Radiographic determination of proventricular diameter in psittacine birds.
To establish an objective method of determining proventricular diameter in psittacine birds by assessment of lateral whole-body radiographic views. Retrospective case-control study. 100 parrots with no signs of gastric disease and 19 parrots with signs of gastric disease. Measurements were obtained for the following variables: proventricular diameter at the level of the junction between the last thoracic vertebra and synsacrum, maximum distance between the dorsal serosa of the proximal aspect of the proventriculus and dorsal border of the sternum, maximum coelomic cavity height at the level of the proximal aspect of the proventriculus, and maximum dorsoventral height of the keel of the sternum. The ratio of proventricular diameter to each of those measurements was calculated and compared among species within the group without signs of gastric disease and between the gastric and nongastric disease groups. No significant differences were seen among species of parrots without signs of gastric disease for any ratio, but there were significant differences between parrots with gastric signs and those without gastric signs for all ratios. Only the proventricular diameterto-maximum dorsoventral height of the keel of the sternum ratio had no numeric overlap between groups. Sensitivity and specificity of the ratio for detection of proventricular enlargement were both 100%. Six causes associated with proventricular enlargement were identified. Evaluation of the proventricular diameter-to-keel height ratio is a new method for evaluating proventricular size in psittacines. Ratio values < 0.48 indicate normal proventricular diameter and the absence of proventricular disease.


Talking with terminally ill patients and their caregivers about death, dying, and bereavement: is it stressful? Is it helpful?
Discussing end-of-life issues with terminally ill patients is often considered distressing and harmful. This study was conducted to assess whether interviewing terminally ill patients and their caregivers about death, dying, and bereavement is stressful and/or helpful. Patients from 6 sites in the United States who were estimated to have 6 months or less to live were interviewed in person and reinterviewed 2 to 6 months later. Their caregivers were interviewed separately. At the end of the interviews, patients and caregivers were asked how stressful and how helpful the interview had been. Of 1131 eligible patients, 988 (87.4%) were interviewed, and of 915 eligible caregivers, 893 (97.6%) were interviewed. At the end of the first interview, 1.9% of the patients reported having experienced a great deal of stress, 7.1% some stress, and 88.7% little or no stress from the interview. Among the caregivers, 1.5% reported a great deal of stress, 8.4% some stress, and 89.7% little or no stress. Slightly more stress was reported to have been caused by the reinterview. Overall, 16.9% of the patients reported the initial interview as very helpful, 29.6% as somewhat helpful, and 49.6% as offering little or no help. Among the caregivers, 19.1% reported the initial interview as very helpful, 34.3% as somewhat helpful, and 44.9% as offering little or no help. The reported helpfulness of the second interview was slightly less. Patients experiencing pain (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.02-1.56), more personal meaning in dying (OR, 3.05; 95% CI, 2.02-4.59), and less ease with talking about the end of life (OR, 1.32; 95% CI, 1.09-1.60) were significantly more likely to report stress. Patients who were from an ethnic minority (OR, 1.85; 95% CI, 1.31-2.63), anxious about the end of their life (OR, 1.39; 95% CI 1.16-1.67), more spiritual (OR, 1.30; 95% CI, 1.06-1.61), and serene (OR, 1.25; 95% CI, 1.08-1.45) were significantly more likely to report the interview helpful. There was no relationship between stress and helpfulness. Terminally ill patients and their caregivers can discuss death, dying, and bereavement in a structured interview with minimal stress and report that the interview was helpful. Institutional review boards should not preemptively restrict surveys with terminally ill patients without reliable evidence that they will be stressful or otherwise harmful.


Prognostic implication of retrocrural lymph node involvement revealed by (18)F-FDG PET/CT in patients with uterine cervical cancer.
Lymph node involvement in cervical cancer is an indication of poor prognosis and the risk tends to increase according to the level of lymph node involvement. However, the specific prognostic significance of retrocrural lymph node involvement has not been well characterized because of its small size and deep location. The aim of this study was to assess its prognostic value. A total of 217 patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IA2-IVA cervical cancer were retrospectively enrolled. All the patients had undergone pretreatment (18)F-fluorodeoxy-D-glucose ((18)F-FDG) PET/CT. Of these patients 145 were treated with concurrent chemoradiotherapy, and in this group we assessed the relationship of retrocrural lymph node involvement with the risk of disease progression. Retrocrural lymph node involvement was seen in 7.4% of patients (16/217). All of them had para-aortic lymph node involvement and 56% of the 16 patients (9/16) had concomitant supraclavicular lymph node involvement. In the patients treated with concurrent chemoradiotherapy it was found that the higher the level of (18)F-FDG-positive lymph nodes detected in them, the worse the progression-free survival experienced by them (none vs. pelvic, pelvic vs. para-aortic, para-aortic vs. retrocrural; P<0.05); however, there was no difference in progression outcome between retrocrural and supraclavicular areas (P=NS). On multivariate Cox proportional hazard analysis, the highest level of (18)F-FDG PET/CT-positive lymph nodes in the para-aortic [hazard ratio (HR) 6.05, 95% confidence interval (CI) 2.18-16.81], retrocrural (HR 17.05, 95% CI 5.34-54.44), and supraclavicular areas (HR 19.56, 95% CI 7.15-53.54) was a significant prognostic factor. The highest level of lymph node involvement in para-aortic, retrocrural, supraclavicular areas was a significant prognostic factor for progression in uterine cervical cancer patients who were treated with concurrent chemoradiotherapy. Retrocrural lymph node involvement shows a similar outcome with supraclavicular involvement, but leads to a worse outcome in terms of progression compared with para-aortic lymph node involvement.


A population-based study of the effectiveness of inferior vena cava filter use among patients with venous thromboembolism.
There are few population-based data regarding the effectiveness of inferior vena cava filter use in the prevention of symptomatic pulmonary embolism. To determine the 1-year cumulative incidence of rehospitalization for venous thrombosis or pulmonary embolism among patients with thromboembolism treated with a vena cava filter compared with the incidence in a control population with thromboembolism. Population-based retrospective analysis of linked hospital discharge abstracts in California. From January 1, 1991, through December 30, 1995, 3632 patients were treated with a filter and 64,333 controls were admitted with a principal diagnosis of venous thromboembolism. Filter-treated patients had significantly greater comorbidity, with a higher frequency of previous pulmonary embolism, recent major bleeding, malignant neoplasm, and stroke. Patients who initially manifested pulmonary embolism were significantly more likely to be rehospitalized for pulmonary embolism than patients with an initial diagnosis of venous thrombosis alone, among filter-treated patients (relative risk, 6.72; 95% confidence interval, 3.61-12.49) and controls (relative risk, 5.30; 95% confidence interval, 4.61-6.10). Risk-adjusted proportional hazards modeling showed no significant difference between filter-treated patients and controls in the relative hazard of rehospitalization for pulmonary embolism. However, filter placement was associated with a significantly higher relative hazard of rehospitalization for venous thrombosis among patients who initially manifested pulmonary embolism (relative hazard, 2.62; 95% confidence interval, 2.09-3.29), but not among those who presented with venous thrombosis (relative hazard, 1.14; 95% confidence interval, 0.92-1.43). Insertion of a vena cava filter was not associated with a significant reduction in the 1-year incidence of rehospitalization for pulmonary embolism. Use of a filter was associated with a higher incidence of rehospitalization for venous thrombosis, but only among patients who initially manifested pulmonary embolism. A prospective clinical study is needed to determine the efficacy of filter use among patients with pulmonary embolism who do not meet strict guidelines for insertion of a vena cava filter.


[The influence of stroke laterality on coping with stroke outcome].
Objective of this study was to asses the influence of coping activities on stroke disability- and handicap-outcomes. Of special interest was to investigate if and how the variable "side of lesion" influenced the relationship between coping activities and outcomes. 105 stroke patients (50 women, 55 men, mean age 71.1 years) were investigated. The coping activities of the stroke patients were investigated with the "Freiburg Questionnaire of Coping with Illness" (PQCI). The Disability Outcomes were investigated with the "Depression Status Inventory" (DSI) and the "Self Concept Scale for General Feelings of Self Worth". The Handicap-Outcomes were investigated with the "Perceived Quality of Life Scale" (PQoL) and the "Oxford Handicap Scale" (OHS). Unaffected by the side of lesion, depressive coping showed negative influences on the investigated outcomes. The strategy "trivialization and wishful thinking" intensified significantly the prevailing mood of depression of patients who suffered a right hemisphere stroke. The same negative influence of this strategy was detected on the psycho-social condition of these patients. The influence of the strategies "active and problem-focused coping", "distractive and self-reconstructive coping" and "religious and meaning-searching coping" remained unaffected by the stroke side. These strategies showed no influence on the investigated outcomes. Depressive coping should be avoided.


The effect of prednisone on the non-stimulated and the stimulated NBT test.
The non-stimulated and stimulated nitroblue tetrazolium (NBT) dye test was studied in five normal adults in sequence, viz. before and at intervals after prednisone was given as one large dose. A negative effect of prednisone on the NBT response was seen. This applied to both the non-stimulated and stimulated NBT test. For the latter five different toxins were used. At the same time a pronounced neutrophil granulocytosis was seen. The depression of the NBT test is present both in the percentage of NBT-stained neutrophils and when expressed in absolute counts of NBT-strained neutrophils.


