Giving heart.
A new procedure for donating hearts and other organs is saving lives. But for some it challenges the definition of death.


Metabonomics reveals altered metabolites related to inflammation and energy utilization at recovery of cystic fibrosis lung exacerbation.
Cystic fibrosis lung disease is characterized by chronic bacterial infections in the setting of mucus abnormalities. Patients experience periodic exacerbations that manifest with increased respiratory symptoms that require intensification of therapy with enhanced airway clearance and intravenous (IV) antibiotics. In an observational study we tested if the profile of metabolites in serum distinguished the pre-from post-exacerbation state and which systemically measurable pathways were affected during the process to recovery. Serum collected within 48 h of start and completion, respectively of IV antibiotics was collected from people with CF ages 6-30 years. Three day food records were collected prior to each sample. To reduce variation between subjects only subjects who had pancreatic insufficiency, had similar CF mutations, and did not have CF liver disease or diabetes were included. Metabolomic profiling was conducted by Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy with metabolites being identified based on retention time/index, mass to charge ratio and comparison to known compounds. Biostatistical analyses used paired t-test with correction for multiple comparisons and orthogonal partial least square discriminant analysis. Thirty subjects (20 male) with a mean ± SEM age of 15.3 ± 1.2 years participated, 17 of whom had matched food-records. Lung function was significantly improved post-therapy compared to pre-therapy, (mean ± SEM) 75 ± 4% vs. 68 ± 4% predicted (n = 26). Serum metabonomics showed distinction of the pre-vs. post-therapy groups with 123 compounds contributing to the differentiation pre-versus post-antibiotics by multiple biostatistical analyses. Compounds and pathways affected included bile acids and microbial derived amino acid metabolites, increases in lipid classes of the glycerophospholipid, glycerolipids, cholesterol, phopsholipids, and most pronounced, the class of sphingolipids. Changes in n6/n3 fatty acids, decreased polyamines but increased metabolites in the nitric oxide pathway, and changes in the tryptophan-kynurenine pathway indicated decreased inflammation at resolution of exacerbation. Changes in serum metabolites that distinguished CF pulmonary exacerbation vs. resolution of symptoms showed evidence of decreased inflammation and improvement from a catabolic state.


Regulation of bone mineral density in morbidly obese women: a cross-sectional study in two cohorts before and after bypass surgery.
The mechanisms by which increased body weight influence bone mass density (BMD) are still unknown. The aim of our study was to analyze the relationship between anthropometric and body composition variables, insulin growth factor-I (IGF-I), adiponectin and soluble tumor necrosis factor-alpha receptors (sTNFR) 1 and 2 with BMD in two cohorts of morbid obese patients, before and after bypass surgery. The first cohort included 25 women aged 48+/-7.6 years studied before bypass surgery. The second included 41 women aged 46+/-9.2 years, 12 months after surgery. We studied anthropometric variables obtained from whole body DEXA composition analysis. Serum IGF-I, intact serum parathyroid hormone, 25-hydroxivitamin D3, plasma adiponectin concentrations, sTNFR1, sTNFR2 concentrations were measured. In the first cohort, the BMI was 44.5+/-3.6 kg/m2, parathyroid hormone, IGF-I, and adiponectin concentrations were lower, and sTNFR1 concentrations were higher than in the second cohort. In the multiple regression analysis, BMD remained significantly associated with body fat percentage (beta -0.154, p=0.01), lean mass (beta 0.057, p=0.016) and phosphate concentration (beta 0.225, p=0.05). In the second cohort, BMI was 31+/-5.1 kg/m2. In the multiple regression analysis, BMD remained significantly associated with lean mass (beta 0.006, p=0.03). The inverse correlation found between body fat and BMD in the first cohort indicates morbid obesity increases the risk of osteoporosis and we found a positive correlation with lean and fat mass before bariatric surgery and with lean mass after bypass surgery.


Relationship of pertussis immunization to the onset of epilepsy, febrile convulsions and central nervous system infections: a retrospective epidemiologic study.
A change in the pertussis immunization schedule in Denmark allowed a retrospective study examining the relationship of the time of onset of selected neurologic disorders with the time of pertussis immunization in two core cohorts of children. Records of 2,199 children with febrile seizures were reviewed and a significant association between first febrile seizures and the scheduled age of pertussis immunization was noted (p = 0.004). The occurrence of epilepsy and CNS infections did not appear to be related to the time of pertussis immunization.


[Alloreactive helper T cell responses in kidney transplant patients].
To study allo-specific immune responses of CD4+ helper T lymphocytes (Th) in patients with long-term and well-functioning renal grafts. Peripheral blood mononuclear cells (PBMC) were collected from 16 patients with long-term (3-15 years) and well-functioning live-related renal grafts. Donor-specific Th precursor (Th-p) frequencies in the PBMC were determined by limiting dilution analysis(LDA). Eight out of the 16 patients showed donor-specific hyporesponsiveness. Donor-specific Th-p from the other 8 patients was susceptible to anti-CD4 inhibition. Some of the patients carrying long-term and well-functioning renal grafts had become immunologic tolerant to donor cells. Donor-specific Th-p from patients who did not show donor-specific hyporesponsiveness were of low avidity type.


Pituitary adenoma presenting as painful intermittent third nerve palsy.
We report the case of a woman with short nocturnal attacks of peri- and retro-orbital pain, diplopia, ptosis, rhinorrhea and lacrimation of five months evolution. Neurological examination was normal between attacks. The latter presented with partial third nerve palsy, which finally became complete and permanent. Brain CT showed a sellar and supraseller tumor with parasellar extension to the right side. We stress the atypical clinical presentation and evolution of this case, and discuss its pathophysiology.


