Assessment of metastatic liver disease in patients with primary extrahepatic tumors by contrast-enhanced sonography versus CT and MRI.
To evaluate contrast-enhanced ultrasonography (CEUS) using SonoVue in the detection of liver metastases in patients with known extrahepatic primary tumors versus the combined gold standard comprising CT, MRI and clinical/histological data. It is an international multicenter study, and there were 12 centres and 125 patients (64 males, 61 females, aged 59+/-11 years) involved, with 102 patients per protocol. Primary tumors were colorectal in 35%, breast in 27%, pancreatic in 17% and others in 21%. CEUS using SonoVue was employed with a low-mechanical-index technique and contrast-specific software using Siemens Elegra, Philips HDI 5000 and Acuson Sequoia; continuous scanning for at least five minutes. CEUS with SonoVue increased significantly the number of focal liver lesions detected versus unenhanced sonography. In 31.4% of the patients, more lesions were found after contrast enhancement. The total numbers of lesions detected were comparable with CEUS (55), triple-phase spiral CT (61) and MRI with a liver-specific contrast agent (53). Accuracy of detection of metastatic disease (i.e. at least one metastatic lesion) was significantly higher for CEUS (91.2%) than for unenhanced sonography (81.4%) and was similar to that of triple-phase spiral CT (89.2%). In 53 patients whose CEUS examination was negative, a follow-up examination 3-6 mo later confirmed the absence of metastatic lesions in 50 patients (94.4%). CEUS is proved to be reliable in the detection of liver metastases in patients with known extrahepatic primary tumors and suspected liver lesions.


The CARM1-p300-c-Myc-Max (CPCM) transcriptional complex regulates the expression of CUL4A/4B and affects the stability of CRL4 E3 ligases in colorectal cancer.
The transcription factor c-Myc and two cullin family members CUL4A/4B function as oncogenes in colorectal cancer. Our recent publication reveals that c-Myc specifically activates the expression of CUL4A/4B through binding to their promoters. However, the underlying mechanism of how c-Myc actions in this process is still unknown. Using mass spectrometry and immunoprecipitation assays, we identified c-Myc formed a transcriptional complex with its partner Max (Myc-associated factor X), a histone acetyltransferase p300 and a coactivator associated arginine methyltransferase 1 (CARM1) in the present study. Knockdown or overexpression of the components of CARM1-p300-c-Myc-Max (CPCM) complex resulted in a decrease or increase of CUL4A/4B levels, respectively. Individual knockdown or inhibition of CPCM components decreased cell proliferation, colony formation, and cell invasion. Biochemically, knockdown or inhibition of CPCM components decreased their occupancies on the promoters of CUL4A/4B and resulted in their downregulation. Importantly, inhibition of CPCM components also caused a decrease of CRL4 E3 ligase activities and eventually led to an accumulation of ST7 (suppression of tumorigenicity 7), the specific substrate of CRL4 E3 ligases in colorectal cancer. Moreover, the in vivo tumor formation results indicated that knockdown or inhibition of CPCM components significantly decreased the tumor volumes. Together, our results suggest that the CPCM complex mediates explicitly the expression of CUL4A/4B, and thus affects the stability of CRL4 E3 ligases and the ubiquitination of ST7. These results provide more options by targeting the CPCM components to inhibit tumor growth in the therapy of colorectal cancer.


CDK12: an emerging therapeutic target for cancer.
Cyclin-dependent kinase 12 (CDK12) belongs to the cyclin-dependent kinase (CDK) family of serine/threonine protein kinases that regulate transcriptional and post-transcriptional processes, thereby modulating multiple cellular functions. Early studies characterised CDK12 as a transcriptional CDK that complexes with cyclin K to mediate gene transcription by phosphorylating RNA polymerase II. CDK12 has been demonstrated to specifically upregulate the expression of genes involved in response to DNA damage, stress and heat shock. More recent studies have implicated CDK12 in regulating mRNA splicing, 3' end processing, pre-replication complex assembly and genomic stability during embryonic development. Genomic alterations in CDK12 have been detected in oesophageal, stomach, breast, endometrial, uterine, ovarian, bladder, colorectal and pancreatic cancers, ranging from 5% to 15% of sequenced cases. An increasing number of studies point to CDK12 inhibition as an effective strategy to inhibit tumour growth, and synthetic lethal interactions have been described with MYC, EWS/FLI and PARP/CHK1 inhibition. Herein, we discuss the present literature on CDK12 in cell function and human cancer, highlighting important roles for CDK12 as a clinical biomarker for treatment response and potential as an effective therapeutic target.


The efficacy of the ROM Dance Program for adults with rheumatoid arthritis.
This study examined the efficacy of an exercise and relaxation program for adults with rheumatoid arthritis. The program integrates principles of occupational therapy and T'ai-Chi Ch'uan and was expected to be more effective than traditional exercise and rest regimens because of its expressive and pleasurable elements. There were significant differences between 17 experimental and 16 control subjects on two categories of dependent variables after the former group's participation in the experimental program. These dependent variables were range of motion measures and subject self-reports of frequency, enjoyment, and benefits of home exercise and rest routines. Pretest, posttest, and 4-month follow-up data were analyzed. Program participants showed significantly greater upper extremity range of motion 4 months after completing the program although the reported frequency of exercise and rest was greater in the control group. Postprogram reports of enjoyment were significantly higher for experimental than for control subjects. If these initial results are confirmed in further studies, the efficacy of the use of purposeful activity for exercise and rest will be supported. This study also supports the integration of Eastern and Western frames of reference in the treatment of patients with chronic illness.


Incidence of multiple myeloma in Olmsted County, Minnesota: Trend over 6 decades.
Previous studies have indicated that the incidence and mortality rates for multiple myeloma have increased in the United States. The authors reported on the incidence of multiple myeloma in Olmsted County, Minnesota, between 1991 and 2001 and on trends in multiple myeloma incidence over the last 56 years. Using the files of the Mayo Clinic and the Olmsted Medical Center (Rochester, MN), the authors identified all residents of Olmsted County who had multiple myeloma, suspected myeloma, or a related disorder. Reports of all laboratory determinations, in addition to autopsy findings and death certificates, were obtained. The criteria for the diagnosis of multiple myeloma have not changed during the last 6 decades. All but 1 of the 47 residents with multiple myeloma first diagnosed between 1991 and 2001 were recognized antemortem. Fifty-five percent had a previous monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or solitary plasmacytoma before multiple myeloma was diagnosed. From 1991 to 2001, the overall annual incidence rate, age-adjusted to the 2000 U.S. population, was 4.3 per 100,000 (95% confidence interval, 3.0-5.5 per 100,000). Poisson regression analysis showed no statistically significant trend in Olmsted County incidence rates over 56 years. In similar fashion, the authors adjusted multiple myeloma incidence rates from nine other studies worldwide for which adequate data were available and documented similar findings in each case, except for one study that included patients with smoldering multiple myeloma. The overall incidence of multiple myeloma in Olmsted County, Minnesota, has not changed in almost 6 decades. The apparent increase in incidence elsewhere is unexplained but probably is attributable to improvements in diagnostic techniques, particularly in older patients.


Thermal activation of catalytic microjets in blood samples using microfluidic chips.
We demonstrate that catalytic microjet engines can out-swim high complex media composed of red blood cells and serum. Despite the challenge presented by the high viscosity of the solution at room temperature, the catalytic microjets can be activated at physiological temperature and, consequently, self-propel in diluted solutions of blood samples. We prove that these microjets self-propel in 10× diluted blood samples using microfluidic chips.


Characterization of hepatitis C virus core-specific immune responses primed in rhesus macaques by a nonclassical ISCOM vaccine.
Current therapies for the treatment of hepatitis C virus (HCV) infection are only effective in a restricted number of patients. Cellular immune responses, particularly those mediated by CD8(+) CTLs, are thought to play a role in the control of infection and the response to antiviral therapies. Because the Core protein is the most conserved HCV protein among genotypes, we evaluated the ability of a Core prototype vaccine to prime cellular immune responses in rhesus macaques. Since there are serious concerns about using a genetic vaccine encoding for Core, this vaccine was a nonclassical ISCOM formulation in which the Core protein was adsorbed onto (not entrapped within) the ISCOMATRIX, resulting in approximately 1-microm particulates (as opposed to 40 nm for classical ISCOM formulations). We report that this Core-ISCOM prototype vaccine primed strong CD4(+) and CD8(+) T cell responses. Using intracellular staining for cytokines, we show that in immunized animals 0.30-0.71 and 0.32-2.21% of the circulating CD8(+) and CD4(+) T cells, respectively, were specific for naturally processed HCV Core peptides. Furthermore, this vaccine elicited a Th0-type response and induced a high titer of Abs against Core and long-lived cellular immune responses. Finally, we provide evidence that Core-ISCOM could serve as an adjuvant for the HCV envelope protein E1E2. Thus, these data provide evidence that Core-ISCOM is effective at inducing cellular and humoral immune responses in nonhuman primates.


Diet-Independent Correlations between Bacteria and Dysfunction of Gut, Adipose Tissue, and Liver: A Comprehensive Microbiota Analysis in Feces and Mucosa of the Ileum and Colon in Obese Mice with NAFLD.
Development of non-alcoholic fatty liver disease (NAFLD) is linked to obesity, adipose tissue inflammation, and gut dysfunction, all of which depend on diet. So far, studies have mainly focused on diet-related fecal microbiota changes, but other compartments may be more informative on host health. We present a first systematic analysis of microbiota changes in the ileum and colon using multiple diets and investigating both fecal and mucosal samples. Ldlr-/-.Leiden mice received one of three different energy-dense (ED)-diets (n = 15/group) for 15 weeks. All of the ED diets induced obesity and metabolic risk factors, altered short-chain fatty acids (SCFA), and increased gut permeability and NAFLD to various extents. ED diets reduced the diversity of high-abundant bacteria and increased the diversity of low-abundant bacteria in all of the gut compartments. The ED groups showed highly variable, partially overlapping microbiota compositions that differed significantly from chow. Correlation analyses demonstrated that (1) specific groups of bacteria correlate with metabolic risk factors, organ dysfunction, and NAFLD endpoints, (2) colon mucosa had greater predictive value than other compartments, (3) correlating bacteria differed per compartment, and (4) some bacteria correlated with plasma SCFA levels. In conclusion, this comprehensive microbiota analysis demonstrates correlations between the microbiota and dysfunctions of gut, adipose tissue, and liver, independent of a specific disease-inducing diet.