Evaluating retinal toxicity of intravitreal caspofungin in the mouse eye.
Caspofungin is a synthetic echinocandin antifungal agent that inhibits the synthesis of β(1,3)-D-glucan, an essential component of the cell wall of susceptible Aspergillus and Candida species. In this study, retinal toxicity was determined after intravitreal injection of caspofungin in a mouse model to assess its safety profile for the treatment of fungal endophthalmitis. Caspofungin acetate was injected intravitreally in the left eyes of male C57BL/6 mice, with final vitreal concentrations corresponding to 0.41, 1.2, 2.5, 4.1, and 41 μM (five mice per cohort). A total of 25 age-matched male C57BL/6 mice injected with balanced salt solution were used as control subjects (five for each of the five different caspofungin acetate concentrations). Electroretinograms (ERGs) were recorded 7 weeks after the injections, and the injected eyes were examined histologically. Mice injected with caspofungin at vitreal concentrations from 0.41 to 4.1 μM did not have significant alterations in their ERG waveforms, and their retinas had no detectable morphologic changes or loss of cells. At the vitreal concentration of 41 μM, caspofungin reduced the amplitudes of the a-waves, b-waves, and scotopic threshold responses of the ERG and also produced a decrease in the number of cells in the ganglion cell layer. Caspofungin is a safe antifungal agent at vitreal concentrations of 0.41 to 4.1 μM in mice and consequently shows promise for the treatment of fungal endophthalmitis in humans. Much higher doses produce toxicity and should not be used.


tat Exon 1 exhibits functional diversity during HIV-1 subtype C primary infection.
Human immunodeficiency virus type 1 (HIV-1) Tat is a mediator of viral transcription and is involved in the control of virus replication. However, associations between HIV-1 Tat diversity and functional effects during primary HIV-1 infection are still unclear. We estimated selection pressures in tat exon 1 using the mixed-effects model of evolution with 672 viral sequences generated from 20 patients infected with HIV-1 subtype C (HIV-1C) over 500 days postseroconversion. tat exon 1 residues 3, 4, 21, 24, 29, 39, and 68 were under positive selection, and we established that specific amino acid signature patterns were apparent in primary HIV-1C infection compared with chronic infection. We assessed the impact of these mutations on long terminal repeat (LTR) activity and found that Tat activity was negatively affected by the Ala(21) substitution identified in 13/20 (65%) of patients, which reduced LTR activity by 88% (± 1%) (P < 0.001). The greatest increase in Tat activity was seen with the Gln(35)/Lys(39) double mutant that resulted in an additional 49% (± 14%) production of LTR-driven luciferase (P = 0.012). There was a moderate positive correlation between Tat-mediated LTR activity and HIV-1 RNA in plasma (P = 0.026; r = 0.400) after 180 days postseroconversion that was reduced by 500 days postseroconversion (P = 0.043; r = 0.266). Although Tat activation of the LTR is not a strong predictor of these clinical variables, there are significant linear relationships between Tat transactivation and patients' plasma viral loads and CD4 counts, highlighting the complex interplay between Tat mutations in early HIV-1C infection.


[Utility and validity of indicators from the Nursing Outcomes Classification as a support tool for diagnosing Ineffective Self Health Management in patients with chronic conditions in primary health care].
Self-care and management of therapeutic regime (drugs adherence, preventive behaviours and development of healthy life-styles) are key components for managing chronic diseases. Nursing has standardized languages which describe many of these situations, such as the diagnosis "Ineffective Self Health Management" (ISHM) or many of the Nursing Outcomes Classification (NOC) indicators. The aims of this study were to determine the interobserver reliability of a NOC-based instrument for assessment and aid in diagnosis of the ISHM in patients with chronic conditions in Primary Health Care, to determine its diagnostic validity and to describe the prevalence of patients with this problem. Cross-sectional validation study developed in the provinces of Málaga, Cádiz and Almería from 2006 to 2009. Each patient was assessed by 3 independent observers: the first two observers evaluated scoring of the NOC indicators and the third one acted as the "gold-standard". Two hundred and twenty-eight patients were included, 37.7% of them with more than one chronic condition. NOC indicators showed a high interobserver reliability (ICC>0,70) and a consistency (Cronbach's alpha: 0.81). With a cut-point of 10.5, sensitivity was 61% and specificity 85%, and the area under the curve was 0.81 (CI95%: 0.77 to 0.85). The prevalence of patients with ISHM was 36% (CI 95%: 34 to 40). The use of NOC indicators allows evaluation of management of the therapeutic regime in people with chronic conditions with a satisfactory validity and it provides new approaches for dealing with this problem.


Evaluating the Recovery Curve for Clinically Assessed Reaction Time After Concussion.
A change in reaction time is one of various clinical measures of neurocognitive function that can be monitored after concussion and has been reported to be among the most sensitive indicators of cognitive impairment. To determine the timeline for clinically assessed simple reaction time to return to baseline after a concussion in high school athletes. Observational study. Athletic training room. Twenty-one high school-aged volunteers. Participants completed 8 trials of the ruler-drop test during each session. Along with baseline measures, a total of 6 additional test sessions were completed over the course of 4 weeks after a concussion (days 3, 7, 10, 14, 21, and 28). The mean reaction times calculated for all participants from each of the 7 test sessions were analyzed to assess the change in reaction time over the 7 time intervals. After a concussion and compared with baseline, simple reaction time was, on average, 26 milliseconds slower at 48 to 72 hours postinjury (P < .001), almost 18 milliseconds slower on day 7 (P < .001), and about 9 milliseconds slower on day 10 (P < .001). Simple reaction time did not return to baseline levels until day 14 postinjury. Clinically assessed simple reaction time appeared to return to baseline levels within a timeframe that mirrors other measures of cognitive performance (approximately 14 days).


Integration of proviral DNA in Kirsten murine sarcoma virus-infected mouse fibroblasts.
The structure and sites of integration of proviral DNA were studied in 19 clonally related Kirsten murine sarcoma virus-transformed non-producer NIH/3T3 cell lines. The majority of these cell lines contained a single provirus, inserted colinearly with respect to unintegrated linear viral DNA, and lacking detectable methylation at MspI/HpaII sites. Although all proviruses were located at distinct integration sites in the host cell genome, the possible existence of similarities between some adjacent host flanking sequences, suggested from restriction mapping data, could not be ruled out. In three phenotypically reverted cell lines no change in either proviral DNA or adjacent host flanking sequences was detectable. In addition, the revertant proviruses lacked detectable methylation at MspI/HpaII sites. These findings suggest that changes in cellular function(s) may be responsible for loss of transformed phenotype in these cells.


Intergenotypic replacement of lyssavirus matrix proteins demonstrates the role of lyssavirus M proteins in intracellular virus accumulation.
Lyssavirus assembly depends on the matrix protein (M). We compared lyssavirus M proteins from different genotypes for their ability to support assembly and egress of genotype 1 rabies virus (RABV). Transcomplementation of M-deficient RABV with M from European bat lyssavirus (EBLV) types 1 and 2 reduced the release of infectious virus. Stable introduction of the heterogenotypic M proteins into RABV led to chimeric viruses with reduced virus release and intracellular accumulation of virus genomes. Although the chimeras indicated genotype-specific evolution of M, rapid selection of a compensatory mutant suggested conserved mechanisms of lyssavirus assembly and the requirement for only few adaptive mutations to fit the heterogenotypic M to a RABV backbone. Whereas the compensatory mutant replicated to similar infectious titers as RABV M-expressing virus, ultrastructural analysis revealed that both nonadapted EBLV M chimeras and the compensatory mutant differed from RABV M expressing viruses in the lack of intracellular viruslike structures that are enveloped and accumulate in cisterna of the degranulated and dilated rough endoplasmic reticulum compartment. Moreover, all viruses were able to bud at the plasma membrane. Since the lack of the intracellular viruslike structures correlated with the type of M protein but not with the efficiency of virus release, we hypothesize that the M proteins of EBLV-1 and RABV differ in their target membranes for virus assembly. Although the biological function of intracellular assembly and accumulation of viruslike structures in the endoplasmic reticulum remain unclear, the observed differences could contribute to diverse host tropism or pathogenicity.


Malaria and Parasitic Neglected Tropical Diseases: Potential Syndemics with COVID-19?
The COVID-19 pandemic, caused by SARS-CoV-2, have surpassed 5 million cases globally. Current models suggest that low- and middle-income countries (LMICs) will have a similar incidence but substantially lower mortality rate than high-income countries. However, malaria and neglected tropical diseases (NTDs) are prevalent in LMICs, and coinfections are likely. Both malaria and parasitic NTDs can alter immunologic responses to other infectious agents. Malaria can induce a cytokine storm and pro-coagulant state similar to that seen in severe COVID-19. Consequently, coinfections with malaria parasites and SARS-CoV-2 could result in substantially worse outcomes than mono-infections with either pathogen, and could shift the age pattern of severe COVID-19 to younger age-groups. Enhancing surveillance platforms could provide signals that indicate whether malaria, NTDs, and COVID-19 are syndemics (synergistic epidemics). Based on the prevalence of malaria and NTDs in specific localities, efforts to characterize COVID-19 in LMICs could be expanded by adding testing for malaria and NTDs. Such additional testing would allow the determination of the rates of coinfection and comparison of severity of outcomes by infection status, greatly improving the understanding of the epidemiology of COVID-19 in LMICs and potentially helping to mitigate its impact.


Vitamin D insufficiency and its contributing factors in primary school-aged children in Indonesia, a sun-rich country.
The prevalence of rickets is increasing worldwide in association with an increase in vitamin D deficiency. This study aimed to investigate the vitamin D profile of healthy school-aged children in a sun-rich country and its contributing factors. This cross-sectional study was conducted in 120 healthy children from 7-12 years of age who live in Jakarta, Indonesia. Their demographic status, sun exposure duration time, and lifestyle were recorded using a structured questionnaire. Serum calcium, phosphate, bone-alkaline phosphatase (B-ALP), and 25-hydroxy vitamin D (25(OH)2D3) levels were measured. The participants were categorized into vitamin D sufficient and non-vitamin D sufficient groups, and we analyzed variables that contributed to the 25(OH)2D3 level. Of the participants, 73 (60.8%) were vitamin D sufficient, 45 (37.5%) were vitamin D insufficient, and 2 (1.7%) were vitamin D deficient. Sex, age, body mass index, Fitzpatrick skin type, daily milk intake, and clothing type were not different between the vitamin D sufficient and non-vitamin D sufficient groups. There were no differences in serum calcium, phosphate, and B-ALP between the 2 groups. Sun exposure time was significantly longer in the vitamin D sufficient group compared with that in the non-vitamin D sufficient group (511.4 min/wk vs. 318.7 min/wk, P=0.004), and this effect remained consistent on multivariate analysis after adjustment for covariates (adjusted odds ratio, 1.002; 95% confidence interval, 1.000-1.003). More participants in the vitamin D sufficient group did not use sunscreen (59 vs. 27, P=0.02), but this finding was inconsistent with our multivariate analysis. Despite year-round sun exposure, approximately 1 in 3 primary school-aged children had insufficient vitamin D level. Sun exposure duration was a major contributing factor.