A randomised phase II trial of Stereotactic Ablative Fractionated radiotherapy versus Radiosurgery for Oligometastatic Neoplasia to the lung (TROG 13.01 SAFRON II).
Stereotactic ablative body radiotherapy (SABR) is emerging as a non-invasive method for precision irradiation of lung tumours. However, the ideal dose/fractionation schedule is not yet known. The primary purpose of this study is to assess safety and efficacy profile of single and multi-fraction SABR in the context of pulmonary oligometastases. The TROG 13.01/ALTG 13.001 clinical trial is a multicentre unblinded randomised phase II study. Eligible patients have up to three metastases to the lung from any non-haematological malignancy, each < 5 cm in size, non-central targets, and have all primary and extrathoracic disease controlled with local therapies. Patients are randomised 1:1 to a single fraction of 28Gy versus 48Gy in four fractions of SABR. The primary objective is to assess the safety of each treatment arm, with secondary objectives including assessment of quality of life, local efficacy, resource use and costs, overall and disease free survival and time to distant failure. Outcomes will be stratified by number of metastases and origin of the primary disease (colorectal versus non-colorectal primary). Planned substudies include an assessment of the impact of online e-Learning platforms for lung SABR and assessment of the effect of SABR fractionation on the immune responses. A total of 84 patients are required to complete the study. Fractionation schedules have not yet been investigated in a randomised fashion in the setting of oligometastatic disease. Assuming the likelihood of similar clinical efficacy in both arms, the present study design allows for exploration of the hypothesis that cost implications of managing potentially increased toxicities from single fraction SABR will be outweighed by costs associated with delivering multiple-fraction SABR. ACTRN12613001157763 , registered 17th October 2013.


Minimal invasive biopsy of intraconal expansion by PET/CT/MRI image-guided navigation: a new method.
Intraorbital tumours are often undetected for a long period and may lead to compression of the optic nerve and loss of vision. Although CT, MRI's and ultrasound can help in determining the probable diagnosis, most orbital tumours are only diagnosed by surgical biopsy. In intraconal lesions this may prove especially difficult as the expansions are situated next to sensitive anatomical structures (eye bulb, optic nerve). In search of a minimally invasive access to the intraconal region, we describe a method of a three-dimensional, image-guided biopsy of orbital tumours using a combined technique of hardware fusion between (18)F-FDG Positron Emission Tomography ((18)F-FDG PET), magnetic resonance imaging (MRI) and Computed Tomography (CT). We present 6 patients with a total of 7 intraorbital lesions, all of them suffering from diplopia and/or exophthalmos. There were 3 female and 3 male patients. The patients age ranged from 20 to 75 years. One of the patients showed beginning loss of vision. Another of the patients had lesions in both orbits. The decision to obtain image-guided needle biopsies for treatment planning was discussed and decided at an interdisciplinary board comprising other sub-specialities (ophthalmology, neurosurgery, maxillofacial surgery, ENT, plastic surgery). All patients underwent 3D imaging preoperatively ((18)F-FDG PET/CT or (18)F-FDG PET/CT plus MRI). Data was transferred to 3D navigation system. Access to the lesions was planned preoperatively on a workstation monitor. Biopsy-needles were then calibrated intraoperatively and all patients underwent three-dimensional image-guided needle biopsies under general anaesthesia. 7 biopsies were performed. The histologic subtype was idiopathic orbital inflammation in 2 lesions, lymphoma in 2, Merkel cell carcinoma in 1, hamartoma in 1 and 1 malignant melanoma. The different pathologies were subsequently treated in consideration of the actual state of the art. In cases where surgical removal of the lesion was performed the histological diagnosis was confirmed in all cases. There is a wide range of possible treatment modalities for orbital tumours depending on the nature of the lesion. Histological diagnosis is mandatory to select the proper management and operation. The presented method allows minimal-invasive biopsy even in deep intraconal lesions, enabling the surgeon to spare critical anatomical structures. Vascular lesions such as cavernous haemangioma, tumour of the lacrimal gland or dermoid cysts present a contraindication and have to be excluded.


Crystal structure of 1,1',2,2',4,4'-hexa-iso-propyl-magnesocene.
The title compound, 3Cp2Mg or [Mg(C14H23)2], was synthesized from the cor-res-ponding triiso-propyl-cyclo-penta-diene by treatment with n-butyl-sec-butyl-magnesium. The structural characterization by single-crystal X-ray diffraction revealed that the compound crystallizes in the triclinic space group P with half a mol-ecule per asymmetric unit and a staggered arrangement of the cyclo-penta-dienide ligands.


DNMT3A Haploinsufficiency Results in Behavioral Deficits and Global Epigenomic Dysregulation Shared across Neurodevelopmental Disorders.
Mutations in DNA methyltransferase 3A (DNMT3A) have been detected in autism and related disorders, but how these mutations disrupt nervous system function is unknown. Here, we define the effects of DNMT3A mutations associated with neurodevelopmental disease. We show that diverse mutations affect different aspects of protein activity but lead to shared deficiencies in neuronal DNA methylation. Heterozygous DNMT3A knockout mice mimicking DNMT3A disruption in disease display growth and behavioral alterations consistent with human phenotypes. Strikingly, in these mice, we detect global disruption of neuron-enriched non-CG DNA methylation, a binding site for the Rett syndrome protein MeCP2. Loss of this methylation leads to enhancer and gene dysregulation that overlaps with models of Rett syndrome and autism. These findings define the effects of DNMT3A haploinsufficiency in the brain and uncover disruption of the non-CG methylation pathway as a convergence point across neurodevelopmental disorders.