DNA barcode discovers two cryptic species and two geographical radiations in the invasive drosophilid Zaprionus indianus.
Comparing introduced to ancestral populations within a phylogeographical context is crucial in any study aiming to understand the ecological genetics of an invasive species. Zaprionus indianus is a cosmopolitan drosophilid that has recently succeeded to expand its geographical range upon three continents (Africa, Asia and the Americas). We studied the distribution of mitochondrial DNA (mtDNA) haplotypes for two genes (CO-I and CO-II) among 23 geographical populations. mtDNA revealed the presence of two well-supported phylogenetic lineages (phylads), with bootstrap value of 100%. Phylad I included three African populations, reinforcing the African-origin hypothesis of the species. Within phylad II, a distinct phylogeographical pattern was discovered: Atlantic populations (from the Americas and Madeira) were closer to the ancestral African populations than to Eastern ones (from Madagascar, Middle East and India). This means that during its passage from endemism to cosmopolitanism, Z. indianus exhibited two independent radiations, the older (the Eastern) to the East, and the younger (the Atlantic) to the West. Discriminant function analysis using 13 morphometrical characters was also able to discriminate between the two molecular phylads (93.34 ± 1.67%), although detailed morphological analysis of male genitalia using scanning electron microscopy showed no significant differences. Finally, crossing experiments revealed the presence of reproductive barrier between populations from the two phylads, and further between populations within phylad I. Hence, a bona species status was assigned to two new, cryptic species: Zaprionus africanus and Zaprionus gabonicus, and both were encompassed along with Z. indianus and Zaprionus megalorchis into the indianus complex. The ecology of these two species reveals that they are forest dwellers, which explains their restricted endemic distribution, in contrast to their relative cosmopolitan Z. indianus, known to be a human-commensal. Our results reconfirm the great utility of mtDNA at both inter- and intraspecific analyses within the frame of an integrated taxonomical project.


Biological characterization of bristle extract of Lonomia descimoni caterpillar (Lepidoptera, Saturniidae) and effectiveness of Lonomia antivenom to neutralize experimental envenomation in rats.
Contact with Lonomia caterpillars can cause severe envenomation with hemorrhagic syndrome, consumptive coagulopathy, acute renal failure, and death. In Brazil, an antivenom was produced using extracts from L. obliqua caterpillar bristles as antigen and has been used in other countries in South America to treat envenomation caused by distinct species of Lonomia. This study aimed to characterize the activities of toxins from Lonomia descimoni caterpillars found in Colombia and the neutralization of these toxins by the Brazilian Lonomia antivenom. The protein composition and coagulant, phospholipase A2, hyaluronidase, and defibrinogenating activities were evaluated and compared with the same parameters of the L. obliqua bristle extract. Immune recognition and the neutralizing ability of Lonomia antivenom were also determined. The results showed that the L. descimoni bristle extract presented marked differences in electrophoretic and mass spectrometry profiles and had coagulant, phospholipase A2, and hyaluronidase activities significantly less intense than those of the L. obliqua extract. In rats, L. descimoni extract induced coagulopathy and hemoglobinuria when injected by intravenous or intraperitoneal routes. The Lonomia antivenom recognized the toxins in the extract of L. descimoni and reversed the experimental envenomation in rats. Our results indicate that L. descimoni caterpillars possess toxins with weaker activities than those of L. obliqua but with the potential to cause envenomation. Moreover, the Lonomia antivenom recognized and neutralized the toxins in the L. descimoni bristle extract.


Development and Validation of an Effective Spectrophotometric Method for Simultaneous Determination of Synthetic Colorants After Cloud Point Extraction and Comparision with New Green HPLC Method.
Background: Synthetic colorants are largely used in the pharmaceutical products to increase the attractiveness of products and to help patients distinguish between pharmaceuticals. Despite their commercial advantages, synthetic colorants may, in some cases, have a negative impact on the human body. It is therefore imperative to measure the quantities in food products and pharmaceuticals with a fast, reliable, and sensitive method. Objective: The analyzed synthetic colorants in this study are Erythrosine [(E) E127], Quinoline Yellow [(QY) E104], and Indigo Carmine [(IC) E132]. The aim of this study was to develop and validate a new method for the preconcentration and simultaneous determination of these colorants in pharmaceutical preparations. Method: The developed method has many advantages such as novelty, sensitivity, cost effectiveness, speed, and environmental friendliness. This method is based on the cloud-point extraction (CPE) method coupled with first-derivative spectrophotometry (FDS). In the proposed method, QY, E, and IC were extracted from an aqueous solution by using mixed micelles of TritonX-100 and cetyltrimethylammonium bromide. The effect of the main parameters such as solution pH, surfactant and salt concentration, incubation time, and temperature on the CPE of colorants were investigated and optimized. Under the optimal conditions, the extracted surfactant-rich phase was diluted with acetone, and the first-derivative absorbance values were measured at wavelengths 408, 497, and 637 nm for QY, E, and IC, respectively. The CPE-FDS method was applied in the range of 1.0-6.0 μg/mL for E and QY, and 0.3-1.8 μg/mL for IC. Results: The results showed higher correlation coefficients of 0.9990-0.9993 for each colorant. Furthermore, the method was validated for precision and accuracy and assessed the colorants' contents in the synthetic mixtures that contained different ratios of colorants and pharmaceutical samples. The LOD and LOQ values were 31.0 and 103.0 ng/mL for E, 57.0 and 190.0 ng/mL for QY, and 48.0 and 160.0 ng/mL for IC, respectively. The RSDs at the intermediate concentration level (1.2 μg/mL for IC and 3 μg/mL for QY and for E) were <5%. The recovery values in different ratios of colorants were in the ranges of 90.42-101.14, 92.40-105.54, and 96.15-101.25% for E, IC, and QY, respectively. CPE-FDS was also successfully applied to the simultaneous analysis of the QY, IC, and E contents in the various pharmaceutical samples. The obtained results were statistically compared with those obtained by the green HPLC method that was previously reported by Yoshioka et al. and modified by us in this study. Conclusions: The data observed indicated that the CPE-FDS method does not require use of great samples for determination of trace amounts of E, IC, and QY and allows for the determination of analytes in high matrix effect samples such as suspension and syrup. The study concludes that the proposed CPE-FDS method could be considered an alternative to the existing chromatographical methods for the simultaneous determination of trace amounts of E, IC, and QY in pharmaceutical dosage forms for routine analysis. Highlights: A new and effective procedure, simultaneous determination, trace amounts of E, QY, and IC was developed. This is the first report that uses CPE coupled with FDS for the analysis of E, QY, and IC. CPE avoids the use of costly, hazardous, and flammable solvents in large quantities. FDS resolves two or three overlapping spectra and eliminates matrix interferences. CPE-FDS did not require use of large samples for determination of trace colorants.


Assessing nonsuperiority, noninferiority, or equivalence when comparing two regression models over a restricted covariate region.
In many scientific problems the purpose of the comparison of two regression models, which describe the relationship between a same response variable and several same covariates for two different groups, is to demonstrate that one model is no higher than the other by a negligible amount, or to demonstrate that the models have only negligible differences and so they can be regarded as describing practically the same relationship between the response variable and the covariates. In this article, methods based on one-sided pointwise confidence bands are proposed for assessing the nonsuperiority of one model to the other and for assessing the equivalence of two regression models. Examples from QT/QTc study and from drug stability study are used to illustrate the methods.


Alcohol-related aggression and drinking at off-campus parties and bars: a national study of current drinkers in college.
This study examines relationships between alcohol-related aggression and drinking at off-campus parties and bars. Other background variables include gender, year in school, residence and heavy drinking in college. The study participants were respondents in the 1997 and 1999 Harvard School of Public Health College Alcohol Study, national surveys of students attending 119 4-year U.S. colleges. Based on responses from 8,426 students, 18-24 years of age, who were never married and who reported attendance at off-campus parties and bars in the past month, an exploratory factor analysis of the alcohol problem items was specified in a confirmatory factor analysis framework based on a two-factor solution (disruptive behavior and victims of altercations). In addition, the two factors were related to study variables. Among students attending both off-campus parties and bars, level of drinking was related to higher levels of Factor 1 (disruptive behaviors) at off-campus parties and bars. Level of drinking was related to higher levels of Factor 2 (victims of altercations) at off-campus bars but not off-campus parties. Factor 1 was higher among men, freshmen and residents in coed dorms and lower among students living off-campus with parents. Factor 2 was higher among women, freshmen compared with seniors and residents of Greek houses and lower among students living off-campus residence with parents. Findings from this study highlight environmental factors in collegiate drinking practices and support targeted and diverse strategies for prevention activities.


Breast Cancer Recurrence Is not Increased With Lipofilling Reconstruction: A Case-Controlled Study.
Lipofilling use has become a revolutionary technique for the correction of breast defect including breast cancer sequelae. The potential risk that progenitor cells included in fat graft tissue may contribute to disease progression by stimulation of residuary breast cancer cells in a tumor bed has set alarms regarding its safety. The aim of this study was to identify lipofilling interference over breast recurrence in patients with cancer history. We reviewed 205 patients with fat grafting reconstruction after breast cancer surgery performed in our institution between the years 2007 and 2015. For comparative analysis, we selected 2 matched control patients with similar characteristics who did not undergo any lipofilling procedure. No significant differences in recurrence were observed in patients who had lipofilling compared with controls, local (2.4% vs 3.2%, P = 0. 485), regional (1.0 vs 0.7, P = 0.968), and distant (3.4% vs 3.9%, P = 0.590) recurrence. An increased risk of locoregional recurrence (P = 0.014) was detected when lipofilling took place within the first 36 months after cancer surgery. This study provides patients and surgeons with the confidence to keep using lipofilling reconstruction in women with breast cancer history when it is performed in a hospital setting by trained surgeons.