Analysis of autolysins in temperature-sensitive morphological mutants of Bacillus subtilis.
The content and distribution of autolysin were measured in temperature-sensitive morphological mutants of Bacillus subtilis. Strains RUB1000 and RUB1012 grew as rods at 30 C. At 45 C the mutants contained disproportionately less teichoic acid than peptidoglycan and grew as irregular spheres. The amount of enzyme that could be extracted from rods was at least 31 times the amount extracted from spheres. The rate of autolysis of cell walls was 7- to 28-fold greater in rods than in spheres. The low activity found associated with the cell walls of spheres was not compensated for by larger amounts of autolytic activity in the cytoplasm. No activity was found in the growth medium at either temperature. The failure of the mutant cells to autolyze was due to low amidase activity and relatively resistant cell walls. Revertants of RUB1012 were isolated that had 13, 23, and 55% of the normal proportions of teichoic acid when grown at the nonpermissive temperature. Cell walls from the revertants were as sensitive to added amidase as the wild-type strain. None of the revertant strains regained the wild-type ability to produce more amidase at 45 C. However, the deficiency in autolysin observed with RUB1012 was partially restored in revertants containing higher proportions of teichoic acid.


Surface-Enhanced Raman Scattering and Fluorescence on Gold Nanogratings.
Surface-enhanced Raman scattering (SERS) spectroscopy is a sensitive sensing technique. It is desirable to have an easy method to produce SERS-active substrate with reproducible and robust signals. We propose a simple method to fabricate SERS-active substrates with high structural homogeneity and signal reproducibility using electron beam (E-beam) lithography without the problematic photoresist (PR) lift-off process. The substrate was fabricated by using E-beam to define nanograting patterns on the photoresist and subsequently coat a layer of gold thin film on top of it. Efficient and stable SERS signals were observed on the substrates. In order to investigate the enhancement mechanism, we compared the signals from this substrate with those with photoresist lifted-off, which are essentially discontinuous gold stripes. While both structures showed significant grating-period-dependent fluorescence enhancement, no SERS signal was observed on the photoresist lifted-off gratings. Only transverse magnetic (TM)-polarized excitation exhibited strong enhancement, which revealed its plasmonic attribution. The fluorescence enhancement showed distinct periodic dependence for the two structures, which is due to the different enhancement mechanism. We demonstrate using this substrate for specific protein binding detection. Similar periodicity dependence was observed. Detailed theoretical and experimental studies were performed to investigate the observed phenomena. We conclude that the excitation of surface plasmon polaritons on the continuous gold thin film is essential for the stable and efficient SERS effects.


[Determination of micro Pb in preserved egg by flame atomic absorption spectrometry].
The method for the determination of micro Pb in preserved egg by flame atomic absorption spectrometry was studied in this paper. These samples are treated with ammonium persulfate, it is not necessary to preconcentrate the lead by extraction, the method is sensitive, easy to operate and has good precision and accuracy. The detection limit was 0.016 microgram.mL-1, the relative standard deviation of Pb was 3.2%, and the rates of recovery were 94.0%-98.0%.


Toxicity of ammonia, cadmium, and nitrobenzene to four local fishes in the Liao River, China and the derivation of site-specific water quality criteria.
Water quality criteria (WQC) are considered to be an effective management tool for protecting aquatic environments. To derive site-specific WQC for an area, local data based on local species are essential to improve the applicability of WQC derived. Due to the paucity of local fish data available for the development of site-specific WQC for the Liao River, China, four local and widespread fishes (Pseudorasbora parva, Abbottina liaoningensis, Ctenogobius giurinus, and Misgurnus anguillicaudatus) were chosen to test their sensitivities to ammonia, cadmium and nitrobenzene. These compounds are common and regularly-measured pollutants in Chinese rivers. In addition to the published data for species resident in the Liao River, site-specific WQC for the three chemicals were derived using both a log-logistic species sensitivity distribution (SSD) and the method recommended by the USEPA, in line with current best practice, which were then compared with Chinese national WQC. It was found that A. liaoningensis was the most sensitive, followed, in order, by P. parva, C. giurinus and M. anguillicaudatus was the least sensitive, and this trend was the same to all three chemicals tested. When comparing the SSD derived solely from previously-published data with that including our data on local fish, there were significant differences identified among parameters describing the SSD curves for ammonia and nitrobenzene and significant differences were detected for site-specific WQC derived for all of the three chemicals. Based on the dataset with local fish data taxa, site-specific WQC of Liao River for ammonia, cadmium, and nitrobenzene were derived to be 20.53mg/L (at a pH of 7.0 and temperature of 20°C), 3.76μg/L (at a hardness of 100mg/L CaCO3), and 0.49mg/L, respectively. Using the same deriving method for each chemical, the national Chinese WQC were higher than site-specific WQC derived in this study for ammonia (national WQC of 25.16mg/L) and nitrobenzene (national WQC of 0.57mg/L), while the national WQC for cadmium was lower (national WQC of 1.81μg/L). These results indicated that published data can be helpful for use when deriving site-specific WQC but that there were differences between site-specific and national WQC which may lead to either over- or under-protection depending on the pollutant if national WQC were used as the basis for the water management of specific river systems, like the Liao River.


Aflatoxin exposure measured by urinary excretion of aflatoxin B1-guanine adduct and hepatitis B virus infection in areas with different liver cancer incidence in Kenya.
Two major etiological agents, hepatitis B virus and aflatoxin B1, are considered to be involved in the induction of liver cancer in Africa. In order to elucidate any synergistic effect of these two agents we conducted a study in various parts of Kenya with different liver cancer incidence in order to establish the rate of exposure to aflatoxin and the prevalence of hepatitis infections. Of all tested individuals 12.6% were positive for aflatoxin exposure as indicated by the urinary excretion of aflatoxin B1-guanine. Assuming no annual and seasonal variation, a regional variation in the exposure was observed. The highest rate of aflatoxin exposure was found in the Western Highlands and Central Province. The incidence of hepatitis infection nationwide as measured by the presence of the surface antigens was 10.6%, but a wide regional variation was observed. A multiplicative and additive regression analysis to investigate if hepatitis and aflatoxin exposure had a synergetic effect in the induction of liver cancer was negative. However, a moderate degree of correlation between the exposure to aflatoxin and liver cancer was observed when the study was limited to certain ethnic groups. The study gives additional support to the hypothesis that aflatoxin is a human liver carcinogen.


COVID-19 severity scoring systems in radiological imaging - a review.
The current reference standard to make a definitive diagnosis of SARS-CoV-2 infection is the reverse transcription- polymerase chain reaction assay (rt-PCR). However, radiological imaging plays a crucial role in evaluating the course of COVID-19 and in choosing proper management of infected patients. Chest X-ray (CXR) is generally considered not to be sensitive for the detection of pulmonary abnormalities in the early stage of the disease. However, in the emergency setting CXR can be a useful diagnostic tool for monitoring the rapid progression of lung involvement in COVID-19, especially in patients admitted to intensive care units. The rapid course of SARS-CoV-2 infection and the severity and progression of lung aberrations require a method of radiological evaluation to implement and manage the appropriate treatment for infected patients. Computed tomography (CT) imaging is considered to be the most effective method for the detection of lung abnormalities, especially in the early stage of the disease. Moreover, serial chest CT imaging with different time intervals is also effective in estimating the evolution of the disease from initial diagnosis to discharge from hospital. Despite having low specificity in distinguishing abnormalities in viral infections, the high sensitivity of CT makes this method ideal for assessing the severity of the disease in patients with confirmed COVID-19. In this review, we present and discuss currently available scales that can be used to assess the severity of lung involvement in COVID-19 patients in everyday work, both for CXR and CT imaging.


Lycopene Alleviates Chronic Stress-Induced Hippocampal Microglial Pyroptosis by Inhibiting the Cathepsin B/NLRP3 Signaling Pathway.
Lycopene (LYC) exerts a strong neuroprotective and antipyroptotic effects. This study explored the effects and mechanisms of LYC on chronic stress-induced hippocampal microglial damage and depression-like behaviors. The caspase-1 inhibitor VX-765 attenuated chronic restrain stress (CRS)-induced hippocampal microglial pyroptosis and depression-like behaviors. Moreover, the alleviation of CRS-induced hippocampal microglial pyroptosis and depression-like behaviors by LYC was associated with the cathepsin B/NLRP3 pathway. In vitro, the caspase-1 inhibitor Z-YVAD-FMK alleviated pyroptosis in highly aggressively proliferating immortalized (HAPI) cells. Additionally, the alleviation of corticosterone-induced HAPI cell damage and pyroptosis by LYC was associated with the cathepsin B/NLRP3 pathway. Furthermore, the cathepsin B agonist pazopanib promoted HAPI cell pyroptosis, whereas LYC inhibited pazopanib-induced pyroptosis via the cathepsin B/NLRP3 pathway. Similarly, Z-YVAD-FMK inhibited pazopanib-induced HAPI cell pyroptosis. These results suggest that LYC alleviates chronic stress-induced hippocampal microglial pyroptosis via the cathepsin B/NLRP3 pathway inhibition. This study provides a new strategy for treating chronic stress encephalopathy.


Predictors of hospital mortality in the global registry of acute coronary events.
Management of acute coronary syndromes (ACS) should be guided by an estimate of patient risk. To develop a simple model to assess the risk for in-hospital mortality for the entire spectrum of ACS treated in general clinical practice. A multivariable logistic regression model was developed using 11 389 patients (including 509 in-hospital deaths) with ACS with and without ST-segment elevation enrolled in the Global Registry of Acute Coronary Events (GRACE) from April 1, 1999, through March 31, 2001. Validation data sets included a subsequent cohort of 3972 patients enrolled in GRACE and 12 142 in the Global Use of Strategies to Open Occluded Coronary Arteries IIb (GUSTO-IIb) trial. The following 8 independent risk factors accounted for 89.9% of the prognostic information: age (odds ratio [OR], 1.7 per 10 years), Killip class (OR, 2.0 per class), systolic blood pressure (OR, 1.4 per 20-mm Hg decrease), ST-segment deviation (OR, 2.4), cardiac arrest during presentation (OR, 4.3), serum creatinine level (OR, 1.2 per 1-mg/dL [88.4- micro mol/L] increase), positive initial cardiac enzyme findings (OR, 1.6), and heart rate (OR, 1.3 per 30-beat/min increase). The discrimination ability of the simplified model was excellent with c statistics of 0.83 in the derived database, 0.84 in the confirmation GRACE data set, and 0.79 in the GUSTO-IIb database. Across the entire spectrum of ACS and in general clinical practice, this model provides excellent ability to assess the risk for death and can be used as a simple nomogram to estimate risk in individual patients.


Leg lengthening and bone transport in children.
It is now possible to reliably lengthen limbs for inequality or short stature by distraction osteogenesis using external fixators. Similar techniques offer new methods of treating infected fractures and non-unions and correcting soft tissue contractures and bony deformities. This article outlines the techniques and indications for leg lengthening and bone transport.