Time series analysis of cutaneous leishmaniasis incidence in Shahroud based on ARIMA model.
Leishmaniasis is a zoonotic disease and Iran is one of the ten countries with has the highest estimated cases of leishmaniasis. This study aimed to determine the time trend of cutaneous leishmaniasis (CL) incidence using the ARIMA model in Shahroud County, Semnan, Iran. In this study, 725 patients with leishmaniasis were selected in the Health Centers of Shahroud during 2009-2020. Demographic characteristics including; history of traveling, history of leishmaniasis, co-morbidity of other family members, history of treatment, underlying disease, and diagnostic measures were collected using the patients' information listed in the Health Ministry portal. The Box-Jenkins approach was applied to fit the SARIMA model for CL incidence from 2009 to 2020. All statistical analyses were done by using Minitab software version 14. The mean age of patients was 28.2 ± 21.3 years. The highest and lowest annual incidence of leishmaniasis were in 2018 and 2017, respectively. The average ten-year incidence was 132 per 100,000 population. The highest and lowest incidence of the disease were 592 and 195 for 100,000 population in the years 2011 and 2017, respectively. The best model was SARIMA (3,1,1) (0,1,2)4 (AIC: 324.3, BIC: 317.7 and RMSE: 0.167). This study suggested that time series models would be useful tools for predicting cutaneous leishmaniasis incidence trends; therefore, the SARIMA model could be used in planning public health programs. It will predict the course of the disease in the coming years and run the solutions to reduce the cases of the disease.


Sham feeding experience produces a conditioned increase of meal size.
The effect on intake of reversing the flavors and locations that had been associated with sham feeding and real feeding was measured in two experiments. Rats were equipped with chronic gastric cannulas to permit sham feeding. Flavors and locations were associated with a real meal of milk or with sham feeding the same volume of flavored milk or with sham feeding about six times as much milk. In both experiments, the flavors and locations with sham feeding produced a conditioned increase in meal size during real feeding. This conditioned increase in meal size appeared to be primarily due to a conditioned decrease in the satiating potency of the milk because it was dissociated from a conditioned increase in preference measured in a four-minute choice test.


Non-seminomatous germ cell tumors of the testis. Analysis of CEA production in primary tumors and in retroperitoneal lymph node metastases after PVB chemotherapy.
In the present investigation we compared CEA immunoperoxidase staining in testicular tumors (before PVB chemotherapy) and retroperitoneal tumors (after PVB chemotherapy) with CEA levels in the cyst fluid of retroperitoneal mature teratoma and in the patients' serum. CEA had no value as a serum tumor marker since serum CEA elevations were not associated with tumor activity. Only one elevated CEA level after chemotherapy was associated with bleomycin pneumonitis. Despite normal serum levels, CEA was localized immunohistochemically in yolk sac tumor and mature teratoma in the primary tumors and in retroperitoneal mature teratoma following PVB chemotherapy. The presence of CEA in cells lining cystic mature teratoma was associated with high CEA levels in the cyst fluid.


Surgical treatment for bilateral carotid arterial stenosis.
Carotid endarterectomy (CEA) is a beneficial procedure for patients with high-grade carotid stenosis. However, patients with bilateral carotid stenosis have a higher surgical risk during CEA. Since the introduction of carotid stenting (CAS) may decrease some of the surgical complications of CEA, a combined treatment using CEA and CAS may be favorable for patients with bilateral carotid stenosis. We analyzed the safety and efficacy of this treatment strategy. Eighteen patients with bilateral carotid stenosis were treated from January 2000. Bilateral CEA was performed on the first two patients, CAS then CEA of contra-lateral symptomatic side in 13 patients, and bilateral CAS in three patients. There were no perioperative neurological complications or strokes during the follow-up period (mean 17 months). The combined treatment of CAS and CEA was a safe and effective strategy for bilateral carotid stenosis.


Age at menopause as a marker of reproductive ageing.
Ages of menopause and of the preceding reproductive events such as the beginning of subfertility and infertility, are likely to be dictated by the process of follicle depletion leading to loss of oocyte quantity and quality. To some extent this process is influenced by lifestyle factors like smoking, and possibly also by the use of oral contraceptives. Genetic factors and possibly also events during intrauterine life, probably play a more important role in the age-dependent decrease of female fertility.


Antimineralization treatment and patient-prosthesis mismatch are major determinants of the onset and incidence of structural valve degeneration in bioprosthetic heart valves.
We examined the influence of multiple valve-related parameters on the onset and incidence of valve degeneration in aortic bioprostheses through detailed echocardiographic follow-up. In 648 patients (mean age, 73.8 ± 4.9 years) receiving an aortic valve bioprosthesis, long-term clinical (mean, 7.5 ± 3.2 years) and echocardiographic (mean, 6.5 ± 3.4 years) follow-up were performed. The occurrence of signs of structural valve degeneration (stenosis type and regurgitation type) was studied through multivariate analysis, including tissue origin, design and label size of the prosthesis, effective orifice area index (EOAi), patient-prosthesis mismatch (PPM; EOAi <0.85 cm(2)/m(2)), and antimineralization treatment. Structural valve degeneration (SVD) was diagnosed in 12.6% of patients. In 7.6%, it was of the stenosis type (S-SVD); in 5%, it was the regurgitation type (R-SVD). The absence of antimineralization treatment is an independent predictor of SVD, S-SVD, and R-SVD. Patient-prosthesis mismatch is an independent predictor of SVD and S-SVD, but not of R-SVD. Patients receiving a nontreated valve show a freedom of SVD at 10 years follow-up of 70.1 ± 4.3% versus 90.9 ± 3.6% in patients receiving a treated valve (P < .0001). Patients having PPM and receiving a nontreated valve show a freedom of SVD at 10 years of follow-up of only 59.8 ± 7.0% versus 88.7 ± 3.6% in patients also having PPM but receiving a treated valve (P < .0001). In patients not having PPM, the corresponding values were 78.0 ± 4.3% and 92.7 ± 3.4% for nontreated versus treated valves respectively (P = .01). Antimineralization treatment of bioprosthetic heart valves is effective and reduces the incidence of SVD significantly. Because valve type and size are determined at the moment of implantation, the surgeon carries an important responsibility in protecting the patient from valve degeneration.