Hippocampal and amygdala volumes in children and adults with childhood maltreatment-related posttraumatic stress disorder: a meta-analysis.
Little work has directly examined the course of hippocampal volume in children and adults with childhood maltreatment-related posttraumatic stress disorder (PTSD). Data from adults suggest that hippocampal volume deficits are associated with PTSD, whereas findings from children with PTSD generally show no hippocampal volume deficits in PTSD. Additionally, the role of the amygdala in emotional response makes it a possible region for investigation in children and adults with childhood maltreatment-related PTSD. The objectives of this study were 2-fold: (1) to meta-analytically determine whether hippocampal and amygdala volumes in children and adults with PTSD from childhood maltreatment differ from those in healthy controls, and (2) to use cross-sectional findings performed with meta-analyses as a proxy for longitudinal studies to estimate the course of hippocampal and amygdala volumes in child and adult subjects with PTSD from childhood maltreatment. Using electronic databases, we identified articles containing hippocampal and amygdala data for children with PTSD and adults with PTSD from childhood maltreatment. Data were extracted and effect sizes were calculated using Comprehensive Meta-Analysis Version 2.0. Reduced bilateral hippocampal volume was found in adults with childhood maltreatment-related PTSD compared with healthy controls, but this deficit was not seen in children with maltreatment-related PTSD, suggesting hippocampal volume deficits from childhood maltreatment may not be apparent until adulthood. Greater left than right hippocampal volume was found in the adult healthy control group but not in the PTSD group. Amygdala volume in children with maltreatment-related PTSD did not differ from that in healthy controls. Hippocampal volume is normal in children with maltreatment-related PTSD but not in adults with PTSD from childhood maltreatment, suggesting an initially volumetrically normal hippocampus with subsequent abnormal volumetric development occurring after trauma exposure. However, longitudinal studies are needed to support these preliminary findings.


The emerging threat of fluroquinolone-, bedaquiline-, and linezolid-resistant Mycobacterium tuberculosis in China: Observations on surveillance data.
Drug-resistant tuberculosis (TB), especially multidrug-resistant tuberculosis (MDR-TB), constitutes a major obstacle to fulfill end TB strategy globally. Although fluoroquinolones (FQs), linezolid (LZD) and bedaquiline (BDQ) were classified as Group A drugs for MDR-TB treatment, our knowledge of the prevalence of TB which were resistant to Group A drugs in China is quite limited. In this study, we conducted a prospective multicenter surveillance study in China to determine the proportion of TB patients that were resistant to Group A drugs. A total of 1877 TB patients were enrolled from 2022 at four TB specialized hospitals. The drug susceptibility of isolated strains was conducted using the MGIT 960 system and the molecular mechanisms conferring drug resistance were investigated by Sanger sequencing. 12.9% of isolates were resistant to levofloxacin (LFX), 13.2% were resistant to moxifloxacin (MOX), 0.2% were resistant to bedaquiline (BDQ), and 0.8% were resistant to linezolid (LZD). Totally, 14.0% and 0.4% were classified as multidrug resistant- (MDR-) and extensively drug resistant- (XDR-) TB. The drug resistance was more common in retreated TB cases compared to new cases. In addition, 70.0% of fluoroquinolone (FQ)-resistant isolates harbored mutations in the gyrA and gyrB gene. By contrast, the common drug-resistant mutations were only found in 50% BDQ-resistant and 20% LZD-resistant isolates. Our data demonstrate that approximate half of MDR -TB patients are resistant to fluoroquinolones, with extremely low prevalence of initial BDQ and LZD resistance. Findings from this study provide important implications for the current management of MDR-TB patients.


Severity and pattern of peri-implantitis-associated bone loss.
The purpose of the present study was to describe the severity and pattern of peri-implantitis-associated bone loss. Intra-oral radiographs from 182 subjects were analysed. Bone-level measurements were performed in 419 implants with a history of bone loss. All radiographs obtained in the interval from the 1-year follow-up to the end-point examination (5-23 years) were analysed. The amount of bone loss that occurred from 1 year after prosthesis insertion was assessed and the pattern of bone loss was evaluated. The average bone loss after the first year of function was 1.68 mm and 32% of the implants demonstrated bone loss > or =2 mm. The multilevel model revealed that the bone loss showed a non-linear pattern and that the rate of bone loss increased over time. The model also revealed that the pattern of peri-implantitis associated bone loss was similar within the same subject. It is suggested that peri-implantitis-associated bone loss varies between subjects and is, in most cases, characterized by a non-linear progression, with the rate of loss increasing over time.


Guidelines for the diagnosis and treatment of celiac disease in children.
Jennifer, age 2 years, is being seen for her regular 2-year well child visit. You note her weight is only at the 5% and has been dropping percentiles over the past year When you ask her mother about Jennifer's diet, she reports Jennifer is a "picky eater" and often complains of a "stomach ache." Her mother reports her stomach looks "bloated. " Steven, age 7 years, is brought into the clinic because of recurrent abdominal pain with occasional constipation or diarrhea. Steven's mother had been told in the past that he probably had "irritable bowel syndrome" but changes in his diet, occasional use of a laxative, and relaxation techniques have not improved his symptoms. Rebecca, age 12 years, is brought into your clinic because her mother has recently learned that two first cousins have been diagnosed with celiac disease. She is wondering if Rebecca should be screened for this condition since she has heard it runs in families.


[Distributive regularity of pressing sensitive acupoints in chronic non-atrophic gastritis patients].
To compare the distribution regularity of the pressure-sensitive acupoints in patients with chronic non-atrophic gastritis (CNAG) and healthy subjects, so as to provide suitable acupoint combinations for clinical treatment. A total of 120 volunteer subjects including 60 CNAG patients (29 men and 31 women, (40.7±10.3) years at the average age) and 60 healthy subjects (28 men and 32 women, and (40.8±10.2) years at the average age) were enrolled in the present study. The pressure-sensitive acupoints were checked by a fixed operator using his finger pulp along the body trunk and the four limbs and marked on a prepared human dermatome graph. The number of pressing sensitive acupoints were counted, and the relationship between the distribution of the detected sensitive acupoints and the position of meridians and nerve segments was analyzed. The incidence of pressure-sensitive acupoint in CNAG patients and healthy subjects were 86.7% and 15.0%, respectively. In 60 CNAG patients, the most frequently met sensitive acupoints were Xuehai (SP10), Zhongwan (CV13), and Zhongting (CV17) in sequence, mainly covering the Conception Vessel, Spleen Meridian of Foot-Taiyin (SP), and the Stomach Meridian of Foot-Yangming (ST). The sensitive acupoints presented a nerve-segmental distribution within T7-T10 and L3-L5. The pressure-sensitive acupoints present a nerve-segmental distribution and have a higher corresponding rate with some meridians related to the stomach, especially under diseased conditions.


Context and Approach in Reporting Evaluations of Electronic Health Record-Based Implementation Projects.
Electronic health records (EHRs) are ubiquitous yet still evolving, resulting in a moving target for determining the effects of context (features of the work environment, such as organization, payment systems, user training, and roles) on EHR implementation projects. Electronic health records have become instrumental in effecting quality improvement innovations and providing data to evaluate them. However, reports of studies typically fail to provide adequate descriptions of contextual details to permit readers to apply the findings. As for any evaluation, the quality of reporting is essential to learning from, and disseminating, the results. Extensive guidelines exist for reporting of virtually all types of applied health research, but they are not tailored to capture some contextual factors that may affect the outcomes of EHR implementations, such as attitudes toward implementation, format and amount of training, post go-live support, amount of local customization, and time diverted from direct interaction with patients to computers. Nevertheless, evaluators of EHR-based innovations can choose reporting guidelines that match the general purpose of their evaluation and the stage of their investigation (planning, protocol, execution, and analysis) and should report relevant contextual details (including, if pertinent, any pressures to help justify the huge investments and many years required for some implementations). Reporting guidelines are based on the scientific principles and practices that underlie sound research and should be consulted from the earliest stages of planning evaluations and onward, serving as guides for how evaluations should be conducted as well as reported.


TB control in the hospital environment.
Tuberculosis is again on the rise in the United States. Several outbreaks of TB in hospitals have heightened interest in the development and use of mechanisms that prevent the spread of this airborne pathogen. Controlling the spread of TB to hospital patients, workers, and others can be accomplished through various administrative engineering and design controls, and infection control programs, as recommended by the Centers for Disease Control and Prevention (CDC). The hazard of TB is real, but workers, patients, and visitors can be protected by implementing programs that guard against the diseases spread in the hospital environment.


Root abnormalities and nonsurgical management of generalized aggressive periodontitis.
To investigate long-term nonsurgical treatment outcomes in patients with generalized aggressive periodontitis (GAgP) and the impact of root abnormalities (RAs) and other patient-level factors in relation to GAgP progression. Patients (n = 64) from a GAgP cohort who completed active nonsurgical periodontal treatment and consented to re-evaluation after 3 to 11 (mean 5.3) years, were enrolled. RAs were identified using radiographs. Periodontal parameters (e.g., probing depths [PDs], and tooth loss [TL]) were investigated. Multivariate analysis was performed to identify factors contributing to TL and bone level alteration (∆BL). After treatment, the mean number of sites with PDs > 5 mm decreased from 54.3 to 17.2. Annual TL was 0.11/patient. Twenty-one patients (32.8%) had >4 teeth with root abnormalities (RA-teeth) and exhibited a higher risk for TL (univariate odds ration [OR] = 3.52, multivariate logistic OR = 6.57). Factors correlated to ∆BL were sites with residual PD > 5 mm (β = -0.400) and observation time (β = -0.210). Nonsurgical treatment provides beneficial outcomes in GAgP patients. Higher incidence of RAs and high prevalence of residual deep pockets have a negative impact on long-term outcomes. in cases of GAgP with residual deep pockets and high incidence of RAs, clinicians must emphasize that long-term outcomes of nonsurgical treatment may be compromised.


Vasopressin V2-receptor mobile fraction and ligand-dependent adenylate cyclase activity are directly correlated in LLC-PK1 renal epithelial cells.
The role of hormone receptor lateral mobility in signal transduction was studied using a cellular system in which the receptor mobile fraction could be reversibly modulated to largely varying extents. The G-protein-coupled vasopressin V2-type receptor was labeled in LLC-PK1 renal epithelial cells using a fluorescent analogue of vasopressin, and receptor lateral mobility measured using fluorescence microphotolysis (fluorescence photobleaching recovery). The receptor mobile fraction (f) was approximately 0.9 at 37 degrees C and less than 0.1 at 10 degrees C, in accordance with previous studies. When cells were incubated for 1 h at 4 degrees C without hormone, and then warmed up to 37 degrees C and labeled with the vasopressin analogue, f increased from approximately 0.4 to 0.8 over approximately 1 h. The apparent lateral diffusion coefficient was not markedly affected by temperature pretreatment. Studies with radiolabeled vasopressin indicated that temperature pretreatment influenced neither receptor number nor binding/internalization kinetics. F-actin staining revealed that temperature change resulted in reversible changes of cytoskeletal structure. The maximal rate of in vivo cAMP production at 37 degrees C in response to vasopressin, but not to forskolin (receptor-independent agonist), was also markedly influenced by preincubation of cells at 4 degrees C, thus paralleling the effects of temperature preincubation on f. A linear correlation between f and maximal cAMP production was observed, suggesting that the receptor mobile fraction is a key parameter in hormone signal transduction in vivo. We conclude that mobile receptors are required to activate G-proteins, and discuss the implications of this for signal transduction mechanisms.