Potential roles of interleukin-17A in the development of skin fibrosis in mice.
Although transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) have been considered to play central roles in the pathogenesis of systemic sclerosis (SSc), other cytokines may also be crucial for the development of SSc. The aim of this study was to examine the roles of T helper cytokines in the development of skin fibrosis. To compare the roles of Th1, Th2, and Th17 cytokines, we examined bleomycin-induced SSc in mice deficient for interferon-γ (IFNγ), interleukin-4 (IL-4), and IL-17A. The mechanism by which IL-17A contributes to bleomycin-induced fibrosis was investigated in vivo and in vitro. The outcome of mice lacking IL-17A was also investigated in TSK-1 mice. The loss of IL-17A significantly attenuated bleomycin-induced skin fibrosis, whereas a deficiency of IFNγ or IL-4 did not. Leukocyte infiltration and the expression of TGFβ and CTGF messenger RNA in bleomycin-injected skin were significantly reduced in IL-17A-deficient mice compared with wild-type (WT) mice. Daily bleomycin injections induced the expression of IL-17A in the skin and potent IL-17A producers in splenic CD4+ T cells from WT mice. Furthermore, a skin fibroblast cell line expressed increased TGFβ, CTGF, and collagen after the addition of recombinant IL-17A. IL-17A deficiency also attenuated skin thickness in TSK-1 mice. This study demonstrates that IL-17A contributes to skin fibrosis in 2 mouse models of SSc. These findings suggest that inhibition of IL-17A represents a therapeutic target for antagonizing fibrotic skin disorders such as SSc.


Contrasting Effects of Gambling Consumption and Gambling Problems on Subjective Wellbeing.
Most research on gambling focuses on the negative consequences associated with excessive consumption, which implicitly leads to a reduction in health and wellbeing. However, few studies have measured subjective wellbeing with respect to gambling involvement, and almost none has attempted to distinguish the separate effects of consumption and problems. We used the Personal Wellbeing Index (PWI) in two surveys with different recruitment criteria. Study 1 (N = 1524, 50.6% female) was designed to compare differences in personal wellbeing among gamblers, and Study 2 (N = 1586, 70.2% female) compared wellbeing between gamblers and non-gamblers. Participants provided demographic information, and answered questions allowing them to be grouped into high/low levels of consumption, and problem gambling risk categories. After accounting for gambling problems, higher consumption was associated with higher wellbeing. Study 2 showed consistent results; revealing that both high and low consumption non-problem gamblers (NPGs) had higher personal wellbeing than non-gamblers. Nevertheless, the deleterious effect of gambling problems on wellbeing was larger than the effect of consumption. After accounting for population prevalence (i.e., per capita), only 15.3% of the negative influence of gambling problems on PWI was attributable to problem gamblers; the remainder associated with lower risk categories. Although results were consistent when controlling for demographic covariates, the positive link between consumption and wellbeing may be due to unmeasured variables such as personality traits, health, and socioeconomic status. Nevertheless, the assessment of subjective wellbeing provides a unique perspective on both the positive and negative effects of gambling.


The Visual Acuity Outcome and Relevant Factors Affecting Visual Improvement in Pediatric Sporadic Chiasmatic-Hypothalamic Glioma Patients Who Received Surgery.
Background: The role and effectiveness of primary surgical treatment for sporadic chiasmatic-hypothalamic glioma (CHG) are not clear. The present study was to describe sporadic CHG visual acuity (VA) outcomes after surgery and to analyze the relevant factors affecting VA improvement. Methods: Forty-five pediatric sporadic CHG patients who met the inclusion criteria were included in a retrospective study. All patients received primary intratumor partial resection. Disease characteristics, treatment strategies, complications, and VA outcome were analyzed. Univariate and multivariate analyses were performed to identify relevant factors of VA improvement. Receiver operating characteristic (ROC) analysis was performed to evaluate the predictive accuracy of measurement indexes. Results: There were 77 eyes of 45 children suffering from various levels of VA impairment before surgical treatment, and only 13 eyes had normal vision. Patients with resection extents >70, 50-70, and <50% accounted for 26.67, 24.44, and 48.89%, respectively. The percentages of VA maintained and deteriorated in normal vision eyes were 61.54 and 38.46%. The percentages of VA improved, maintained, and deteriorated in visually impaired eyes after surgery were 29.87, 45.45, and 24.68%, respectively. There was a positive correlation between the IVA level and VA improvement. There was no significant difference in VA improvement between the different resection extents. Blindness occurred in ~4.4%. Approximately 11.1% of the children had complications that affected quality of life, which correlated with resection extent. IVA and tumor size were correlated with VA improvement. The AUC for IVA + tumor size predicting VA improvement was 0.831. The cutoff points for IVA level and tumor volume were 4.5 and 43.50 cm3, respectively. Conclusions: IVA and tumor size were correlated with VA improvement after primary intratumor partial resection. Children with IVA ≥ level 5 were more likely to achieve visual improvement after decompression surgery, but decompression had limited effectiveness on vision improvement in patients with tumor volumes ≥ 43.50 cm3. Performing resections < 50% was safe and did not reduce the effect of decompression to improve VA.


Comparative toxicity of allelochemicals and their enzymatic oxidation products to maize fungal pathogens, emphasizing Fusarium graminearum.
A series of stable quinones and their precursors, and enzymatic oxidation products of plant allelochemicals were tested for their effect on maize fungal pathogens, primarily Fusarium graminearum. Benzoquinone was typically significantly more toxic than hydroquinone, while 1,2-naphthoquinone was typically significantly more toxic than 1,2-dihydroxynaphthalene. Aspergillus flavus was the most resistant fungus to these compounds, while Phoma medicaginis was the most susceptible. Applying tyrosinase in conjunction with several phenolic compounds only increased the toxicity of gallic acid to Fusarium graminearum. Applying peroxidase generally increased toxicity of all compounds tested to this fungus in a dose-dependent fashion. Ferulic acid was generally the most toxic compound, both alone and when combined with peroxidase and H2O2, followed by coumaric acid. These results suggest that enzymatic oxidation of plant allelochemicals may result in the generation of products that either are directly toxic to maize pathogens, or indirectly inhibitory due to their ability to tie up nutrients.


Biological activities of toxins A and B of Clostridium difficile.
Examination of the biological activities of the two known toxins of Clostridium difficile revealed that one of the toxins (toxin A) elicited a hemorrhagic fluid response in rabbit intestinal loops and a positive fluid response in infant mice. The other toxin (toxin B) did not produce a significant fluid response in either model, although the toxin was more lethal in infant mice. Both toxins elicited erythematous and hemorrhagic skin reactions and increased vascular permeability in rabbit skin.


Thrombolysis in acute ischemic stroke: controlled trials and clinical experience.
Thrombolytic therapy with recombinant tissue plasminogen activator (rtPA) is approved in the United States for treatment of acute ischemic stroke. Approval was granted after a large, randomized, placebo-controlled study by the National Institute of Neurological Disorders and Stroke (NINDS) showed a significant improvement in 3-month outcomes with rtPA despite a significant risk for symptomatic hemorrhage. Two other trials, the first and second European Cooperative Acute Stroke Study (ECASS I and II), have shown comparable results, but neither was statistically positive for the predefined primary end point. An analysis of the risk/benefit profile of rtPA therapy based on the results of these three trials indicates that the treatment is effective and, when administered within 3 hours of symptom onset at a dose of 0.9 mg/kg, the benefits by far outweigh the risks for eligible patients. Even with the 6-hour time window of the two ECASS trials, a combined analysis of the three studies shows the number of disabled or dead patients to be significantly reduced. Preliminary data collected on the use of rtPA outside of clinical trials in the United States and Europe suggest that, when rtPA is used according to the trial protocol, the risks and benefits are similar to those observed in clinical trials. However, even within the United States, rtPA is underutilized. The most substantial treatment barrier is the narrow time window, which may be expanded if long-term experience shows that this is possible. Most stroke patients arrive at the hospital too late to be eligible for screening and treatment. Education of the public and physicians may help to overcome this difficulty.


No benefit of flat head positioning in early moderate-severe acute ischaemic stroke: a HeadPoST study subgroup analysis.
Although the Head Positioning in acute Stroke Trial (HeadPoST) showed no effect of the flat head position (FP; vs sitting up head position (SUP)) on functional outcome, we hypothesised that it could still offer benefits if commenced early in those with acute ischaemic stroke (AIS) of at least moderate severity. Subgroup analysis of HeadPoST in participants with National Institutes of Health Stroke Scale (NIHSS) scores ≥7, ≥10 and ≥14, randomised to FP or SUP <4.5 hours of AIS onset on functional outcomes defined by a shift in scores on the modified Rankin scale (mRS) and death/disability (mRS scores 3-6), and any cardiovascular serious adverse event. Logistic regression analyses were undertaken adjusted for study design and baseline risk factors. There was no significant differential treatment effect in patient subgroups defined by increasing baseline NIHSS scores: adjusted OR and 95% CI for ordinal shift and binary (3-6) mRS scores: for NIHSS ≥7 (n=867) 0.92 (0.67 to 1.25) and 0.74 (0.52 to 1.04); NIHSS ≥ 10 (n=606) 0.80 (0.58 to 1.10) and 0.77 (0.49 to 1.19); NIHSS ≥14 (n=378) 0.82 (0.54 to 1.24) and 1.22 (0.69 to 2.14). Early FP had no significant effect in patients with moderate-severe AIS. NCT02162017.


Novel Wet Electrospinning Inside a Reactive Pre-Ceramic Gel to Yield Advanced Nanofiber-Reinforced Geopolymer Composites.
Electrospinning is a versatile approach to generate nanofibers in situ. Yet, recently, wet electrospinning has been introduced as a more efficient way to deposit isolated fibers inside bulk materials. In wet electrospinning, a liquid bath is adopted, instead of a solid collector, for fiber collection. However, despite several studies focused on wet electrospinning to yield polymer composites, few studies have investigated wet electrospinning to yield ceramic composites. In this paper, we propose a novel in-situ fabrication approach for nanofiber-reinforced ceramic composites based on an enhanced wet-electrospinning method. Our method uses electrospinning to draw polymer nanofibers directly into a reactive pre-ceramic gel, which is later activated to yield advanced nanofiber-reinforced ceramic composites. We demonstrate our method by investigating wet electrospun Polyacrylonitrile and Poly(ethylene oxide) fiber-reinforced geopolymer composites, with fiber weight fractions in the range 0.1-1.0 wt%. Wet electrospinning preserves the amorphous structure of geopolymer while changing the molecular arrangement. Wet electrospinning leads to an increase in both the fraction of mesopores and the overall porosity of geopolymer composites. The indentation modulus is in the range 6.76-8.90 GPa and the fracture toughness is in the range 0.49-0.76 MPam with a clear stiffening and toughening effect observed for Poly(ethylene oxide)-reinforced geopolymer composites. This work demonstrates the viability of wet electrospinning to fabricate multifunctional nanofiber-reinforced composites.