The joint effects of physical activity and air pollution on type 2 diabetes in older adults.
Older adults with type 2 diabetes are at higher risk of developing common geriatric syndromes and have a lower quality of life. To prevent type 2 diabetes in older adults, it's unclear whether the health benefits of physical activity (PA) will be influenced by the harms caused by increased exposure to air pollution during PA, especially in developing countries with severe air pollution problem. We aimed to investigate the joint effects of PA and long-term exposure to air pollution on the type 2 diabetes in older adults from China. This cross-sectional study was based on the China Multi-Ethnic cohort (CMEC) study. The metabolic equivalent of PA was calculated according to the PA scale during the CMEC baseline survey. High resolution air pollution datasets (PM10, PM2.5 and PM1) were collected from open products. The joint effects were assessed by the marginal structural mean model with generalized propensity score. A total of 36,562 participants aged 50 to 79 years were included in the study. The prevalence of type 2 diabetes was 10.88%. The mean (SD) level of PA was 24.93 (18.60) MET-h/d, and the mean (SD) level of PM10, PM2.5, and PM1 were 70.00 (23.32) µg/m3, 40.45 (15.66) µg/m3 and 27.62 (6.51) µg/m3, respectively. With PM10 < 92 µg/m3, PM2.5 < 61 µg/m3, and PM1 < 36 µg/m3, the benefit effects of PA on type 2 diabetes was significantly greater than the harms due to PMs when PA levels were roughly below 80 MET-h/d. With PM10 ≥ 92 µg/m3, PM2.5 ≥ 61 µg/m3, and PM1 ≥ 36 µg/m3, the odds ratio (OR) first decreased and then rose rapidly with confidence intervals progressively greater than 1 and break-even points close to or even below 40 MET-h/d. Our findings implied that for the prevention of type 2 diabetes in older adults, the PA health benefits outweighed the harms of air pollution except in extreme air pollution situations, and suggested that when the air quality of residence is severe, the PA levels should ideally not exceed 40 MET-h/d.


Pattern of prenatal care utilization in Tehran: A population based longitudinal study.
To assess the pattern of prenatal care utilization in Tehran in 2015. A total of 2005 pregnant women who lived in the catchment area of the study participated. Participants were followed from the sixth week of pregnancy until birth. Data were collected either through interviews or from written medical records. More than 95% of mothers completed all eight prenatal care visits. Some 99% of mothers completed at least four visits. The prenatal care utilization was equal among all different socio-economic regions in Tehran. Gynecologists were the main healthcare providers in prenatal care visits. In addition, 75% of mothers went to gynecologists at their office or in hospitals for ordering first-trimester screening tests. Prenatal care utilization complied with both national guidelines and recommendations of World Health Organization regarding the number of conducted visits. Equal accessibility and availability of prenatal care service despite the socio-economical differences of families is suggestive of equity and social justice in terms of providing health services in both public and private sectors. Among healthcare providers, gynecologists were the main healthcare provider for prenatal care visits.


Plasma volume nomograms for use in therapeutic plasma exchange.
Nomograms have been developed for the convenient estimation of the plasma volumes of patients undergoing therapeutic plasma exchange (TPE), based on equations employing height, body weight, and hematocrit. These nomograms are offered as an aid to prescribing continuous-flow TPE procedure exchange volumes.


Serum levels of leptin, adiponectin and resistin in patients with ankylosing spondylitis: A systematic review and meta-analysis.
Various studies have researched the serum levels of leptin, adiponectin and resistin in patients with ankylosing spondylitis (AS), but the results were inconclusive. The purpose of this study was to systematically evaluate the correlations between serum levels of these adipokines and AS. Electronic databases were retrieved to search relevant publications. Pooled standard mean difference (SMD) with 95% confidence interval (CI) was calculated by the random-effect model. Cochrane Q test and I2 statistic were used to test heterogeneity. Subgroup analysis and meta-regression were applied to assess possible sources of heterogeneity. A total of sixteen articles were included. Meta-analysis results indicated no statistical differences between AS patients and normal controls in serum leptin and adiponectin levels (leptin, SMD=0.829, 95% CI=-0.116 to 1.774, p=0.085; adiponectin, SMD=0.460, 95% CI=-0.004 to 0.924, p=0.052). However, AS patients had higher serum resistin levels than controls (SMD=1.413, 95% CI=0.294 to 2.531, p=0.013). Subgroup analyses suggested that Asian and African AS patients as well as patients aged <40years had higher serum leptin and resistin levels when compared to controls. Serum adiponectin levels were higher in AS patients compared to controls in subgroup of age ≥40, and serum resistin levels in subgroup of BMI ≥25. Measurement method was a source of heterogeneity for resistin. Publication bias was not observed and the robustness of study results was confirmed by sensitivity analysis. Serum resistin, but not leptin or adiponectin levels may be closely associated with the development of AS.


