyzed data (2015-2018) from the NHANES in the United States, and the age of study population was limited to 60 to 80 years (n = 4051). After exclusion of subjects with missing albumin (n = 456) and CRP (n = 16) data, 3579 subjects aged 60 to 80 years were reserved for a cross-sectional study. All measures were calculated accounting for NHANES sample weights. We used the weighted χ2 test for categorical variables and the weighted linear regression model for continuous variables to calculate the difference among each group. The subgroup analysis was evaluated through stratified multivariable linear regression models. Fitting smooth curves and generalized additive models were also carried out. We found albumin negatively correlated with CRP after adjusting for other confounders in model 3 (β = -0.37, 95% CI: -0.45, -0.28, P < .0001). After converting albumin from a continuous variable to a categorical variable (quartiles), albumin level was also negatively associated with serum CRP in all groups (P for trend < .001 for each). In the subgroup analysis stratified by gender, race/ethnicity, smoking, high blood pressure, the negative correlation of albumin with CRP was remained. We also found that the level of CRP further decreased in other race (OR: -0.72, 95% CI: -0.96, -0.47 P < .0001) and participants with smoking (OR: -0.61, 95% CI: -0.86, -0.36 P < .0001). Our findings revealed that albumin levels was negatively associated with CRP levels among in USA elderly. Besides, CRP level decreased faster with increasing albumin level in other race and participants with smoking. Considering this association, hypoalbuminemia could provide a potential predictive biomarker for inflammation. Therefore, studying the relationship between albumin and CRP can provide a screening tool for inflammation to guide therapeutic intervention and avoid excessive correction of patients with inflammation.


Understanding the enemy.
In this issue of Science Translational Medicine, Tanas and colleagues describe a disease-defining genetic alteration for the vascular cancer epithelioid hemangioendothelioma (EHE). The resulting EHE-associated fusion gene encodes an aberrantly expressed putative transcription factor. This molecular information is the latest in a series of genetic discoveries that aid in cancer diagnosis and may pave the way to targeted therapeutic agents.


Significant alteration of IFN stimulated genes expression in MA104 cells infected with bovine rotavirus RF strain.
The pattern recognition receptors (PRRs) trigger signaling cascades, such as nuclear factor kappa B (NF-κB) and interferon regulatory factors (IRFs). Rotavirus (RV) countermeasures against innate responses and understanding of these processes will improve our knowledge regarding immunopathogenesis of RV infection. In this study, we investigated the effect of RV RF strain on the important ISG candidate genes engaging in virus infections for which little information is known in RV RF strain. To this end, MA104 cells were mock/infected with RF followed by incubation in the presence or absence of IFN-α and the expression of MX1, OAS1, STAT1, ISG15, and ISG56 mRNA was analyzed by real-time PCR. All of ISGs' mRNAs showed higher expression levels in IFN I treated cells compared to virus-infected cells except for ISG56. Infecting the cells with RV and treatment with IFN type I led to overexpression of ISG56 compared to cells were either infected with the virus or only treated with IFN I. In conclusion, we showed that the RV RF strain efficiently blocks type I IFN-induced gene expression particularly ISG15, MX1, STAT, and OSA1 as antiviral proteins. Furthermore, viruses may use some ISGs such as ISG 56 to regulate IFN I signaling pathway, negatively.


Mechanisms of Lung Injury and Bronchopulmonary Dysplasia.
Although bronchopulmonary dysplasia (BPD) is the most frequent adverse outcome for infants born at < 30 weeks gestational age, there remain major gaps in understanding the pathophysiology, and thus there are few effective targeted therapies to prevent and treat BPD. This review will focus on the substantial problems and knowledge gaps for the clinician and investigator when considering lung injury and BPD. The epidemiology of BPD is clear: BPD is a lung injury syndrome predominantly in extremely low-birth-weight infants with an incidence that increases as gestation/birth weight decrease, with growth restriction, in males and with fetal exposures and with injury from postdelivery respiratory care. However, we do not have a good definition of BPD that identifies the infants that die of respiratory disease before 36 weeks or that predicts long-term outcomes as well. The injury resulting in BPD likely begins as altered lung development before delivery in many infants (small for gestational age, chorioamnionitis, tobacco exposure), can be initiated by resuscitating at birth, and then amplified by postnatal exposures (oxygen, mechanical ventilation, infection). Conceptually the events leading to BPD are the continued interplay of lung development that is altered progressively by injury and repair to result in poorly defined phenotypes of BPD. The injury pathways prominently cause inflammation, and as a proof of principle, corticosteroids can decrease the incidence and severity of BPD, as demonstrated by three recent trials of the early use of steroids. There are likely "adaptation" and "tolerance" responses that modulate the injury and repair to increase or decrease the damage, interactions that are not understood. BPD is a more complex disease.


A mixed-method evaluation of a workforce development intervention for nursing assistants in nursing homes: the case of WIN A STEP UP.
The purpose of this study was to evaluate WIN A STEP UP, a workforce development program for nursing assistants (NAs) in nursing homes (NHs) involving continuing education by onsite trainers, compensation for education modules, supervisory skills training of frontline supervisors, and short-term retention contracts for bonuses and/or wage increases upon completion. We collected longitudinal semistructured interview and survey data from NAs, supervisors, and managers at 8 program NHs and 10 comparison NHs. To control for selection bias, we matched 77 NA program participants to 81 participating site and 135 comparison site controls using propensity scores in a quasi-experimental design supplemented by qualitative assessments. Managers at seven of eight participating NHs wanted to repeat the program. At 3 months after baseline, participants differed from controls by having (a) more improved nursing care and supportive leadership scores, (b) greater improvement in team care, and (c) stronger ratings of career and financial rewards. Nurse supervisors participating in supervisory skills training reported positive changes in management practices for themselves and peers. Modest 3-month turnover reductions occurred in six settings where the program was fully implemented without incident. Managers', supervisors', and participating NAs' consistent perceptions of improved quality of care and job quality, along with a promise of increased retention, suggest that interventions like WIN A STEP UP are beneficial.


Study of emotional effects of tooth loss in an aging north Indian community.
A study was conducted to study the emotional effects of complete and partial loss of teeth in an aging North Indian community. A questionnaire was prepared for 400 elderly people above the age of 60 years, who were interviewed in dental checkup camps. The data was collected and analyzed using chi-square or chi-square exact tests. 25% of the people were found to have difficulty accepting tooth loss, whereas more than 50% of the people reported to have restricted their food choices. Other problems like reduced attendance in social gatherings for lunch/dinner or eating out in public were also noted. 56% felt that dental consultation prior to tooth loss would have helped them in a significant way. It was concluded that tooth loss did not have a marked impact on emotions of the people but affected their daily social activities, however there was negligible difference between complete and partial tooth loss subjects.