Measurement of superoxide release from single pulmonary alveolar macrophages.
An electrooptical method was developed to quantify superoxide (O2-) release from single rat pulmonary alveolar macrophages (PAM) during adherence to the bottom of a culture dish. This was done by measuring the reduction of nitro blue tetrazolium (NBT) to a diformazan precipitate at 550 nm from videorecorded images of individual cells. Temporal changes in cell optical density, which are proportional to the mass of diformazan produced, were calculated from videophotometric measurements of the change in light intensity over individual cells. Total diformazan produced increased 78 and 126% with an increase in NBT from 0.5 to 1.0 and 2.0 mg/ml, respectively. Total diformazan produced and maximum rate of production among individual PAM varied two- to threefold providing strong evidence for heterogeneity in O2- production. Specific inhibition of O2- production by superoxide dismutase, iodoacetate, and chlorpromazine significantly reduced the total diformazan produced and maximum rate of diformazan production. Hydrogen peroxide was not involved in NBT reduction, since catalase alone did not significantly change diformazan production. This novel method to quantify O2- release from single PAM should be valuable in analyzing heterogeneity and single cell kinetics of O2- production, in assessing the effects of exposure of cells to particulates on O2- release, and in relating release to electrophysiological measurements.


Targeting inflammatory pathways by triterpenoids for prevention and treatment of cancer.
Traditional medicine and diet has served mankind through the ages for prevention and treatment of most chronic diseases. Mounting evidence suggests that chronic inflammation mediates most chronic diseases, including cancer. More than other transcription factors, nuclear factor-kappaB (NF-κB) and STAT3 have emerged as major regulators of inflammation, cellular transformation, and tumor cell survival, proliferation, invasion, angiogenesis, and metastasis. Thus, agents that can inhibit NF-κB and STAT3 activation pathways have the potential to both prevent and treat cancer. In this review, we examine the potential of one group of compounds called triterpenes, derived from traditional medicine and diet for their ability to suppress inflammatory pathways linked to tumorigenesis. These triterpenes include avicins, betulinic acid, boswellic acid, celastrol, diosgenin, madecassic acid, maslinic acid, momordin, saikosaponins, platycodon, pristimerin, ursolic acid, and withanolide. This review thus supports the famous adage of Hippocrates, "Let food be thy medicine and medicine be thy food".


Differential distribution of tight junction proteins suggests a role for tanycytes in blood-hypothalamus barrier regulation in the adult mouse brain.
The median eminence is one of the seven so-called circumventricular organs. It is located in the basal hypothalamus, ventral to the third ventricle and adjacent to the arcuate nucleus. This structure characteristically contains a rich capillary plexus and features a fenestrated endothelium, making it a direct target of blood-borne molecules. The median eminence also contains highly specialized ependymal cells called tanycytes, which line the floor of the third ventricle. It has been hypothesized that one of the functions of these cells is to create a barrier that prevents substances in the portal capillary spaces from entering the brain. In this paper, we utilize immunohistochemistry to study the expression of tight junction proteins in the cells that compose the median eminence in adult mice. Our results indicate that tanycytes of the median eminence express occludin, ZO-1, and claudin 1 and 5, but not claudin 3. Remarkably, these molecules are organized as a continuous belt around the cell bodies of the tanycytes that line the ventral part of the third ventricle. In contrast, the tanycytes at the periphery of the arcuate nucleus do not express claudin 1 and instead exhibit a disorganized expression pattern of occludin, ZO-1, and claudin 5. Consistent with these observations, permeability studies using peripheral or central injections of Evans blue dye show that only the tanycytes of the median eminence are joined at their apices by functional tight junctions, whereas tanycytes located at the level of the arcuate nucleus form a permeable layer. In conclusion, this study reveals a unique expression pattern of tight junction proteins in hypothalamic tanycytes, which yields new insights into their barrier properties.


Region and amino acid residues required for Rad51C binding in the human Xrcc3 protein.
The Xrcc3 protein, which is required for the homologous recombinational repair of damaged DNA, forms a complex with the Rad51C protein in human cells. Mutations in either the Xrcc3 or Rad51C gene cause extreme sensitivity to DNA-damaging agents and generate the genomic instability frequently found in tumors. In the present study, we found that the Xrcc3 segment containing amino acid residues 63-346, Xrcc3(63-346), is the Rad51C-binding region. Biochemical analyses revealed that Xrcc3(63-346) forms a complex with Rad51C, and the Xrcc3(63-346)- Rad51C complex possesses ssDNA and dsDNA binding abilities comparable to those of the full-length Xrcc3-Rad51C complex. Based on the structure of RecA, which is thought to be the ancestor of Xrcc3, six Xrcc3 point mutants were designed. Two-hybrid and biochemical analyses of the Xrcc3 point mutants revealed that Tyr139 and Phe249 are essential amino acid residues for Rad51C binding. Superposition of the Xrcc3 Tyr139 and Phe249 residues on the RecA structure suggested that Tyr139 may function to ensure proper folding and Phe249 may be important to constitute the Rad51C-binding interface in Xrcc3.


Targeting PIK3CA Alterations in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor-2-Negative Advanced Breast Cancer: New Therapeutic Approaches and Practical Considerations.
The phosphatidylinositol-3-kinase (PI3K) pathway is frequently dysregulated in human breast cancer. Approximately 30% of all patients with breast cancer will carry mutations of the PIK3CA gene, which encodes the PI3K catalytic subunit isoform p110α. Mutations in PIK3CA have been associated with resistance to endocrine therapy, HER2-directed therapy, and cytotoxic therapy. Early trials of pan-PI3K inhibitors showed little treatment benefit as monotherapy owing to disease resistance arising through enhanced estrogen receptor pathway signaling. Combining PI3K inhibition with endocrine therapy can help overcome resistance. Clinical trials of pan-PI3K inhibitors combined with endocrine therapy demonstrated modest clinical benefits but challenging toxicity profiles, facilitating the development of more selective PI3K-targeting agents. More recent trials of isoform-specific PI3K inhibitors in patients with PIK3CA mutations have shown promising clinical efficacy with a predictable, manageable safety profile. In the present review, we discuss the clinical relevance of mutations of PIK3CA and their potential use as a biomarker to guide treatment choices in patients with HR+ HER2- advanced breast cancer.


Cost Analysis of All-Polyethylene Compared to Metal-Backed Implants in Total Knee Arthroplasty.
The growing trends of total knee arthroplasty (TKA) foreshadow an inevitable increase in the financial burden on healthcare expenditure estimated to almost nine billion dollars annually. This study aims to demonstrate the potential savings when using all-polyethylene (AP) compared to metal-backed (MB) tibial components and describes the cost variability amongst three major commercially available implants. The cost of AP versus MB implants was analyzed using a large nationwide database, Emergency Care Research Institute (ECRI). Cost of femoral components and patellar buttons were excluded. The three manufacturers included in the study were DePuy, Smith&Nephew, and Stryker (Zimmer data was not available for analysis). Our results show that AP components were significantly less costly in comparison to other manufacturers, and the average AP price was $1,009. The average MB (baseplate plus liner) price was $2,054 (p<0.01). Analysis of variance (ANOVA) of the means of the AP components showed no significant difference in prices among the three studied manufacturers (p=0.946). Our results demonstrate that, regardless of the manufacturing company, AP tibial components are significantly cheaper than their MB counterparts. A literature review revealed that, when indicated, AP implants are not inferior to MB in terms of survivorship or outcome. The average savings was more than $1,000 per TKA when multiplied even by a small portion of the large volume of TKAs completed annually. This can translate into millions of dollars in savings in healthcare expenditures. With the impending legislation of the bundled-payment initiative, orthopaedic surgeons should be aware of less costly implant options that can positively impact outcomes and/or quality of care.


Inhibition of T and B cell proliferation by titanium, cobalt, and chromium: role of IL-2 and IL-6.
The mechanism by which an increased risk of prosthetic infection is induced in patients with total joint arthroplasties is poorly understood. The adverse effects of metallic corrosion products of a prosthesis on host defense mechanisms, particularly immune response and release of immunoregulatory cytokines, remain largely unknown. Titanium, cobalt, and chromium are the materials most often used for joint implantation. Therefore, this study was aimed at investigating the cytotoxicity of titanium, cobalt, and chromium and whether these metals affect T and B cell proliferation and the release of cytokines by human peripheral blood mononuclear cells (PBMC) in vitro. Metal cytotoxicity was not observed judging by cell viability and cell injury after PBMC was extensively exposed to the metals. Phytohemagglutinin (PHA)-induced T cell proliferation and lipopolysaccharide-induced B cell proliferation were significantly inhibited by titanium, chromium, and cobalt. The release of IL-2 and IL-6 by PHA-stimulated PBMC was significantly inhibited by titanium, chromium, and cobalt. Titanium did not alter IFN-gamma production, whereas chromium and cobalt significantly reduced IFN-gamma release by PHA-stimulated PBMC. The addition of IL-2 and IL-6 significantly restored the metal-induced inhibition of T cell and B cell proliferation, respectively. This study sheds light on how the metals impair immune response and cytokine release, suggesting that patients with an extensive exposure to the metals may develop immune dysfunctions. The compromised immune response induced by the metals might significantly contribute to an increased risk of infection in patients with joint prostheses.


The effect of plaque eccentricity on blood hemodynamics and drug release in a stented artery.
Atherosclerosis in the coronary arteries is one of the leading causes of death in the world. Percutaneous coronary interventions (PCI) associated with the implantation of drug eluting stents (DES) is one of the most common forms of revascularization in patients with atherosclerotic coronary artery disease. The use of DES is considered as an effective tool to reduce restenosis after PCI. However despite all the progress made in DES procedures, the rate of restenosis remains relatively high. Mathematical modeling and numerical simulation are believed to play an essential role in identifying zones with a higher risk of in-stent restenosis. In this work the local delivery of a therapeutic agent, from a stent implanted in a coronary artery, is mathematically modeled and numerically simulated. The mathematical model includes the diffusion of the dissolved drug in the biodegradable polymeric coating of the stent, the diffusion and convection of the drug with reversible binding in the viscoelastic arterial wall with plaques of different morphology and the local hemodynamics. The study is an attempt to detect zones with a higher risk of in-stent restenosis and their relation to plaque eccentricity. The location of zones with highest risk of thrombosis and plaque rupture is also addressed. The results are in agreement with claims presented in clinical papers.