TET1 mutations as a predictive biomarker for immune checkpoint inhibitors in colon adenocarcinoma.
The ten-eleven translocation 1 (TET1), which is essential for active DNA demethylation, plays a multifaceted role in the pathogenesis of colorectal cancer. The study has demonstrated the association of TET1 mutations with a high response to immune checkpoint inhibitors (ICIs) in diverse cancers. However, the relationship between TET1 mutations and the response to ICIs in colon cancer is still lacking. The prognosis, predictive markers, immune characteristics, mutation number of DNA damage repair (DDR) pathways, pathway enrichment, and drug sensitivity conditions were all compared between TET1-mutated and wild-type patients with colon adenocarcinoma (COAD). The overall survival of patients with TET1 mutations in the ICI-treated cohort was significantly longer than those without (p = 0.0059). Compared with the wild-type patients, TET1-mutated patients had higher tumor mutational burden and neoantigen load, enhanced abundance of tumor-infiltrating immune cells, increased expression of immune-related genes, and mutation number of DDR pathways. Additionally, the patients with TET1 mutations were found to be more sensitive to lapatinib and 5-fluorouracil. These findings suggest that TET1 mutations may serve as a potential biomarker for the response to ICIs in COAD patients.


Author Correction: Genome assembly and annotation of Meloidogyne enterolobii, an emerging parthenogenetic root-knot nematode.
A Correction to this paper has been published: https://doi.org/10.1038/s41597-020-00747-0.


Clinical utility of bronchoalveolar lavage in the assessment of interstitial lung disease.
Bronchoalveolar lavage is a new bronchoscopic technique which permits assessment of changes in the cellular traffic in the alveolar spaces. One hundred and fourteen patients underwent bronchoalveolar lavage at the Mayo Clinic during a 16-month period. Whereas control subjects had a predominance of alveolar macrophages (93 +/- 1%) with few lymphocytes (5 +/- 1%), 35 subjects with idiopathic pulmonary fibrosis had a marked increase in the number of polymorphonuclear leukocytes (17 +/- 2%), and 32 subjects with sarcoidosis had a marked increase in the number of lymphocytes (26 +/- 2%). Further identification of these lymphocytes by the immunofluorescent detection of cell-surface antigens revealed the lymphocytes, in all 13 cases of sarcoidosis examined, to be from the T-helper subclass. Bronchoalveolar lavage represents an easy method to monitor the "alveolitis" in these disorders, and offers promise as a quantitative means by which to assess disease "activity" as well as the response to therapy.


Dynamic coordination of macronutrient balance during infant growth: insights from a mathematical model.
Complex dynamic changes in body composition, dietary intake, energy expenditure, and macronutrient oxidation occur during infant growth. Although previous investigators have focused on energy requirements for normal growth, little is known about the dynamic coordination of macronutrient balance. Our objective was to develop a mathematical model of the dynamic relations between diet, macronutrient oxidation, and energy expenditure during normal infant growth. We developed a mathematical model that integrates longitudinal data on changes of body composition and carbon dioxide production determined with the doubly labeled water method to calculate both energy intake requirements and macronutrient oxidation rates during normal infant growth. The calculated fat oxidation rate was initially <20 kcal x kg(-1) x d(-1), despite the consumption of >60 kcal x kg(-1) x d(-1) of dietary fat. This discrepancy was maintained until approximately 6 mo, after which fat intake was only slightly greater than fat oxidation. Nonfat oxidation closely followed nonfat dietary intake for the duration of the period studied. Model calculations of the energy intake requirements for normal growth were slightly lower than previous estimates. The calculations were robust to variations of body weight, body composition, and diet composition input data, but depended sensitively on variations of carbon dioxide production data. Our model presents a dynamic picture of how macronutrient oxidation adapts in concert with dietary changes and energy expenditure to give rise to normal tissue deposition. The model integrates a variety of data in a self-consistent way, simulating the complex metabolic adaptations occurring during normal growth while extracting important physiologic information from the data that would otherwise be unavailable.


Dietary patterns, brain morphology and cognitive performance in children: Results from a prospective population-based study.
Dietary patterns in childhood have been associated with child neurodevelopment and cognitive performance, while the underlying neurobiological pathway is unclear. We aimed to examine associations of dietary patterns in infancy and mid-childhood with pre-adolescent brain morphology, and whether diet-related differences in brain morphology mediate the relation with cognition. We included 1888 and 2326 children with dietary data at age one or eight years, respectively, and structural neuroimaging at age 10 years in the Generation R Study. Measures of brain morphology were obtained using magnetic resonance imaging. Dietary intake was assessed using food-frequency questionnaires, from which we derived diet quality scores based on dietary guidelines and dietary patterns using principal component analyses. Full scale IQ was estimated using the Wechsler Intelligence Scale for Children-Fifth Edition at age 13 years. Children with higher adherence to a dietary pattern labeled as 'Snack, processed foods and sugar' at age one year had smaller cerebral white matter volume at age 10 (B = -4.3, 95%CI -6.9, -1.7). At age eight years, higher adherence to a 'Whole grains, soft fats and dairy' pattern was associated with a larger total brain (B = 8.9, 95%CI 4.5, 13.3), and larger cerebral gray matter volumes at age 10 (B = 5.2, 95%CI 2.9, 7.5). Children with higher diet quality and better adherence to a 'Whole grains, soft fats and dairy' dietary pattern at age eight showed greater brain gyrification and larger surface area, clustered primarily in the dorsolateral prefrontal cortex. These observed differences in brain morphology mediated associations between dietary patterns and IQ. In conclusion, dietary patterns in early- and mid-childhood are associated with differences in brain morphology which may explain the relation between dietary patterns and neurodevelopment in children.