Landscape affects the host-seeking patterns of Culex tarsalis (Diptera: Culicidae) in the Coachella Valley of California.
Effective arbovirus transmission requires that the principal vertebrate hosts and vectors have frequent contact. Vegetation and other landscape features used by roosting or nesting birds at night dictate their exposure to nocturnally active host-seeking Culex tarsalis Coquillett and therefore to western equine encephalomyelitis and St. Louis encephalitis viruses. Precipitin tests on 645 Cx. tarsalis that were collected resting and host-seeking near the Salton Sea in Coachella Valley, CA, indicated that passeriform birds (64%) and rabbits (25%) were the most frequent bloodmeal hosts and that the percentage of females feeding on birds varied temporally as an inverse fuction of mosquito abundance. Blood meals were not taken from communally roosting water birds. The spatial distribution of host-seeking females then was investigated by deploying dry ice baited traps within seven sites representative of habitats found along the Salton Sea. Mosquito catch was greatest at traps within elevated vegetation such as Tamarisk, mesquite, cattails, and orchards and lowest at traps positioned at snags over water, sand bars, open fields, and within housing in a small rural community. These data indicate that host-seeking Cx. tarsalis females congregated at specific landscape features that were not necessarily associated with large concentrations of potential bloodmeal hosts.


Body composition assessment in the infant.
Body composition assessment provides a sharper picture of the human biological response to genetic and environmental influences than measures of body size and weight. Infant body composition is particularly important as a marker of fetal adaptation and developmental programming of subsequent health and disease, but until recently, the range of options for measuring infant body composition was relatively narrow. The purpose of this Toolkit: Methods in Human Biology review is to provide a comprehensive overview of methods of body composition methods currently used in infants 0 to 2 years of age, including anthropometric prediction equations, air displacement plethysmography (ADP), dual energy X-ray absorptiometry (DXA), bioelectrical impedance analysis (BIA), isotope dilution, and magnetic resonance imaging (MRI). Information on the reliability, validity, and accuracy of the methods is provided. Unique aspects of infant physiology and behavior create challenges for body composition assessment, but this review provides guidance on suitable testing approaches and environments that may aid researchers in this important area of investigation.


Bombesin/GRP-stimulated somatostatin secretion is mediated by gastrin in the antrum and intrinsic neurons in the fundus.
The mechanism of action of bombesin, also known as gastrin-releasing peptide (GRP), on somatostatin secretion was examined separately in superfused segments of rat antral and fundic mucosa. Bombesin/GRP (1 nM) stimulated somatostatin secretion from both regions. In fundic segments, the somatostatin response was strongly inhibited (86%; P less than 0.01) by tetrodotoxin (5 microM) but augmented by atropine (1 microM) (P less than 0.01). In antral segments, both tetrodotoxin and atropine augmented the somatostatin response to bombesin/GRP by 42-45% (P less than 0.01), whereas the gastrin antagonist L 365260 (1 microM) abolished it. The gastrin antagonist augmented the gastrin response to bombesin/GRP by 103% (P less than 0.01). The results indicate that bombesin/GRP stimulates somatostatin secretion by distinct mechanisms in the fundus and antrum. In the fundus, bombesin/GRP acts indirectly on somatostatin cells by activating stimulatory noncholinergic neurons and, to a lesser extent, inhibitory cholinergic neurons. In the antrum, bombesin/GRP acts indirectly on somatostatin cells by stimulating release of gastrin and, to a lesser extent, by activating inhibitory cholinergic neurons. A dual paracrine pathway links gastrin and somatostatin secretion in the antrum.


Allostasis and allostatic load: expanding the discourse on stress and cardiovascular disease.
The aim of this discursive paper is to introduce allostasis and allostatic load, which are relatively new concepts proposed to explain physiological responses to stress, and to suggest ways in which allostasis theory can be applied to the development of clinical interventions to increase resilience for producing better health outcome. Common explanations of stress have failed adequately to explicate its association with health and chronic illness. Allostasis is the extension of the concept of homeostasis and represents the adaptation process of the complex physiological system to physical, psychosocial and environmental challenges or stress. Allostatic load is the long-term result of failed adaptation or allostasis, resulting in pathology and chronic illness. The concepts of allostasis and allostatic load introduced the idea that external challenges initiate allostasis and chronic stress causes allostatic load that can be measured with multiple biomarkers. Finding from several studies suggests that higher allostatic load is associated with worse health outcomes. Resilience represents successful allostasis and strategies can be implemented to enhance resilience and thereby improve health outcomes. This theoretical model provides a comprehensive explanation of the human body's adaptation processes in response to stress and the results of failed adaptation over time. In addition, combining the concepts of allostasis and resilience may help us to understand and implement clinical strategies better to reduce or prevent the debilitating physiological and psychological effects of chronic stress and chronic illness. Clinical practice should be based on a solid theoretical foundation to improve health outcomes. Strategies to manage stress and increase resilience along with clinical interventions to manage the physiological responses to chronic stress are necessary to assist in preventing and controlling the detrimental effects of chronic disease on human life.


Bile alcohol metabolism in man. Conversion of 5beta-cholestane-3alpha, 7alpha,12alpha, 25-tetrol to cholic acid.
To study the role of C25-HYDROXY BILE ALCOHOLS AS PRECURSORS OF CHOlic acid, [G-3-H]5beta-cholestane-3alpha,7alpha12alpha,25-tetrol was administered intravenously to two subjects with cerebrotendinous xanthomatosis (CTX) and two normal individuals. One day after pulse labeling, radioactivity was present in the cholic acid isolated from the bile and feces of the subjects with CTX and the bile of the normal individuals. In the two normal subjects, the sp act decay curves of [G-3-H]-cholic acid were exponential, and no traces of [G-3-H]-5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol were detected. In contrast, appreciable quantities of labeled 5beta-cholestane-3alpha,-7aopha,12alpha,25-tetrol were present in the bile and feces of the CTX subjects. The sp act vs. time curves of fecal [G-3-H]5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol and [G-3-H]-cholic acid showed a precursor-product relationship. Although these results suggest that 5beta-cholestane-3alpha,7alpha,12alpha,25-tetrol may be a precursor of cholic acid in man, the possibility that C26-hydroxy intermediates represent the normal pathway can not be excluded.


MHC-class-II are expressed in a subpopulation of human neural stem cells in vitro in an IFNγ-independent fashion and during development.
Expression of major histocompatibility antigens class-2 (MHC-II) under non-inflammatory conditions is not usually associated with the nervous system. Comparative analysis of immunogenicity of human embryonic/fetal brain-derived neural stem cells (hNSCs) and human mesenchymal stem cells with neurogenic potential from umbilical cord (UC-MSCs) and paediatric adipose tissue (ADSCs), while highlighting differences in their immunogenicity, led us to discover subsets of neural cells co-expressing the neural marker SOX2 and MHC-II antigen in vivo during human CNS development. MHC-II proteins in hNSCs are functional, and differently regulated upon differentiation along different lineages. Mimicking an inflammatory response using the inflammatory cytokine IFNγ induced MHC-II up-regulation in both astrocytes and hNSCs, but not in UC-MSCs and ADSCs, either undifferentiated or differentiated, though IFNγ receptor expression was comparable. Together, hypoimmunogenicity of both UC-MSCs and ADSCs supports their suitability for allogeneic therapy, while significant immunogenicity of hNSCs and their progeny may at least in part underlie negative effects reported in some patients following embryonic neural cell grafts. Crucially, we show for the first time that MHC-II expression in developing human brains is not restricted to microglia as previously suggested, but is present in discrete subsets of neural progenitors and appears to be regulated independently of inflammatory stimuli.


Amino acid residues necessary for putrescine stimulation of human S-adenosylmethionine decarboxylase proenzyme processing and catalytic activity.
Human S-adenosylmethionine (AdoMet) decarboxylase is synthesized as a 38-kDa proenzyme that is autocatalytically cleaved, forming the covalently attached pyruvate cofactor and the two subunits (67 and 267 amino acid residues) of the mature enzyme. Both the cleavage reaction and the catalytic activity of the mature enzyme are stimulated by putrescine. Using site-specific mutagenesis and in vitro transcription followed by translation of the resultant RNA in a cellfree system, we have examined the importance of several amino acid residues on the processing reaction rate and catalytic activity and on stimulation of each of these by putrescine. Changing Cys82 to Ala decreased the stimulatory effect of putrescine on processing and completely eliminated catalytic activity, indicating a probable role in the active site of the enzyme, whereas changing Cys49 or Cys226 to Ala had minimal effects on processing and activity or the putrescine stimulation of either. Since Cys49 is the only cysteine residue in the smaller subunit, this indicates that disulfide-bond formation between the two subunits cannot be necessary for maintenance of the conformation for proenzyme processing or catalytic activity. Changing Glu8 or Glu11 to Gln produced an AdoMet decarboxylase that processed, but was catalytically inactive. Mutation at Glu11 also completely eliminated the putrescine stimulation of proenzyme processing, as did double mutation at Glu8 and Glu11, whereas the single mutation at Glu8 had no effect on the putrescine stimulation of proenzyme processing. Changing Glu15, Glu61, Glu67, Glu247, or Glu247 and Glu249 to Gln had a minimal effect on processing and activity or putrescine stimulation of either. These results demonstrate a role for the smaller subunit in the catalytic activity of the mature AdoMet decarboxylase enzyme and show that Glu8, Glu11, and Cys82 are essential for catalytic activity, with Glu11 also being essential for the putrescine stimulation of AdoMet decarboxylase proenzyme processing.