Microbial survey of the mummies from the Capuchin Catacombs of Palermo, Italy: biodeterioration risk and contamination of the indoor air.
The Capuchin Catacombs of Palermo contain over 1800 preserved bodies dating from the 16th to 20th centuries AD and showing evidence of biodeterioration. An extensive microbiological and molecular investigation was recently performed. Samples were taken from skin, muscle, hair, bone, stuffing materials, clothes, and surrounding walls as well as from the indoor air. In this study, we witnessed that the different degradation phenomena observed on the variety of materials located at the Capuchin Catacombs of Palermo are biological in origin. Molecular techniques showed the dominance of halophilic species of the domains Bacteria and Archaea on the walls and - as a result of salt emanating from the walls - on the mummies themselves. Nevertheless, specialized microorganisms belonging to taxa well-known for their cellulolytic and proteolytic activities were detected on clothes and stuffing material, and on skin, muscle, hair, and bone, respectively. This specialized microbiota is threatening the conservation of the mummies themselves. Additionally, sequences related to the human skin microbiome and to some pathogenic Bacteria (order Clostridiales) and fungi (genus Phialosimplex) were identified on samples derived from the mummies. Furthermore, a phosphate-reducing fungus, Penicillium radicum, was detected on bone. Finally, the high concentration of airborne fungal spores is not conducive to the conservation of the human remains and is posing a potential health risk for visitors.


Obesity and osteoarthritis in knee, hip and/or hand: an epidemiological study in the general population with 10 years follow-up.
Obesity is one of the most important risk factors for osteoarthritis (OA) in knee(s). However, the relationship between obesity and OA in hand(s) and hip(s) remains controversial and needs further investigation. The purpose of this study was to investigate the impact of obesity on incident osteoarthritis (OA) in hip, knee, and hand in a general population followed in 10 years. A total of 1854 people aged 24-76 years in 1994 participated in a Norwegian study on musculoskeletal pain in both 1994 and 2004. Participants with OA or rheumatoid arthritis in 1994 and those above 74 years in 1994 were excluded, leaving n = 1675 for the analyses. The main outcome measure was OA diagnosis at follow-up based on self-report. Obesity was defined by a body mass index (BMI) of 30 and above. At 10-years follow-up the incidence rates were 5.8% (CI 4.3-7.3) for hip OA, 7.3% (CI 5.7-9.0) for knee OA, and 5.6% (CI 4.2-7.1) for hand OA. When adjusting for age, gender, work status and leisure time activities, a high BMI (> 30) was significantly associated with knee OA (OR 2.81; 95%CI 1.32-5.96), and a dose-response relationship was found for this association. Obesity was also significantly associated with hand OA (OR 2.59; 1.08-6.19), but not with hip OA (OR 1.11; 0.41-2.97). There was no statistically significant interaction effect between BMI and gender, age or any of the other confounding variables. A high BMI was significantly associated with knee OA and hand OA, but not with hip OA.


Evolution of Increased Photosynthetic Capacity and Its Underlying Traits in Invasive Jacobaea vulgaris.
The evolution of increased competitive ability (EICA) hypothesis and the shifting defense hypothesis (SDH) predict that evolutionary changes occur in a suite of traits related to defense and growth in invasive plant species as result of the absence of specialist herbivores. We tested how this suite of traits changed due to the absence of specialist herbivores in multiple invasive regions that differ in climatic conditions with native and invasive Jacobaea vulgaris in a controlled environment. We hypothesized that invasive J. vulgaris in all invasive regions have i) a higher plant growth and underlying traits, such as photosynthetic capacity, ii) lower regrowth-related traits, such as carbohydrate storage, and iii) an increased plant qualitative defense, such as pyrrolizidine alkaloids (PAs). Our results show that invasive J. vulgaris genotypes have evolved a higher photosynthetic rate and total PA concentration but a lower investment in root carbohydrates, which supports the SDH hypothesis. All the traits changed consistently and significantly in the same direction in all four invasive regions, indicative of a parallel evolution. Climatic and soil variables did differ between ranges but explained only a very small part of the variation in trait values. The latter suggests that climate and soil changes were not the main selective forces on these traits.


Peripherally Inserted Central Catheters in Pediatric Patients: To Repair or Not Repair.
Preservation of venous access in children is a major concern in pediatric interventional radiology. If a peripherally inserted central catheter (PICC) breaks, there are two options: repair the line with a repair kit or exchange the line over a wire in the interventional suite. The purpose of this study is to assess the outcome of PICC repairs in children and to compare these with the outcomes of PICC exchange. This is a single-center, retrospective study of central line-associated bloodstream infection (CLABSI) following management of externally broken PICCs (2010-2014). The occurrence of CLABSI within 30 days after repair (Group A) or exchange (Group B) of a line was analyzed, as well as PICCs exchanged following an initial and failed repair. A total of 235 PICC breaks were included in the study, of which 161 were repaired, and 116 of whom were successful (68%, Group A). No repair was performed in 74 PICCs-55/74 of these were exchanged over a wire (74%, Group B), and 19/74 lines were removed. The 30 days post-repair CLABSI rate (Group A) was 2.0 infections per 1000 catheter days, and the calculated risk was 4.3%. In comparison the 30 days post-exchange CLABSI rate (Group B) was 4.0 per 1000 catheter days and the calculated risk 10.9%. This difference was significant when adjusted for antibiotic use (OR 3.87; 95% CI 1.07-14.0, p = 0.039). The results of this study support repairing a broken PICC instead of removing or replacing the line.


Profile and predictors of service needs for families of children with autism spectrum disorders.
Increasing demand for autism services is straining service systems. Tailoring services to best meet families' needs could improve their quality of life and decrease burden on the system. We explored overall, best, and worst met service needs, and predictors of those needs, for families of children with autism spectrum disorders. Parents of 143 children with autism spectrum disorders (2-18 years) completed a survey including demographic and descriptive information, the Family Needs Survey-Revised, and an open-ended question about service needs. Descriptive statistics characterize the sample and determine the degree to which items were identified and met as needs. Predictors of total and unmet needs were modeled with regression or generalized linear model. Qualitative responses were thematically analyzed. The most frequently identified overall and unmet service needs were information on services, family support, and respite care. The funding and quality of professional support available were viewed positively. Decreased child's age and income and being an older mother predicted more total needs. Having an older child or mother, lower income, and disruptive behaviors predicted more total unmet needs, yet only disruptive behaviors predicted proportional unmet need. Child's language or intellectual abilities did not predict needs. Findings can help professionals, funders, and policy-makers tailor services to best meet families' needs.


[Adaptive changes in the body upon exposure to electromagnetic radiation].
The chance to use electromagnetic exposures as active adaptogen and the detecting of adaptive changes following them were objects of our studies. The data of experimental and clinical studies significative the dependence of changes on the functional state of organism were seen. Particular attention is paid to the site of exposure and to the advantages in the action of electromagnetic exposures on areas overlaying the endocrine glands and control centers of central nerve system. In these conditions electromagnetic exposures play a part of trigger initiated natural processes of homeostatic regulation in the organism functional systems. It is shown that the course of electromagnetic exposures in wide frequency range until laser radiation (infrared and red) arises adaptive changes of the regulator systems, of the bioenergetic and the biosynthetic processes in myocardium, liver, brain, thymus and other tissues predetermined genetically and secured the power of the adaptive systems. The cross-adaptation effects underlie the electromagnetic exposures medical action.


Multifractality of instantaneous normal modes at mobility edges.
In terms of the multifractal analysis, we investigate the characteristics of the instantaneous normal modes (INMs) at two mobility edges (MEs) of a simple fluid, where the locations of the MEs in the INM spectrum were identified in a previous work [B. J. Huang and T. M. Wu, Phys. Rev. E 79, 041105 (2009)]. The mass exponents and the singularity spectrum of the INMs are obtained by the box-size and system-size scalings under the typical average. The INM eigenvectors at a ME exhibit a multifractal nature and the multifractal INMs at each ME yield the same results in generalized fractal dimensions and singularity spectrum. Our results indicate that the singularity spectrum of the multifractal INMs agrees well with that of the Anderson model at the critical disorder. This good agreement provides numerical evidence for the universal multifractality at the localization-delocalization transition. For the multifractal INMs, the probability density function and the spatial correlation function of the squared vibrational amplitudes are also calculated. The relation between the probability density function and the singularity spectrum is examined numerically, so are the relations between the critical exponents of the spatial correlation function and the mass exponents of the multifractal INMs.


Is the spring quality of muscle plastic?
During locomotion, major muscle groups are often activated cyclically. This alternate stretch-shorten pattern of activity could enable muscle to function as a spring, storing and recovering elastic recoil potential energy. Because the ability to store and recover elastic recoil energy could profoundly affect the energetics of locomotion, one might expect this to be an adaptable feature of skeletal muscle. This study tests the hypothesis that chronic eccentric (Ecc) training results in a change in the spring properties of skeletal muscle. Nine female Sprague-Dawley rats underwent chronic Ecc training for 8 wk on a motorized treadmill. The spring properties of muscle were characterized by both active and passive lengthening force productions. A single "spring constant (Deltaforce/Deltalength) from the passive length-tension curves was calculated for each muscle. Results from measurements on long heads of triceps brachii muscle indicate that the trained group produced significantly more passive lengthening force (P = 0.0001) as well as more active lengthening force (P = 0.0001) at all lengths of muscle stretch. In addition, the spring constants were significantly different between the Ecc (1.71 N/mm) and the control (1.31 N/mm) groups. A stiffer spring is capable of storing more energy per unit length stretched, which is of functional importance during locomotion.


Psychopharmacology: an update for psychiatric home care.
Psychopharmacology is a critical component of psychiatric home care. Nurses play an important role in medication management for patients who require this intervention. Knowledge of psychopharmacologic assessment, phases of psychopharmacologic treatment, psychobiology, and critical issues related to specific classes of medication is essential in developing a treatment plan with the patient and implementing it. Recent psychobiology research has indicated the importance of neurotransmitters, genetics, and the effect of the immune and endocrine systems. Critical issues related to anxiolytic medications, mood stabilizers, antidepressants, and antipsychotic (neuroleptic) medications are described.