Immunopathologic studies of renal glomerular change in liver cirrhosis with special reference to its pathogenesis.
The kidneys from 62 proven liver cirrhosis cases were examined by immunofluorescence (IF), and 94% of the cases were positive for some immune reactants deposition. Combined deposition of immunoglobulin(s), both or each one of C1q and C4, and further with C3 were observed in about 70% of all IF positive cases. The morphological alterations of the glomeruli correlated with the intensities of regional immune reactants depositions. Guinea pig C3 was frequently activated in vitro on the glomeruli of these cases. Immune reactants depositions in the glomeruli appeared to form immune complex locally. Smooth muscle and liver cell antigens in the immune complex at the glomeruli were examined by indirect method of IF using monospecific antibodies and positive cases concerning each antigen were found in about 1/3 of the kidneys from 21 liver cirrhosis cases. These facts suggest that the high rate of the occurrence of immune complex deposition type glomerulo-nephritis may be due to the glomerular deposition of some autoantigen-antibody complexes including smooth muscle and liver cell antigens.


Hirsutine, a novel megakaryopoiesis inducer, promotes thrombopoiesis via MEK/ERK/FOG1/TAL1 signaling.
Thrombocytopenia (TP) remains a challenge in clinical hematology. TP may have serious consequences, such as recurrent skin and mucosal bleeding and increased risk of intracranial and internal organ hemorrhage. However, effective and safe therapeutic drugs for the long-term management of TP are still lacking. This study aimed to identify more effective active compounds for TP therapy. Liquid chromatography-mass spectrometry-nuclear magnetic resonance analysis was used to confirm the medicinal species and chemical structure of Hirsutine (HS). The proliferation of HS was examined by Cell Counting Kit (CCK-8) assay on cells lines. The effect of HS on megakaryocyte differentiation was analyzed by evaluating the expression of CD41, CD42b, and DNA ploidy via flow cytometry (FCM). The morphology of megakaryocytes and intermediate cells was observed using an optical microscope. K562 cells were then stained with Giemsa and benzidine. qRT-PCR was used to examine the mRNA expression of GATA-1, GATA-2, FOG-1, TAL-1, RUNX-1, NF-E2, and KLF-1 in K562 cells. Protein levels of the transcription factors were analyzed by western blotting. An MEK inhibitor was used to verify the relationship between the MEK/ERK signaling pathway and CD41/CD42b (FCM), FOG-1, and TAL-1. The Kunming thrombocytopenia mouse model was established by X-ray irradiation (4 Gy) and used to test HS activity and related hematopoietic organ index in vivo. Finally, computer simulations of molecular docking were used to predict the binding energies between HS-MEK and HS-ERK. We preliminarily identified HS by screening a plant-sourced compound library for natural compounds with megakaryocytic differentiation and maturation (MKD/MKM)-promoting activity. We found that HS not only enhanced MKD/MKM of K562 and Meg01 cells, but also suppressed the decline of peripheral platelet levels in X-ray-induced myelosuppressive mice. In addition, HS promoted MKD via activation of MEK-ERK-FOG1/TAL1 signaling, which may be the key molecular mechanism of HS action in TP treatment. Molecular docking simulations further verified that HS targets the signaling protein MEK with high-affinity. In this study, we report for the first time that hirsutine boosts MKD/MKM through the MEK/ERK/FOG1/TAL1 signaling pathway and thus represents a promising treatment option for TP.


Large-area unmodified superhydrophobic copper substrate can be prepared by an electroless replacement deposition.
Using an electroless replacement deposition method, large-area superhydrophobic metal substrate could be obtained. The superhydrophobic surfaces were prepared via a replacement reaction between copper substrate and HAuCl(4) solution. The roughness of the copper substrate increased much after the replacement reaction. X-ray powder diffraction (XRD) pattern and energy dispersive X-ray (EDX) spectroscopy have proved that gold, CuCl and Cu(2)O formed on the surface of copper substrate after the replacement reaction. The surface showed remarkable superhydrophobic properties with a contact angle higher than 150 degrees without any modification with a self-assembled monolayer (SAM) of long chain thiol or perfluoro molecules.


Diana Scully's Legacy: Reflections From Former Students.
Six former students of Dr. Diana Scully share their memories of her and reflections on how she influenced them personally and professionally.


The effect of implantable collamer Lens V4c on ocular biometric measurements and intraocular lens power calculation based on Pentacam-AXL and IOLMaster 500.
To investigate the possible effect of implantable collamer lens (ICL) V4c on ocular biometric measurements by a new biometer Pentacam-AXL and partial coherence interferometry (PCI)-based IOLMaster 500 and intraocular lens power calculation using fourth-generation formula. We retrospectively enrolled patients who underwent ICL (EVO-V4c, STAAR Surgical Co. Nidau, Switzerland) implantation surgery from September 2020 to November 2021. The Pentacam-AXL and IOLMaster 500 biometers were used to measure axial length (AL), anterior chamber depth (ACD), keratometry (K), white to white (WTW), and central corneal thickness (CCT) values before and at least 2 months after ICL V4c implantation. The IOL power was calculated using the Barrett Universal II formula. The study included 45 eyes in 28 patients. There was a significant increase in ALs (average 0.03 ± 0.07 mm, p = 0.01) and a significant decrease of ACDs (average 0.19 ± 0.17 mm, p < 0.001) based on Pentacam-AXL. Similar changes in ALs and ACDs were also found in IOLMaster 500. In addition, the difference in WTWs in the two devices and that of CCTs in Pentacam-AXL were statistically significant. However, the preoperative and postoperative K1 and K2 were separately comparable using either device. The IOL power calculated by the Barrett Universal II formula did not change significantly either by the software built in Pentacam-AXL or by manually putting the parameters of the IOLMaster 500 into the formula manually (p = 0.058, p = 0.675, respectively). Ocular parameters including ALs, ACDs, WTWs, and CCTs using a new Pentacam-AXL and standard PCI-based IOLMaster 500 changed significantly before and after the ICL V4c implantation, while IOL power prediction using the Barrett Universal II formula was little affected.