Community-based studies of Alzheimer's disease: statistical challenges in design and analysis.
Alzheimer's disease is a chronic disease, primarily of the elderly, characterized by progressive dementia and eventual death. Community-based studies will likely provide a better representation of the spectrum of disease than will studies drawn solely from clinical sources, because an unknown and possibly substantial fraction of the cases do not come to the attention of the medical care system, or are diagnosed only very late in the disease. Community-based studies will provide not only more accurate estimates of prevalence and incidence, but also more directly comparable unaffected people for studies of risk factors for onset and progression. Such studies are likely to consist of a census component where relatively inexpensive but useful auxiliary information is collected and a probability sample from the census, with the detailed and costly clinical diagnosis of Alzheimer's disease restricted to the sample. The statistician faces challenges both in designing a sample that meets multiple objectives efficiently and in analysing data from the resulting complex survey designs.


The effect of dissolved gas on coalescence of oil drops studied with microfluidics.
In literature it is stated that the stability of oil-in-water emulsions could be enhanced by decreasing the so-called "hydrophobic interactions" between surfaces through removal of dissolved atmospheric gases. Since the effect of the dissolved gases depends on the hydrophobicity of the oil phase, as well as the system pressure, we vary this effect systematically and monitor droplet coalescence in a tailor-made microfluidic device. The coalescence of oil drops in standard and degassed conditions was studied by direct observation using a microfluidic setup. Two model oils (heptane and xylene) were used to represent different hydrophobicity of the dispersed phases, together with an oil with dynamic interfacial behaviour (diluted crude oil). In addition, the effect of the volume fraction, droplet size and degassing method was studied. At ambient pressure, the degassing of the continuous phase reduced the extent of coalescence for the model oils, which is in agreement with other reports. No effect of the dissolved gases was found on the drop formation process. At elevated pressures, the dissolved gases influenced only the most hydrophobic oil (heptane), while causing no effect in the other systems. The coalescence frequencies decreased upon the reduction of the drop sizes, which was justified with the theory for two interacting spheres.


Evaluating Whether Sight Is the Most Valued Sense.
Sight is often considered to be the sense most valued by the general public, but there are limited empirical data to support this. This study provides empirical evidence for frequent assertions made by practitioners, researchers, and funding agencies that sight is the most valued sense. To determine which senses are rated most valuable by the general public and quantify attitudes toward sight and hearing loss in particular. This cross-sectional web-based survey was conducted from March to April 2016 through a market research platform and captured a heterogeneous sample of 250 UK adults ages 22 to 80 years recruited in March 2016. The data were analyzed from October to December 2018. Participants were first asked to rank the 5 traditional senses (sight, hearing, touch, smell, and taste) plus 3 other senses (balance, temperature, and pain) in order of most valuable (8) to least valuable (1). Next, the fear of losing sight and hearing was investigated using a time tradeoff exercise. Participants chose between 10 years without sight/hearing vs varying amounts of perfect health (from 0-10 years). Of 250 participants, 141 (56.4%) were women and the mean (SD) age was 49.5 (14.6) years. Two hundred twenty participants (88%) ranked sight as their most valuable sense (mean [SD] rating, 7.8 [0.9]; 95% CI, 7.6-7.9). Hearing was ranked second (mean [SD] rating, 6.2 [1.3]; 95% CI 6.1-6.4) and balance third (mean [SD] rating, 4.9 [1.7]; 95% CI, 4.7-5.1). All 3 were ranked above the traditional senses of touch, taste, and smell (F7 = 928.4; P < .001). The time tradeoff exercise indicated that, on average, participants preferred 4.6 years (95% CI, 4.2-5.0) of perfect health over 10 years without sight and 6.8 years (95% CI, 6.5-7.2) of perfect health over 10 years without hearing (mean difference between sight and hearing, 2.2 years; P < .001). In a cross-sectional survey of UK adults from the general public, sight was the most valued sense, followed by hearing. These results suggest that people would on average choose 4.6 years of perfect health over 10 years of life with complete sight loss, although how this generalizes to other parts of the world is unknown.


The influence of visual flow and perceptual load on locomotion speed.
Visual flow is used to perceive and regulate movement speed during locomotion. We assessed the extent to which variation in flow from the ground plane, arising from static visual textures, influences locomotion speed under conditions of concurrent perceptual load. In two experiments, participants walked over a 12-m projected walkway that consisted of stripes that were oriented orthogonal to the walking direction. In the critical conditions, the frequency of the stripes increased or decreased. We observed small, but consistent effects on walking speed, so that participants were walking slower when the frequency increased compared to when the frequency decreased. This basic effect suggests that participants interpreted the change in visual flow in these conditions as at least partly due to a change in their own movement speed, and counteracted such a change by speeding up or slowing down. Critically, these effects were magnified under conditions of low perceptual load and a locus of attention near the ground plane. Our findings suggest that the contribution of vision in the control of ongoing locomotion is relatively fluid and dependent on ongoing perceptual (and perhaps more generally cognitive) task demands.


Non-Hodgkin lymphoma risk in adults living with HIV across five continents.
To compare non-Hodgkin lymphoma (NHL) incidence rates in adults who started antiretroviral therapy (ART) across the Asia-Pacific, South Africa, Europe, Latin, and North America. We included cohort data of adults living with HIV who started ART after 1995 within the framework of the International epidemiology Databases to Evaluate AIDS (IeDEA) and the Collaboration of Observational HIV Epidemiological Research in Europe (COHERE). We used flexible parametric survival models to compare regional NHL rates at 2 years after ART start and to identify risk factors for NHL. We included 210 898 adults with 1.1 million person-years (pys) of follow-up and 1552 incident NHL cases (raw overall incidence rate 142/100 000 pys). After adjusting for age at ART start, first-line ART regimen, calendar period of ART start, and especially current CD4 cell count, NHL rates were similar across regions for most population groups. However, South African women remained at increased risk of developing NHL compared with their European counterparts [adjusted hazard ratio [aHR] 1.79, 95% CI 1.19-2.70]. In Europe, Latin, and North America, NHL risk was highest in MSM (aHR 1.30, 95% CI 1.14-1.48), followed by heterosexual men (referent), and women (aHR 0.66, 95% CI 0.57-0.78). The risk of developing NHL is higher in women in South Africa than in Europe and higher in MSM compared with heterosexual men and women. Reasons for these differences remain unclear. Early ART access and regular patient monitoring to avert low CD4 cell counts remain key for NHL prevention.


An immunomics approach for the analysis of natural antibody responses to Plasmodium vivax infection.
High throughput immunomics is a powerful platform to discover potential targets of host immunity and develop diagnostic tests for infectious diseases. We screened the sera of Plasmodium vivax-exposed individuals to profile the antibody response to blood-stage antigens of P. vivax using a P. vivax protein microarray. A total of 1936 genes encoding the P. vivax proteins were expressed, printed and screened with sera from P. vivax-exposed individuals and normal subjects. Total of 151 (7.8% of the 1936 targets) highly immunoreactive antigens were identified, including five well-characterized antigens of P. vivax (ETRAMP11.2, Pv34, SUB1, RAP2 and MSP4). Among the highly immunoreactive antigens, 5 antigens were predicted as adhesins by MAAP, and 11 antigens were predicted as merozoite invasion-related proteins based on homology with P. falciparum proteins. There are 40 proteins that have serodiagnostic potential for antibody surveillance. These novel Plasmodium antigens identified provide the clues for understanding host immune response to P. vivax infection and the development of antibody surveillance tools.


Effect of insulin-like-growth factor and its receptors regarding lung development in fetal mice.
In congenital diaphragmatic hernia (CDH), both mortality and morbidity are mainly caused by pulmonary hypoplasia and persistent pulmonary hypertension. Insulin-like growth factors (IGFs) are one of the growth factors that may play an important role in the fetal lung development. Elucidating the roles of these growth factors regarding fetal lung development would thus provide new insight regarding the optimal therapy for CDH patients. The aim of this study is to investigate the role of IGFs in the fetal lung development. The mRNA expression of IGFs and its receptors was analyzed by real-time RT-PCR from embryonic day (E) 11.5 to E18.5 mice. In addition, the lungs dissected from the E17.5 mice were divided into the following three groups; lungs cultured only in the serum-free medium (group I n = 5), lungs cultured in medium containing either IGF-I (group II n = 5), or IGF-II (group III n = 5). All cultures were investigated by immunohistochemistry, using the antibodies of thyroid transcription factor (TTF)-1, prosurfactant protein (proSp)-C, alpha smooth muscle actin (alpha-SMA), and anti-proliferating cell nuclear antigen (PCNA). The mRNA expression level of both IGF-I and IGF-II was higher during the earlier stage than that of later stage. In contrast, the mRNA expression of both IGF-I receptor (IGF-IR) and IGF-II receptor (IGF-IIR) was higher from the E17.5 to E18.5 than that at any other stage. The number of positive cells for TTF-1, proSp-C, alpha-SMA and PCNA increased more in both groups II and III than in group I. Based on our findings, IGFs are suggested to induce alveolar and vascular maturation in the late stages of fetal lung development. Therefore, the administration of IGFs to the fetal CDH lung may thus be able to effectively improve the symptoms of hypoplastic lung.


Structure-Emission Property Relationships in Cyclometalated Pt(II) β-Diketonate Complexes.
Extending the ligand π-system of phosphorescent (C∧C*) or (C∧N) cyclometalated platinum(II) β-diketonate complexes can lead to large and seemingly abrupt variations of the photophysical properties such as triplet quantum yields and phosphorescence lifetimes. Quantum chemical studies using methods including elements from density functional theory (DFT) and multireference configuration interaction (MRCI) as well as spin-orbit coupling (SOC) provide a rationale for these observations. In the Franck-Condon region, the first excited singlet states (S1) of these complexes are characterized by mixed metal-to-ligand charge-transfer (MLCT) and ligand-centered (LC) excitations. With increasing extension of the effective π-system, the lowest-lying triplet state yields more and more LC character, thus leading to a decrease of the phosphorescence rate constant. The ability to undergo efficient intersystem crossing from S1 to T1 is not diminished as the S1 state largely retains its character. In the N-heterocyclic carbene (NHC) complexes investigated here, at least two triplet states are found energetically below the S1 state. Out-of-plane distortion enhances the probability for nonradiative decay of the triplet population. In the smaller compounds emitting in the violet or blue spectral region, the phosphorescent state is separated from the lowest-lying dark metal-centered (MC) triplet state by a small barrier only, explaining their experimentally observed low photoluminescence quantum yields in liquid solution. The semiempirical DFT/MRCI-R2018 Hamiltonian employed in our studies proves well-suited for investigating the absorption and emission properties of these platinum(II) complexes. Generally, good agreement is observed between our calculated data and the experimental findings.