Effects of in utero and childhood tobacco smoke exposure and beta2-adrenergic receptor genotype on childhood asthma and wheezing.
Associations between single-nucleotide polymorphisms in the beta2-adrenergic receptor gene and asthma and wheeze have been inconsistent. Recent studies indicated that tobacco smoke affects beta2-adrenergic receptor gene expression and associations of beta2-adrenergic receptor gene variants with asthma in adults. We aimed to investigate the joint effects of in utero and childhood secondhand tobacco smoke exposure and 2 well-characterized functional single-nucleotide polymorphisms (Arg16Gly and Glu27Gln) of beta2-adrenergic receptor gene on asthma and wheezing in 3128 non-Hispanic and Hispanic white children of the Children's Health Study. We fitted logistic regression models to estimate odds ratios and 95% confidence intervals for the independent and joint effects of these single-nucleotide polymorphisms and in utero and secondhand tobacco smoke exposure on asthma and wheeze outcomes. Exposures to in utero maternal smoking and secondhand tobacco smoke were associated with wheezing. Children who were homozygous for the Arg16 allele and were exposed to maternal smoking in utero were at a threefold increased risk for lifetime wheeze compared with children who were unexposed and had at least 1 Gly16 allele. We found similar joint effects of secondhand tobacco smoke and Arg16Gly with wheezing. The risk for lifetime, current, and nocturnal wheeze increased with the number of smokers at home among Arg16 homozygous children. The results were consistent in 2 cohorts of children recruited in 1993 and 1996. Diplotype-based analyses were consistent with the single-nucleotide polymorphism-specific results. No associations were found for Glu27Gln. Both in utero and childhood exposure to tobacco smoke were associated with an increased risk for wheeze in children, and the risks were greater for children with the Arg16Arg genotype or 2 copies of the Arg16-Gln27 diplotype. Exposures to smoking need to be taken into account when evaluating the effects of beta2-adrenergic receptor gene variants on respiratory health outcomes.


[Drugs used in bone marrow transplantation: a study about combinations of antimicrobial potentially interactives].
The study aimed at characterizing the profile of the drugs and identify combinations between potentially interactive anti-microbial drugs used in patients who underwent bone marrow transplantation (BMT). The analysis covered 70 prescription medications for BMT patients hospitalized at Instituto do Coração, São Paulo, Brazil. Medications were classified according to the Alpha system, listing their interactive potential and pharmacological characteristics according to literature. Data were analyzed through descriptive statistics. Results showed that 72.7% of drugs presented an interactive potential, with precipitators (79.2%) and fluconazole (85.7%), highlighted as the most involved anti-microbial in the combinations, associated to omeprazole in 40% of the samples. BMT patients were frequently administered combinations of potentially interactive drugs. This condition, when associated with simultaneous schedules, could predispose patients to undesirable events, thus affecting the security of the therapy.


Urinary loss of thyroid hormones: An issue to remember.
A 45-year-old woman suffering from primary hypothyroidism, previously well substituted with levothyroxine, was urgently referred from Primary Care to Endocrinology due to very elevated thyrotropin, free thyroxine at low limit of normality, very high cholesterol and generalised oedema. Hypothyroidism was suspected as the main aetiology of this clinical condition. A detailed examination showed nephrotic range proteinuria and the patient was finally diagnosed with lupus nephritis. Urinary loss of thyroid hormones, fundamentally linked to their transport proteins, in patients affected by nephrotic syndrome is sometimes a forgotten phenomenon and one which should be considered in patients with increased levothyroxine requirements. In this report, we present the details of this case and a brief review of the literature on this topic.


Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease.
Thymus-dependent reconstitution of the peripheral T-cell compartment is critical for the successful outcome of bone marrow transplantation. However, graft-versus-host disease (GVHD) affects thymic stromal function and thus prevents normal T-cell maturation and selection. To determine whether cytoprotection of thymic epithelial cells (TECs) by keratinocyte growth factor (KGF) averts GVHD-related injury to the thymus, a nonirradiated murine parent-->F(1) transplantation model was investigated. Administration of KGF between days -3 and +3 of GVHD induction preserved normal thymic size, cellularity, and thymocyte phenotype when measured 2 weeks after transplantation and compared with saline-treated parent-->F(1) mice that received allogeneic transplants. Moreover, the characteristic GVHD-induced impairment in cell cycle progression of pro- and pre-T cells was prevented by KGF. However, the normal phenotypic and functional status of the thymus did not correlate with the higher number of GVHD-inducing mature donor T cells in thymi of KGF-treated mice. Importantly, extensive analysis of the different TEC populations within the thymic cortex and medulla revealed an almost normal stromal architecture and composition in GVHD mice treated with KGF. These observations are likely to reflect an indirect effect of KGF on thymopoiesis as KGF-receptor expression was demonstrated to be restricted to TECs. Thus, pharmacologic doses of KGF appear to exert a potent effect on TEC function, which in turn allows for normal T lymphopoiesis to occur during acute GVHD.


Partitioning of the pesticide trifluralin between dissolved organic matter and water using automated SPME-GC/MS.
Solid-phase microextraction (SPME) was used to determine the equilibrium association constant for a pesticide, trifluralin (TFR), with dissolved organic matter (DOM). After optimization of the SPME method for the analysis of TFR, partition coefficients (K DOM) with three different sources of DOM were determined in buffered solutions at pH 7. Commercial humic acids and DOM fractions isolated from two surface waters were used. The values of log K DOM varied from 4.3 to 5.8, depending on the nature of the organic material. A good correlation was established between log K DOM and DOM properties (as measured with the H/O atomic ratio and UV absorbance), in agreement with literature data. This is consistent with the effect of polarity and aromaticity for governing DOM-pollutant associations, regardless of the origin of DOM. This association phenomenon is relevant to better understand the behavior of pesticides in the environment since it controls part of pesticide leaching and fate in aquatic systems.


Evaluation of a morphine maturation model for the prediction of morphine clearance in children: how accurate is the predictive performance of the model?
The pharmacokinetics of morphine are well known in pre-term and term neonates, infants, younger and older children, as well as in adults. There are circumstances when a pharmacokinetic study may not be possible in children (especially neonates and infants), and as a result one would like to predict drug clearance in children. Several methods, such as allometric scaling and prediction based on incorporation of physiological parameters, have been suggested. Recently a morphine maturation model has been proposed to predict morphine clearance in the paediatric population. The current study evaluates the predictive performance of the morphine maturation model for the prediction of morphine clearance in pre-term, term, infants and children up to 5 years of age. The results of the study highlight the shortcomings of the model to predict morphine clearance in children in aforementioned age groups. Recently, a maturation model that incorporates a sigmoidal E(max) type model has been proposed for the estimation of morphine clearance in paediatric patients. The primary objective of this report is to evaluate the predictive performance of the morphine maturation model for the prediction of morphine clearance in children of different ages. The secondary objective of this report is to evaluate the predictive performance of exponent 0.75 on bodyweight in the absence of the sigmoidal part of the morphine maturation model. In order to evaluate the predictive performance of the morphine maturation model, the clearance values of morphine for individual children (preterm neonates to 5-year-old children; n= 147) were obtained from the literature. The predicted clearance of morphine in an individual child, obtained from the maturation model as well as from the fixed exponent 0.75 was compared with the observed clearance in that individual child. The morphine maturation model's predictive power in neonates, infants and younger children is poor and the inclusion of the sigmoidal part in the model only helps in reducing the substantial error introduced in the prediction due to the application of exponent 0.75 on bodyweight. Furthermore, the real benefit of the sigmoidal E(max) part of the model disappears by 1 year of age. The morphine maturation model has a poor predictive power of morphine clearance in preterm and term neonates, infants and very young children and may not be of any practical value for the prediction of morphine clearance in this age group.


In silico predicted mycobacterial epitope elicits in vitro T-cell responses.
Epitope-based vaccines permit the selection of only a specific subset of epitopes to induce the necessary immune response, thus providing a rational alternative to conventional design approaches. Using a range of immunoinformatics tools, we identified a novel, contiguous 28 amino acid multi-epitope cluster within the highly conserved secretory protein Ag85B of Mycobacterium tuberculosis, the causative agent of TB. This cluster, named Ep85B, is composed of epitopes which bind to three HLA Class I and 15 Class II molecules, and harbors the potential to generate 99% population coverage in TB-endemic regions. We experimentally evaluated the capacity of Ep85B to elicit T-cell immune responses using whole blood cells and, as predicted, observed significant increases in populations of both CD4+ and memory CD4+ CD45RO+ T-cells. Our results demonstrate the practical utility of an epitope-based design methodology - a strategy that, following further evaluation, may serve as an additional tool for the development of novel vaccine candidates against TB and other diseases.


Patient satisfaction and high-reliability organizations: what's the connection?
Patients' perceptions of their care is extremely varied based on their expectations and of the actual variability of the care provided to them. The signature experience is the concept by which we can clearly develop the vision of the ideal experience for patients and staff. Patients can't heal effectively when their environment does not support an atmosphere where the signature experience is foremost in everyone's mind and activity.


Stress-inducible DNA repair in Saccharomyces cerevisiae.
Saccharomyces cerevisiae shows altered radiation response under various stress conditions, such as nutrition depletion, nitrogen starvation, osmotic shock, heat shock, and mild chemical treatments. In general, the cells show higher levels of UV or gamma radiation resistance under the stress. However, not all the stress conditions affect the repair system in the same manner. For example, depletion of nitrogen supply in the growth medium has been shown to enhance the repair of gamma ray-induced DNA damage without significantly affecting the UV response of the cells. On the other hand, a mild treatment with alkali or hydrogen peroxide improves the response to UV light but not to gamma radiation. It has further been shown that the effect of these stresses are not additive, e.g., the alkali and hydrogen peroxide treatments given simultaneously show the same effect as either of them alone. Low levels of gamma and UV radiation exposures are also treated as stress in the present context. Studies show that irradiation of low-dose gamma rays results in enhanced excision repair of UV-induced pyrimidine dimers. However, in all the wild-type strains tested, none showed any effect on gamma rays response. The exposure to low doses of UV light did not show any effect on either the gamma rays or the UV response. It is suggested that the stress-induced enhancement of DNA repair can be of two types: 1) A general response to stress, which prepares the organism to survive in adverse circumstances (some of the proteins produced during this response also take part in the DNA repair), and 2) a particular response involving DNA damage, such as that caused by gamma irradiation. In this case, the DNA damage may act as a signal for enhancement of the DNA repair.