Molecular dynamic simulations of diacridine binding to DNA: Indications that C6 diacridine can bisintercalate spanning two base pairs.
Dimers of 9-aminoacridine linked via the 9-amino group with polymethylene chains, termed diacridines, are known to bisintercalate into DNA when the linker comprises 6 or more methylene units. There are no literature reports of crystal or NMR solution structures for bisintercalated diacridine-DNA complexes, and the issue of the structure of the C6 ([CH2 ]n linker where n = 6) diacridine complex remains unresolved. Previously, based on simple geometric considerations, it was proposed that C6 diacridine could only span a single base pair, which requires that its bifunctional reaction violates the widely-observed "neighbor exclusion principle" where bound intercalators are separated by at least 2 base pairs. Here we have explored the structure of diacridine-DNA complexes using unrestrained molecular dynamics in explicit solvent using the parmbsc0 forcefield in AMBER14. We studied the C4 to C8 dimers, intercalated via both the minor and major DNA grooves, to a variety of nucleotide sequences. We find that C6, C7, and C8 diacridine are able to form 2 base pair bisintercalated complexes from either groove, whereas the C4 and C5 homologues cannot. We conclude that C6 diacridine does have the capacity to bisintercalate without violating neighbor exclusion, and that the previous proposed binding model needs revision.


Prediction and assessment of acute encephalopathy syndromes immediately after febrile status epilepticus.
This study aimed to predict occurrence of acute encephalopathy syndromes (AES) immediately after febrile status epilepticus in children and to explore the usefulness of electroencephalogram (EEG) in the early diagnosis of AES. We reviewed data from 120 children who had febrile status epilepticus lasting >30 min and were admitted to our hospital between 2012 and 2019. AES with reduced diffusion on brain magnetic resonance imaging was diagnosed in 11 of these patients. EEG and serum cytokines were analyzed in AES patients. Clinical symptoms and laboratory data were compared between AES and non-AES patients. Logistic regression analysis was used to identify early predictors of AES. Multivariate logistic regression identified serum creatinine as a risk factor for developing AES. A scoring model to predict AES in the post-ictal phase that included serum creatinine, sodium, aspartate aminotransferase, and glucose was developed, and a score of 2 or more predicted AES with sensitivity of 90.9% and specificity of 71.6%. Post-ictus EEG revealed non-convulsive status epilepticus in four of the seven AES patients. Children with febrile status epilepticus may be at risk of developing severe AES with reduced diffusion. Post-ictus EEG and laboratory data can predict the occurrence of severe AES.


Contamination and cancer risk assessment of polycyclic aromatic hydrocarbons (PAHs) in urban dust from different land-uses in the most populated city of Iran.
Due to population growth and the considerable increase in usage of the resources, Human environment quality has been highly threatened by pollutants in recent decades. Polycyclic aromatic hydrocarbons (PAHs) are widespread, persistent organic pollutants which are of great concern due to their carcinogenicity. The present study is the first investigation that assesses contamination, sources and cancer risk of 16 priority PAHs proposed by US EPA in urban dust samples (n = 80) taken in different land-uses of Tehran metropolis, the capital of Iran. Gas chromatography-mass spectrometry (GC-MS) is used to measure PAHs concentrations. The results showed that the average concentration of the total 16 PAHs and the average Benzo[a]pyrene total potency equivalency were 566 μg kg-1 dry weight and 36.4 μg kg-1, respectively. In the commercial and residential land-uses high molecular weight (HMW) PAHs were dominated, whereas in green lands, light molecular weight (LMW) PAHs showed maximum contribution. The highest concentration of total PAHs were observed in the commercial areas due to limited air circulation and heavy traffic loads. Incremental Lifetime Cancer Risk (ILCR) model was applied to evaluate the cancer risk of exposure to PAHs contaminated dust. Based on the results, Tehran's residents (children and adults) in various land-uses except for green lands, are in high potential cancer risk of PAHs via ingestion and dermal contact exposure routs. Ace, Chr, Pyr, and BghiP which are indicators of traffic emissions, were found to be predominant PAH contributors in urban dust of commercial areas. Also, Ace, Fl, Phe, and BghiP which are derived from fossil fuel combustion, were mainly observed in the industrial land-use. Based on the results of factor analysis and diagnostic ratios, Diesel/gasoline engine vehicular emissions and combustion were found to be the main sources of PAHs in urban dust of Tehran.


Effects of photoperiod and temperature on development and reproduction of Hydromedion sparsutum (Müller) (Coleoptera, Perimylopidae) from South Georgia (Subantarctic).
1. Under laboratory conditions complete development of H. sparsutum is shown within a temperature range of-0.7°C to +8°C. Constant temperatures above 10°C are lethal to the population. Larval growth (L1 to L5) is strictly temperature-dependent between-0.7 and +3.5°C, but slightly temperature compensated between +3.5 and +8°C. 2. Rate of egg production is highest at an average daily temperature of-0.7°C. 3. The sixth larval stage (L6) can be subdivided into a wandering and feeding period of about 40 days (at 7.3°C) and a following prepupal resting stage (PPR) with a high variability in duration, even at one and the same temperature, which ends with pupation. 4. Entrance into this resting stage seems to be independent of environmental changes and can occur at every time of the year. Termination of the PPR depends upon light stimuli received during the entire larval period. 5. Readiness for pupation exists when the photoperiod in the PPR exceeds that during hatching of first larva. A decreasing photoperiod during PPR triggers pupation in prepupae of various age. 6. The diapause stage seems to be a primary factor synchronizing the life cycle with seasonal changes in the environment.