Classification of Bleeding Events: Comparison of ECASS III (European Cooperative Acute Stroke Study) and the New Heidelberg Bleeding Classification.
Intracranial hemorrhage (ICH) after acute ischemic stroke treatments represents a feared complication with possible prognostic implications. In recent years, ICHs were commonly classified according to the ECASS (European Cooperative Acute Stroke Study). To improve the clinical applicability and relevance, the new Heidelberg Bleeding Classification (HBC) has been proposed in 2015. Here, we compared the ECASS and HBC classification with regard to observed events and prognostic relevance. A retrospective analysis of a prospectively compiled database of patients with acute ischemic stroke in the anterior circulation who received mechanical thrombectomy between February 2011 and March 2016 was performed. Presence of ICH after mechanical thrombectomy was evaluated on postinterventional computed tomographic imaging. ICHs were specified according to both ECASS III and HBC classification and analyzed with regard to their symptoms and outcome. ICHs were observed in 156 of 768 patients (20.3%). Using ECASS III classification, 101 ICHs could be unambiguously assigned, of which 28 (27.7%; 3.6% of all treated patients) were symptomatic ICHs. Using HBC, 55 additional ICHs could be categorized. Of these total 156 ICHs, 29 (18.6%; 3.8% of all treated patients) were classified as symptomatic according to HBC. Classification of ICH by ECASS III and HBC criteria show distinct differences. These differences warrant special attention during interpretation and comparison of scientific publications.


Mechanism for controlling the dimer-monomer switch and coupling dimerization to catalysis of the severe acute respiratory syndrome coronavirus 3C-like protease.
Unlike 3C protease, the severe acute respiratory syndrome coronavirus (SARS-CoV) 3C-like protease (3CLpro) is only enzymatically active as a homodimer and its catalysis is under extensive regulation by the unique extra domain. Despite intense studies, two puzzles still remain: (i) how the dimer-monomer switch is controlled and (ii) why dimerization is absolutely required for catalysis. Here we report the monomeric crystal structure of the SARS-CoV 3CLpro mutant R298A at a resolution of 1.75 A. Detailed analysis reveals that Arg298 serves as a key component for maintaining dimerization, and consequently, its mutation will trigger a cooperative switch from a dimer to a monomer. The monomeric enzyme is irreversibly inactivated because its catalytic machinery is frozen in the collapsed state, characteristic of the formation of a short 3(10)-helix from an active-site loop. Remarkably, dimerization appears to be coupled to catalysis in 3CLpro through the use of overlapped residues for two networks, one for dimerization and another for the catalysis.


Eisosomes and plasma membrane organization.
Membrane compartmentalization allows the spatial segregation of different functions, such as signal transduction and protein trafficking, and ensures their fidelity and efficiency. Eisosomes constitute nanoscale furrow-like invaginations of the plasma membrane where proteins and lipids segregate. The intense interest elicited by eisosomes over the last few years has led to the identification and molecular characterization of their key constituents. This review addresses eisosome structure, functions and its implications for the mechanistic understanding of curvature-induced membrane nanodomains formation and signaling compartmentalization in living cells.


Effect of dietary fat on pancreatic lipase activity in chicken.
Pancreatic lipase activity was measured in young chicks receiving experimental diets for 18 to 24 days. The addition of 15% soybean oil to a commercial-type diet, without changing the calorie-protein ratio, produced a slight but significant increase in lipase activity. No differences in lipolytic activity were found when chicks received a semipurified diet with or without the addition of 10% partially hydrogenated soybean oil, nor did fasting and fasting-refeeding affect the activity. Pancreatic lipase activity in chicks appears to depend on factors other than the amount or type of fat consumed.


Tamoxifen favoured the rat sensorial cortex regeneration after a penetrating brain injury.
A penetrating brain injury produces a glial scar formed by astrocytes, oligodendrocytes, microglia and NG2 cells. Glial scar is a barrier preventing the extent of damage but it has deleterious effects in the regeneration of the axons. Estradiol and tamoxifen reduce gliosis and have neuroprotective effects in the hippocampus and the spinal cord. We evaluated the proliferation of glia and the electrocorticogram in the sensorial cortex in a brain injury model. At seven days post-injury, estradiol, tamoxifen and estradiol plus tamoxifen reduced the number of resident and proliferative NG2 and reactive astrocyte vimentin+ cells. Estradiol and tamoxifen effects on NG2 cells could be produced by the classical oestrogen receptors found in these cells. The glial scar was also reduced by tamoxifen. At thirty days post-injury, the amount of resident and proliferative astrocytes increased significantly, except in the estradiol plus tamoxifen group, whilst the oligodendrocytes proliferation in the glial scar was reduced in treated animals. Tamoxifen promotes the survival of FOX-3+ neurons in the injured area and a recovery in the amplitude of electrocorticogram waves. At thirty days, estradiol did not favour the survival of neurons but produced a greater number of reactive astrocytes. In contrast, the number of oligodendrocytes was reduced. Tamoxifen could favour brain repair promoting neuron survival and adjusting glial cell number. It seems to recover adequate neural communication.


Identification and characterization of a cluster of transcription start sites located in the E6 ORF of human papillomavirus type 16.
Human papillomavirus type 16 (HPV-16) is the prototype strain among the malignant types of HPV in the western world. The main promoter, P97, located in front of the E6 ORF, has been shown to control expression of the oncogenes E6 and E7. These oncogenes are expressed continuously in HPV-16-transformed cells. In contrast to malignant HPV types, non-malignant HPV types have separate promoters driving the expression of E6 and E7. Experiments have shown that the translation of E7 is more efficient from monocistronic than bicistronic transcripts encoding both E6 and E7. Here, identification of a cluster of transcription start sites located in the E6 ORF of HPV-16 is presented. Transcripts from this region contain the E7 ORF as the first reading frame. The cluster consists of multiple transcription start sites located around nt 441. Additional transcription start sites were identified in a cluster around nt 480. A transcription start site has been identified previously at nt 480 but has never been characterized further. The region responsible for transcription activity was mapped to nt 272-448. Mutational analysis showed that initiation of transcription is independent of a TATA-box element, which is consistent with the finding of multiple transcription start sites. Furthermore, it is shown that proteins from HeLa and SiHa nuclear cell extracts bind to the two regions at nt 291-314 and 388-411, and that these two regions influence transcription activity in a cell type-dependent manner.


Structural characterization of the N-terminal mineral modification domains from the molluscan crystal-modulating biomineralization proteins, AP7 and AP24.
The AP7 and AP24 proteins represent a class of mineral-interaction polypeptides that are found in the aragonite-containing nacre layer of mollusk shell (H. rufescens). These proteins have been shown to preferentially interfere with calcium carbonate mineral growth in vitro. It is believed that both proteins play an important role in aragonite polymorph selection in the mollusk shell. Previously, we demonstrated the 1-30 amino acid (AA) N-terminal sequences of AP7 and AP24 represent mineral interaction/modification domains in both proteins, as evidenced by their ability to frustrate calcium carbonate crystal growth at step edge regions. In this present report, using free N-terminal, C(alpha)-amide "capped" synthetic polypeptides representing the 1-30 AA regions of AP7 (AP7-1 polypeptide) and AP24 (AP24-1 polypeptide) and NMR spectroscopy, we confirm that both N-terminal sequences possess putative Ca (II) interaction polyanionic sequence regions (2 x -DD- in AP7-1, -DDDED- in AP24-1) that are random coil-like in structure. However, with regard to the remaining sequences regions, each polypeptide features unique structural differences. AP7-1 possesses an extended beta-strand or polyproline type II-like structure within the A11-M10, S12-V13, and S28-I27 sequence regions, with the remaining sequence regions adopting a random-coil-like structure, a trait common to other polyelectrolyte mineral-associated polypeptide sequences. Conversely, AP24-1 possesses random coil-like structure within A1-S9 and Q14-N16 sequence regions, and evidence for turn-like, bend, or loop conformation within the G10-N13, Q17-N24, and M29-F30 sequence regions, similar to the structures identified within the putative elastomeric proteins Lustrin A and sea urchin spicule matrix proteins. The similarities and differences in AP7 and AP24 N-terminal domain structure are discussed with regard to joint AP7-AP24 protein modification of calcium carbonate growth.


Blood gas transport at high altitude.
As a model of human hypoxia, exposure to high altitude causes a number of ventilatory, circulatory and hemopoietic adaptations. A review of the literature on blood gas transport responses to hypoxia indicates that they are influenced not only by altitude, but also by factors related to acclimatization. In addition, it appears that the need to oxygenate tissues conflicts with the need to maintain H+ homeostasis. Thus, the final situation represents a compromise between the respiratory adjustment aimed at increasing blood alkalosis in order to optimize the oxygen transport system, and the metabolic readjustment aimed at reestablishing normal blood pH. There are factors like red cell 2,3-diphosphoglycerate, a compound that decreases the hemoglobin affinity for oxygen, that can influence that balance by affecting arterial oxygen saturation through mechanisms independent of respiration.


MEKK3 regulates IFN-gamma production in T cells through the Rac1/2-dependent MAPK cascades.
MEKK3 is a conserved Ser/Thr protein kinase belonging to the MAPK kinase kinase (MAP3K) family. MEKK3 is constitutively expressed in T cells, but its function in T cell immunity has not been fully elucidated. Using Mekk3 T cell conditional knockout (T-cKO) mice, we show that MEKK3 is required for T cell immunity in vivo. Mekk3 T-cKO mice had reduced T cell response to bacterial infection and were defective in clearing bacterial infections. The Ag-induced cytokine production, especially IFN-γ production, was impaired in Mekk3-deficient CD4 T cells. The TCR-induced ERK1/2, JNK, and p38 MAPKs activation was also defective in Mekk3-deficient CD4 T cells. In vitro, MEKK3 is not required for Th1 and Th2 cell differentiation. Notably, under a nonpolarizing condition (Th0), Mekk3 deficiency led to a significant reduction of IFN-γ production in CD4 T cells. Furthermore, the IL-12/IL-18-driven IFN-γ production and MAPK activation in Mekk3-deficient T cells was not affected suggesting that MEKK3 may selectively mediate the TCR-induced MAPK signals for IFN-γ production. Finally, we found that MEKK3 activation by TCR stimulation requires Rac1/2. Taken together, our study reveals a specific role of MEKK3 in mediating the TCR signals for IFN-γ production.