Computer-assisted stereotactic ventralis lateralis thalamotomy with microelectrode recording control in patients with Parkinson's disease.
Stereotactic ventralis lateralis thalamotomy can be performed in selected patients with medically intractable parkinsonian tremor and rigidity. New technology, including computed tomography-based stereotaxis and microelectrode recording techniques, provides a data base for precise localization of thalamic lesions tailored to each patient and thus reduces the risk associated with such a procedure. At our institution, 12 patients with medically intractable parkinsonian tremor have undergone this procedure; all experienced alleviation or cessation of the tremor and no permanent disabling neurologic sequelae.


Ilizarov Treatment Protocols in the Management of Infected Nonunion of the Tibia.
We present a treatment algorithm comprising 4 Ilizarov methods in managing infected tibial nonunion, using nonunion mobility and segmental defect size to govern treatment choice. Decision protocol analysis study. A university-affiliated teaching hospital. Seventy-nine patients were treated with 1 of 4 Ilizarov protocols. All patients had undergone at least one previous operation, 38 had associated limb deformity, and 49 had nonviable nonunions. Twenty-six had a new muscle flap at the time of Ilizarov surgery, and 25 had preexisting flaps reused. Twenty-six cases were treated with monofocal distraction, 19 with monofocal compression, 16 with bifocal compression/distraction, and 18 with bone transport. The primary outcome measure was the absence of recurrent infection. Secondary outcomes included bone union, complications, the Association for the Advancement of Methods of Ilizarov (ASAMI) bone and functional classification scores, and any need for further unplanned surgery. Infection was eradicated in 76 cases (96.2%) with a mean follow-up duration of 40.8 months (range 6-131). All 3 infection recurrences occurred in the monofocal compression group. Following the initial Ilizarov method alone, union was achieved in 68 cases (86.1%) and was highest among the monofocal distraction (96.2%) and bifocal compression/distraction groups (93.8%). Monofocal compression achieved the lowest union rate (73.7%), significantly lower ASAMI scores, and a refracture rate of 31.6%. Bone transport secured union in 77.8% with a 44.4% unplanned reoperation rate. However, infection-free union was 100% after further treatment. Monofocal compression is not recommended for treating infected, mobile nonunions. Distraction (monofocal or bifocal) was effective and achieved higher rates of union and infection clearance. Level III.


Reprogramming of the ERRα and ERα target gene landscape triggers tamoxifen resistance in breast cancer.
Endocrine treatment regimens for breast cancer that target the estrogen receptor-α (ERα) are effective, but acquired resistance remains a limiting drawback. One mechanism of acquired resistance that has been hypothesized is functional substitution of the orphan receptor estrogen-related receptor-α (ERRα) for ERα. To examine this hypothesis, we analyzed ERRα and ERα in recurrent tamoxifen-resistant breast tumors and conducted a genome-wide target gene profiling analysis of MCF-7 breast cancer cell populations that were sensitive or resistant to tamoxifen treatment. This analysis uncovered a global redirection in the target genes controlled by ERα, ERRα, and their coactivator AIB1, defining a novel set of target genes in tamoxifen-resistant cells. Beyond differences in the ERα and ERRα target gene repertoires, both factors were engaged in similar pathobiologic processes relevant to acquired resistance. Functional analyses confirmed a requirement for ERRα in tamoxifen- and fulvestrant-resistant MCF-7 cells, with pharmacologic inhibition of ERRα sufficient to partly restore sensitivity to antiestrogens. In clinical specimens (n = 1041), increased expression of ERRα was associated with enhanced proliferation and aggressive disease parameters, including increased levels of p53 in ERα-positive cases. In addition, increased ERRα expression was linked to reduced overall survival in independent tamoxifen-treated patient cohorts. Taken together, our results suggest that ERα and ERRα cooperate to promote endocrine resistance, and they provide a rationale for the exploration of ERRα as a candidate drug target to treat endocrine-resistant breast cancer.


A Diagnostic Model for Kawasaki Disease Based on Immune Cell Characterization From Blood Samples.
Background: Kawasaki disease (KD) is the leading cause of acquired heart disease in children. However, distinguishing KD from febrile infections early in the disease course remains difficult. Our goal was to estimate the immune cell composition in KD patients and febrile controls (FC), and to develop a tool for KD diagnosis. Methods: We used a machine-learning algorithm, CIBERSORT, to estimate the proportions of 22 immune cell types based on blood samples from children with KD and FC. Using these immune cell compositions, a diagnostic score for predicting KD was then constructed based on LASSO regression for binary outcomes. Results: In the training set (n = 496), a model was fit which consisted of eight types of immune cells. The area under the curve (AUC) values for diagnosing KD in a held-out test set (n = 212) and an external validation set (n = 36) were 0.80 and 0.77, respectively. The most common cell types in KD blood samples were monocytes, neutrophils, CD4+-naïve and CD8+ T cells, and M0 macrophages. The diagnostic score was highly correlated to genes that had been previously reported as associated with KD, such as interleukins and chemokine receptors, and enriched in reported pathways, such as IL-6/JAK/STAT3 and TNFα signaling pathways. Conclusion: Altogether, the diagnostic score for predicting KD could potentially serve as a biomarker. Prospective studies could evaluate how incorporating the diagnostic score into a clinical algorithm would improve diagnostic accuracy further.


Phenotypic and functional analysis of natural killer cells in systemic lupus erythematosus patients.
Systemic lupus erythematosus (SLE) manifested with multiple autoantibodies production and glomerulonephritis, is the best example of systemic autoimmune diseases. To further elucidate the role of cytokines and the potential involvement of natural killer cells (NK cells) in the pathogenesis of lupus, phenotypic analysis of peripheral blood mononuclear cells (PBMC), NK cells cytotoxicity and cytokines production pattern of SLE patients and normal controls were examined. In addition, the effect of a variety of cytokines on anti-dsDNA antibodies production was also investigated. Our results showed that: (a) there was an increased percentage of memory T cells and decreased percentage of NK cells in SLE patients when compared to normal controls (p < 0.05); (b) a decreased production of cytokines like gamma-IFN in mitogen-stimulated PBMCs was also noted in SLE patients; (c) cytolytic activity of NK cells was markedly reduced in SLE patients (p < 0.05); (d) spontaneous secretion of IgG anti-dsDNA antibodies by B cells isolated from SLE patients could be inhibited by gamma-IFN, but not by IL-2, IL-4 and IL-5. These data suggested that decreased functions of NK cells and related type 1 T helper cells be closely related to the immune dysregulation and autoantibodies production in SLE.


Gene Expression Profiling and Heterogeneity of Nonspecific Orbital Inflammation Affecting the Lacrimal Gland.
Although a variety of well-characterized diseases, such as sarcoidosis and granulomatosis with polyangiitis, affect the lacrimal gland, many patients with dacryoadenitis are diagnosed as having nonspecific orbital inflammation (NSOI) on the basis of histology and systemic disease evaluation. The ability to further classify the disease in these patients should facilitate selection of effective therapies. To test the a priori hypothesis that gene expression profiles would complement clinical and histopathologic evaluations in identifying well-characterized diseases and in subdividing NSOI into clinically relevant groups. In this cohort study, gene expression levels in biopsy specimens of inflamed and control lacrimal glands were measured with microarrays. Stained sections of the same biopsy specimens were used for evaluation of histopathology. Tissue samples of patients were obtained from oculoplastic surgeons at 7 international centers representing 4 countries (United States, Saudi Arabia, Canada, and Taiwan). Gene expression analysis was done at Oregon Health & Science University. Participants were 48 patients, including 3 with granulomatosis with polyangiitis, 28 with NSOI, 7 with sarcoidosis, 4 with thyroid eye disease, and 6 healthy controls. The study dates were March 2012 to April 2017. The primary outcome was subdivision of biopsy specimens based on gene expression of a published list of approximately 40 differentially expressed transcripts in blood, lacrimal gland, and orbital adipose tissue from patients with sarcoidosis. Stained sections were evaluated for inflammation (none, mild, moderate, or marked), granulomas, nodules, or fibrosis by 2 independent ocular pathologists masked to the clinical diagnosis. Among 48 patients (mean [SD] age, 41.6 [19.0] years; 32 [67%] female), the mclust algorithm segregated the biopsy specimens into 4 subsets, with the differences illustrated by a heat map and multidimensional scaling plots. Most of the sarcoidosis biopsy specimens were in subset 1, which had the highest granuloma score. Three NSOI biopsy specimens in subset 1 had no apparent granulomas. Thirty-two percent (9 of 28) of the NSOI biopsy specimens could not be distinguished from biopsy specimens of healthy controls in subset 4, while other examples of NSOI tended to group with gene expression resembling granulomatosis with polyangiitis or thyroid eye disease. The 4 subsets could also be partially differentiated by their fibrosis, granulomas, and inflammation pathology scores but not their lymphoid nodule scores. Gene expression profiling discloses clear heterogeneity among patients with lacrimal inflammatory disease. Comparison of the expression profiles suggests that a subset of patients with nonspecific dacryoadenitis might have a limited form of sarcoidosis, while other patients with NSOI cannot be distinguished from healthy controls.


Identification of genomic and molecular traits that present therapeutic vulnerability to HGF-targeted therapy in glioblastoma.
Cancer is a complex disease with profound genomic alterations and extensive heterogeneity. Recent studies on large-scale genomics have shed light on the impact of core oncogenic pathways, which are frequently dysregulated in a wide spectrum of cancer types. Aberrant activation of the hepatocyte growth factor (HGF) signaling axis has been associated with promoting various oncogenic programs during tumor initiation, progression, and treatment resistance. As a result, HGF-targeted therapy has emerged as an attractive therapeutic approach. However, recent clinical trials involving HGF-targeted therapies have demonstrated rather disappointing results. Thus, an alternative, in-depth assessment of new patient stratification is necessary to shift the current clinical course. To address such challenges, we have evaluated the therapeutic efficacy of YYB-101, an HGF-neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. Furthermore, we performed genome and transcriptome analysis to determine genetic and molecular traits that exhibit therapeutic susceptibility to HGF-mediated therapy. We have identified several differentially expressed genes, including MET, KDR, and SOX3, which are associated with tumor invasiveness, malignancy, and unfavorable prognosis in glioblastoma patients. We also demonstrated the HGF-MET signaling axis as a key molecular determinant in GSC invasion, and we discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. Upregulation of MET and mesenchymal cellular state are essential in generating HGF-mediated therapeutic responses. Our results provide an important framework for evaluating HGF-targeted therapy in future clinical settings.