Does the Use of Cone-Beam Computed Tomography Before Mandibular Third Molar Surgery Impact Treatment Planning?
We aimed to investigate whether cone-beam computed tomography (CBCT) alters the treatment decision for impacted mandibular third molar (M3M) surgery when the third molars show proximity to the inferior alveolar canal (IAC) on panoramic radiography (OPG) and to examine surgeons' confidence in the various treatment options. We performed a retrospective study evaluating a series of randomized OPG and CBCT images and answering a set of questions regarding impacted M3Ms. The anatomic risk factors studied included the proximity of M3M roots to the IAC, vertical relationship between the M3M and the IAC, and interruption of the IAC cortex by M3M roots. The primary outcome variable was the treatment decision of whether to observe, extract under local anesthesia, extract under general anesthesia, or perform coronectomy. The secondary outcome variable was confidence in the proposed treatment plan. The χ2 test was used to compare proportions and to test the differences in the treatment plan according to the studied independent variables. Binary logistic regression was used to determine the effect of anatomic factors. P < .05 was considered statistically significant. The study sample consisted of 132 impacted M3Ms in 71 patients. No significant differences in the proposed treatment plan were found when the imaging modalities (OPG and CBCT) were compared (P > .05). Examination of CBCT enabled detection of anatomic risk factors (P < .001). Binary logistic regression showed the absence of IAC cortex interruption to be the most significant determinant toward planning for extraction on OPG (odds ratio, 3.1; P < .005) and on CBCT (odds ratio, 5.0; P < .001). Surgeons were more confident when planning for extraction (P < .001). The use of CBCT provides a better understanding of the anatomic relationship between M3M roots and the IAC. However, experienced surgeons dealing with impacted M3Ms with evidence of proximity to the IAC on OPG can decide on the treatment modality without CBCT.


[Choice of esophageal plastic surgery].
The choice of an access to different parts of the esophagus, the need and scope of its resection, the choice of a surgical stage and an organ for creating the artificial esophagus, the position of a graft and the method for forming an esophageal anastomosis are the matters under discussion. A total of 1000 esophageoplasties were performed using different methods. In cancer of the esophagus and its benign diseases, the optimum intervention is esophageal extirpation with one-stage plasty using an isoperistaltic gastric tube; if there are contraindications to this operation, subtotal and total esophageoplasties with the colon are the operations of choice.


Autism spectrum disorders--a genetics review.
Autism is an etiologically and clinically heterogeneous group of disorders, diagnosed solely by the complex behavioral phenotype. On the basis of the high-heritability index, geneticists are confident that autism will be the first behavioral disorder for which the genetic basis can be well established. Although it was initially assumed that major genome-wide and candidate gene association studies would lead most directly to common autism genes, progress has been slow. Rather, most discoveries have come from studies of known genetic disorders associated with the behavioral phenotype. New technology, especially array chromosomal genomic hybridization, has both increased the identification of putative autism genes and raised to approximately 25%, the percentage of children for whom an autism-related genetic change can be identified. Incorporating clinical geneticists into the diagnostic and autism research arenas is vital to the field. Interpreting this new technology and deciphering autism's genetic montage require the skill set of the clinical geneticist including knowing how to acquire and interpret family pedigrees, how to analyze complex morphologic, neurologic, and medical phenotypes, sorting out heterogeneity, developing rational genetic models, and designing studies. The current emphasis on deciphering autism spectrum disorders has accelerated the field of neuroscience and demonstrated the necessity of multidisciplinary research that must include clinical geneticists both in the clinics and in the design and implementation of basic, clinical, and translational research.


An online calculator for marine phytoplankton iron culturing experiments.
Laboratory experiments with iron offer important insight into the physiology of marine phytoplankton and the biogeochemical cycles they influence. These experiments often rely on chelators to buffer the concentration of available iron, but the buffer can fail when cell density increases, causing the concentration of that iron to drop rapidly. To more easily determine the point when the iron concentration falls, we developed an online calculator to estimate the maximum phytoplankton density that a growth medium can support. The results of the calculator were compared to the numerical simulations of a Fe-limited culture of the diatom Thalassiosira weissflogii (Grunow) Fryxell and Hasle. Modeling reveals that the assumptions behind thermodynamic estimates of unchelated Fe concentration can fail before easily perceptible changes in growth rate, potentially causing physiological changes that could alter the conclusions of culture experiments. The calculator is available at http://www.marsci.uga.edu/fidoplankter.


H CHAIN SUBGROUPS OF MYELOMA PROTEINS AND NORMAL 7S GAMMA-GLOBULIN.
Through the use of a variety of antisera to isolated myeloma proteins, four subgroups of 7S gamma-globulin type proteins were readily distinguished. The first, the Vi subgroup, consisted of ten of 64 myeloma proteins studied. The second, the We group, contained the majority of myeloma proteins. The third, the Ge subgroup, included three of 50 myeloma proteins. The fourth remains ill-defined and appears heterogeneous. Counterparts for both the Vi and the Ge subgroup, were found in the Fr II gamma-globulin and in the normal gamma-globulin of all of a large number of individual sera studied. The unique antigenic character of both groups was localized to the H chains, although different determinants were involved for different antisera. An essential role of intact disulfide bonds was apparent with certain rabbit antisera. In addition to the special antigenic characteristics, the Ge subgroup showed in each instance a fast mobility for the F fragments produced by papain which was not found for other myeloma proteins.


Segmentation of the Clustered Cells with Optimized Boundary Detection in Negative Phase Contrast Images.
Cell image segmentation plays a central role in numerous biology studies and clinical applications. As a result, the development of cell image segmentation algorithms with high robustness and accuracy is attracting more and more attention. In this study, an automated cell image segmentation algorithm is developed to get improved cell image segmentation with respect to cell boundary detection and segmentation of the clustered cells for all cells in the field of view in negative phase contrast images. A new method which combines the thresholding method and edge based active contour method was proposed to optimize cell boundary detection. In order to segment clustered cells, the geographic peaks of cell light intensity were utilized to detect numbers and locations of the clustered cells. In this paper, the working principles of the algorithms are described. The influence of parameters in cell boundary detection and the selection of the threshold value on the final segmentation results are investigated. At last, the proposed algorithm is applied to the negative phase contrast images from different experiments. The performance of the proposed method is evaluated. Results show that the proposed method can achieve optimized cell boundary detection and highly accurate segmentation for clustered cells.


Validation of a realistic simulator for veterinary gastrointestinal endoscopy training.
This article reports on the face, content, and construct validity of a new realistic composite simulator (Simuldog) used to provide training in canine gastrointestinal flexible endoscopy. The basic endoscopic procedures performed on the simulator were esophagogastroduodenoscopy (EGD), gastric biopsy (GB), and gastric foreign body removal (FBR). Construct validity was assessed by comparing the performance of novices (final-year veterinary students and recent graduates without endoscopic experience, n=30) versus experienced subjects (doctors in veterinary medicine who had performed more than 50 clinical upper gastrointestinal endoscopic procedures as a surgeon, n=15). Tasks were scored based on completion time, and specific rating scales were developed to assess performance. Internal consistency and inter-rater agreement were assessed. Face and content validity were determined using a 5-point Likert-type scale questionnaire. The novices needed considerably more time than the experts to perform EGD, GB, and FBR, and their performance scores were significantly lower (p<.010). Inter-rater agreement and the internal validity of the rating scales were good. Face validity was excellent, and both groups agreed that the endoscopy scenarios were very realistic. The experts highly valued the usefulness of Simuldog for veterinary training and as a tool for assessing endoscopic skills. Simuldog is the first validated model specifically developed to be used as a training tool for endoscopy techniques in small animals.


Unintended costs and consequences of school closures implemented in preparation for Hurricane Isaac in Harrison County School District, Mississippi, August-September 2012.
School closures, while an effective measure against the spread of disease during a pandemic, may carry unintended social and economic consequences for students and families. We evaluated these costs and consequences following a 4-day school closure in Mississippi's Harrison County School District (HCSD). In a survey of all households with students enrolled in HCSD, we collected information on difficulties related to the school closure, including interruption of employment and pay, loss of access to subsidized school meals, and arrangement of alternative childcare. We analyzed this information in the context of certain demographic characteristics of the survey respondents and households, such as race, level of education, and income. We also estimated the average number of lost work days and documented the childcare alternatives chosen by households affected by the school closure. We received 2,229 (28.4%) completed surveys from an estimated 7,851 households eligible to participate. About half (1,082 [48.5%]) of the households experienced at least some difficulty during the closure, primarily in three areas: uncertainty about duration of the closure, lost income, and the effort of arranging alternate childcare. Adults working outside the home, particularly the major wage earner in the household, were more likely to suffer lost income while schools were closed, an effect mitigated by paid leave benefits. Difficulty arranging childcare was reported most frequently by respondents with lower levels of education and households with younger children. Beyond the top three concerns expressed by households in HCSD, the survey also shed light on the issue of food insecurity when subsidized school meals are not available. Reported by 17.9% of households participating in the subsidized school lunch program, difficulty providing meals during the closure was associated with higher numbers of dependent children, selection of "other" as the race of the household respondent, and lower levels of education. To help prevent undue financial hardship in families of school children, public health authorities and school administrators should provide recommendations for childcare alternatives and paid leave or remote work options during prolonged school closures, particularly to households in which all adults work outside of the home.


[Reorganization of the chloroplast thylakoid system during decay of acquired thermotolerance of photosynthesis and aging of wheat leaves].
A 3 hours heating at 39 degrees C of 14-day old wheat plants increases the termotolerance of photosynthesis, and also the length and number of thylakoids in chloroplast in mature leaves. The acquired termotolerance disappears within 10 days. Simultaneously the intensity of photosynthesis and the length of thylakoids decrease. Reduction of photosynthesis ability and of thylakoid membranes occurs in the first leaves of non-hardened plants during 14-29 days after sowing. The intensity of photosynthesis in plants of both variants positively correlates with the length of grana membranes and with the total length of membranes of all thylakoids. Besides, a positive correlation was detected between the intensity of photosynthesis and the share of small (2-7 thylakoids) grana and the length of their membranes in non-hardened plants. The level of thermotolerance of photosynthesis in leaves in heat hardened plants correlates positively with the length of grana membranes and with the total length of all thylakoid membranes and the share of small grana.


Ultraviolet B radiation sensitizes a murine epidermal dendritic cell line (XS52) to undergo apoptosis upon antigen presentation to T cells.
Ultraviolet B irradiation of skin leads to immunologic tolerance, rather than immunity against newly introduced Ag, by altering the function of Langerhans cells, skin-specific members of the dendritic cell (DC) family. Using the murine epidermal-derived DC line, XS52, which retains important features of resident Langerhans cells, we have tested the hypothesis that UV radiation delivers a signal leading to apoptosis. XS52 cells, when exposed to modest fluences (25-100 J/m2) of radiation, underwent apoptosis during a subsequent 6-h incubation with LPS or upon 6-h coculture with the keyhole limpet hemocyanin-specific Th1 clone HDK-1 in the presence of Ag. Specifically, XS52 cells treated in this way exhibited diminished cell viability, DNA laddering, and condensed staining of DNA. By contrast, none of these changes was induced by radiation alone, LPS alone, or coculture with T cells and Ag. Likewise, neither UV radiation plus T cells nor radiation plus Ag were sufficient to induce apoptosis, indicating that both T cells and Ag are required to induce apoptosis in the UV-sensitized cells. XS52 cells remained fully susceptible to T cell-mediated apoptosis even 16 h after irradiation, indicating the persistence of the sensitized state. These observations establish a model in which UV radiation induces a first event in which DC become sensitive to a second, apoptotic signal that is delivered by Ag-specific interaction with T cells or by LPS. We suggest that DC undergoing apoptosis deliver unusual activation signals to T cells during Ag presentation, signals that lead to cellular unresponsiveness rather than to effective immunity.


[Chronic, unexplained pain: from complaint to action].
Every physician encounters patients with physical symptoms that remain unexplained, despite appropriate investigations. Medical curricula and textbooks fail to provide guidance about the management of such problems. Particularly specialists tend to feel helpless; this often leads to more referrals and unnecessary operations. Three patients, referred to a neurologist for a second opinion, had chronic, unexplained, crippling pains: a woman aged 53 with low back pain radiating to the right leg for 27 years, a man aged 31 with neck pain for 3 years and a woman aged 31 with pain in the left arm for 1.5 years. They had no recognisable features of depression. Their illness behaviour reversed after the neurologist reassured the patients and advised them to embark upon a strict programme of gradually increasing activities. In two of the patients, the scheme was supervised by the general practitioner. A follow-up interview (after a median interval of 3 years) of 27 similar patients referred for a second opinion showed some success with this approach in about half of them. In retrospect no predictive factors at baseline could be identified other than age and duration of symptoms. An indispensable first step in patients with unexplained, chronic pain is unqualified recognition of the symptoms, reassurance, and an explanation that avoids the mind-body division.


Structural Effects of Network Sampling Coverage I: Nodes Missing at Random1.
Network measures assume a census of a well-bounded population. This level of coverage is rarely achieved in practice, however, and we have only limited information on the robustness of network measures to incomplete coverage. This paper examines the effect of node-level missingness on 4 classes of network measures: centrality, centralization, topology and homophily across a diverse sample of 12 empirical networks. We use a Monte Carlo simulation process to generate data with known levels of missingness and compare the resulting network scores to their known starting values. As with past studies (Borgatti et al 2006; Kossinets 2006), we find that measurement bias generally increases with more missing data. The exact rate and nature of this increase, however, varies systematically across network measures. For example, betweenness and Bonacich centralization are quite sensitive to missing data while closeness and in-degree are robust. Similarly, while the tau statistic and distance are difficult to capture with missing data, transitivity shows little bias even with very high levels of missingness. The results are also clearly dependent on the features of the network. Larger, more centralized networks are generally more robust to missing data, but this is especially true for centrality and centralization measures. More cohesive networks are robust to missing data when measuring topological features but not when measuring centralization. Overall, the results suggest that missing data may have quite large or quite small effects on network measurement, depending on the type of network and the question being posed.


Endovascular Therapy for Ruptured Vertebral Artery Dissecting Aneurysms: Results from Nationwide, Retrospective, Multi-Center Registries in Japan (JR-NET3).
Ruptured vertebral artery dissecting aneurysm (VADA) causes subarachnoid hemorrhage (SAH), and parent artery occlusion (PAO) with endovascular technique (EVT) has been the first-line treatment for ruptured VADA. In this study, we have extracted 530 ruptured VADA, treated through PAO with EVT, from a nationwide, retrospective, multi-center registration in Japan (JR-NET3), and analyzed factors associated with outcome at 30 days and procedure-related complications. Complete occlusion was achieved in 497 cases (93.8%) and favorable outcome was obtained in 303 cases (59.1%). Older age (≥60 years), male sex, use of general anesthesia, non-specialist as the responsible doctor, and time delay from onset to treatment (≥24 h) were negative factors for favorable outcome in multivariate analysis, although these factors were not associated with procedure-related complications. Compared with previous studies (JR-NET1 and 2), the number of endovascular treatments for patients with VADA and severe SAH increased in this decade; however, the percentage of patients with favorable outcome did not decrease. This might be due to not only the improvement of endovascular treatment itself, but also increased access to endovascular specialists or standardization of management.


What Does it Take to Make Model-Informed Precision Dosing Common Practice? Report from the 1st Asian Symposium on Precision Dosing.
Model-informed precision dosing (MIPD) is modeling and simulation in healthcare to predict the drug dose for a given patient based on their individual characteristics that is most likely to improve efficacy and/or lower toxicity in comparison to traditional dosing. This paper describes the background and status of MIPD and the activities at the 1st Asian Symposium of Precision Dosing. The theme of the meeting was the question, "What does it take to make MIPD common practice?" Formal presentations highlighted the distinction between genetic and non-genetic sources of variability in drug exposure and response, the use of modeling and simulation as decision support tools, and the facilitators to MIPD implementation. A panel discussion addressed the types of models used for MIPD, how the pharmaceutical industry views MIPD, ways to upscale MIPD beyond academic hospital centers, and the essential role of healthcare professional education as a way to progress. The meeting concluded with an ongoing commitment to use MIPD to improve patient care.


Optimized granulocyte colony-stimulating factor prophylaxis in adult cancer patients: from biological principles to clinical guidelines.
Chemotherapy-induced neutropenia, the depth and length of which are correlated to the risk of febrile neutropenia (FN) and neutropenia sepsis, remains a serious problem in medical oncology. Granulocyte colony-stimulating factors (G-CSF) stimulate the proliferation and survival of neutrophils and their precursors, thereby reducing the incidence, duration and severity of neutropenic events across a broad range of malignancies and regimens, often enabling the delivery of full chemotherapy dose intensity. In this review, areas covered include the physiologic role of G-CSF in granulopoiesis, as well as a related biological model of bone marrow kinetics after chemotherapy. Information relating to the application of clinical guidelines for optimization of prophylaxis of FN in adult cancer patients was critically summarized. The literature and pharmacological data were obtained through an electronic search. There are relevant physiological and clinical evidences for the use of G-CSF to prevent FN and to ameliorate the myelotoxicities of cancer chemotherapy. In particular, biological models are in favor of the prophylactic rather than therapeutic use of G-CSF therapy. Use of a single dose of pegfilgrastim per cycle in appropriate patients provides a more convenient and potentially more effective strategy for assisting neutrophil recovery. While biosimilars may cost less, future developments in their regulation will need to address multiple issues. In the interim, physicians should remember that small differences in biochemical and biophysical characteristics might translate into differences in potency and immunogenic potential.


Paucisalibacillus globulus gen. nov., sp. nov., a Gram-positive bacterium isolated from potting soil.
A Gram-positive bacterium, designated B22(T), was isolated from potting soil produced in Portugal. This organism is a catalase-positive, oxidase-negative, motile, spore-forming, aerobic rod that grows optimally at 37 degrees C and pH 8.0-8.5. Optimal growth occurs in media containing 1 % (w/v) NaCl, although the organism can grow in 0-8 % NaCl. The cell wall peptidoglycan is of the A4alpha type with a cross-linkage containing d-Asp. The major respiratory quinone is menaquinone 7 and the major fatty acids are anteiso-15 : 0, anteiso-17 : 0 and iso-15 : 0. The DNA G+C content is 37.9 mol%. Phylogenetic analysis of 16S rRNA gene sequences revealed that strain B22(T) formed a new branch within the family Bacillaceae. The novel isolate is phylogenetically closely related to members of genera of moderately halophilic bacilli and formed a coherent cluster with species of the genera Salinibacillus, Virgibacillus, Oceanobacillus and Lentibacillus, supported by bootstrap analysis at a confidence level of 71 %. Strain B22(T) exhibited 16S rRNA gene pairwise sequence similarity values of 94.7-94.3 % with members of the genus Salinibacillus, 95.1-92.8 % with members of the genus Virgibacillus, 94.7-93.2 % with members of the genus Oceanobacillus and 93.1-92.3 % with members of the genus Lentibacillus. On the basis of phylogenetic analysis and physiological and biochemical characteristics, it is proposed that strain B22(T) represents a novel species in a new genus, Paucisalibacillus globulus gen. nov., sp. nov. Strain B22(T) (=LMG 23148(T)=CIP 108857(T)) is the type strain of Paucisalibacillus globulus.


[Changes in indices of inflammatory activity in patients with rheumatoid arthritis during early stages of basic therapy with leflunomide].
To assess leflunomide efficacy and tolerance in patients with rheumatoid arthritis (RA) during the first four months of the treatment. The study included 200 RA patients treated in four Moscow clinical centers. Leflunomide was given in a dose of 100 mg/day for 3 days, then 20 mg/day for 16 weeks. The activity of the disease according to the criterion DAS 28 was assessed before the treatment and 4, 8, 12 and 16 weeks after the treatment start. RA activity diminished considerably after one month of leflunomide treatment. Later, the articular syndrome continued to improve. A significant improvement by DAS 28 was observed after 16 weeks of the treatment in 65% (129 of 200) patients, high RA activity persisted only in 17 of 90 patients. Leflunomide reduces articular inflammation and raises RA patients' quality of life at early stages of the treatment. This reduction continued for 4 months of the study. Therefore, adequate assessment of leflunomide efficacy should be made only after 4-6 months of therapy.