Accurate test of chiral dynamics in the γp→π0p reaction.
A precision measurement of the differential cross sections dσ/dΩ and the linearly polarized photon asymmetry Σ≡(dσ⊥-dσ∥)/(dσ⊥+dσ∥) for the γp→π0p reaction in the near-threshold region has been performed with a tagged photon beam and almost 4π detector at the Mainz Microtron. The Glasgow-Mainz photon tagging facility along with the Crystal Ball/TAPS multiphoton detector system and a cryogenic liquid hydrogen target were used. These data allowed for a precise determination of the energy dependence of the real parts of the S- and all three P-wave amplitudes for the first time and provide the most stringent test to date of the predictions of chiral perturbation theory and its energy region of agreement with experiment.


Altered NMDA glutamate receptor antagonist response in recovering ethanol-dependent patients.
Ethanol is an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor. Ethanol dependence upregulates NMDA receptors and contributes to crosstolerance with selective NMDA receptor antagonists in animals. This study evaluated whether recovering ethanol-dependent patients show evidence of a reduced level of response to the effects of the NMDA receptor antagonist, ketamine. In this double-blind study, 34 recently detoxified alcohol-dependent patients and 26 healthy comparison subjects completed 3 test days involving a 40-min infusion of saline, ketamine 0.1 mg/kg, or ketamine 0.5 mg/kg in a randomized order. Recovering ethanol-dependent patients showed reduced perceptual alterations, dysphoric mood, and impairments in executive cognitive functions during ketamine infusion relative to the healthy comparison group. No attenuation of ketamine-induced amnestic effects, euphoria, or activation was observed. The alterations in NMDA receptor function observed in recovering ethanol-dependent patients may have important implications for ethanol tolerance, ethanol dependence, and the treatment of alcoholism.


Primary central nervous system lymphoma in homosexual men. Clinical, immunologic, and pathologic features.
Primary central nervous system lymphoma constitutes one of the criteria for the acquired immune deficiency syndrome (AIDS), yet a paucity of information is currently available regarding the clinical, immunologic, or pathologic features of these patients. Six homosexual men presenting with primary central nervous system lymphoma were evaluated. Five of these patients presented with altered mental status. All lymphomas were intracranial. B cell immunoblastic sarcoma was found in five. Immune phenotyping studies performed in five patients revealed monoclonal lambda light chain in three, whereas one expressed only IgG heavy chain, and one demonstrated another B cell (LN-1) surface antigen. Hypodense, contrast-enhancing lesions were apparent on computed axial tomographic scanning of the brain, in sharp contrast to isodense or hyperdense lesions reported in primary central nervous system lymphomas without underlying immunodeficiency. Immunologic abnormalities in these patients were similar to those in AIDS presenting as Kaposi's sarcoma or with opportunistic infections. In spite of therapeutic interventions, survival was short, and only one patient is currently alive.


Status epilepticus after myelography with iohexol (Omnipaque).
Myelography has been of great use as a diagnostic modality, especially when other modalities were not conclusive.However, considering the invasive nature of myelography, it should receive the attention of medical personnel for them to be aware of its possible complications, especially when newer agents are applied as the contrast media. Myelography could lead to some common adverse effects and complications, but in this case report, we will present one of the most serious and uncommon complications accompanied with myelography using Omnipaque, a nonionic second-generation contrast agent. These complications include lower-extremity myoclonic spasms, tonic seizure leading to status epilepticus, rhabdomyolysis, disseminated intravascular coagulation and anaphylactic shock. Having the knowledge of possible complications and available solutions, particularly fatal ones, could prepare medical staff beforehand for primary and secondary preventions.


The amplitude of post-tetanic potentiation of the EPSP RC1-R15 in Aplysia is modulated by environmental parameters.
Evidence is presented that the EPSP called RC1-R15, which is recorded from cell R15 of the abdominal ganglion of Aplysia californica upon appropriate stimulation of the right connective, is endogenously active. In previous studies we showed that after repetitive stimulation the amplitude of this EPSP increases and then slowly decays over many minutes, a phenomenon called post-tetanic potentiation (PTP). The rate of endogenous firing of this EPSP varies with time of day and tonicity of the animal's external environment. It is shown that this endogenous firing increases the magnitude of the PTP component of the amplitude of the EPSP. The degree of this potentiation varies with the endogenous firing rate. In general, daytime or a hypertonic external environment increases the firing rate of the EPSP and its degree of potentiation. Since the degree of this PTP reflects time of day and environmental tonicity, it is inferred that it conveys physiologically significant information to the postsynaptic cell R15.


Pediatric craniosynostosis computed tomography: an institutional experience in reducing radiation dose while maintaining diagnostic image quality.
Children with craniosynostosis may undergo multiple computed tomography (CT) examinations for diagnosis and post-treatment follow-up, resulting in cumulative radiation exposure. To reduce the risks associated with radiation exposure, we evaluated the compliance, radiation dose reduction and clinical image quality of a lower-dose CT protocol for pediatric craniosynostosis implemented at our institution. The standard of care at our institution was modified to replace pediatric head CT protocols with a lower-dose CT protocol utilizing 100 kV, 5 mAs and iterative reconstruction. Study-ordered, protocol-utilized and radiation-dose indices were collected for studies performed with routine pediatric brain protocols (n=22) and with the lower-dose CT protocol (n=135). Two pediatric neuroradiologists evaluated image quality in a subset (n=50) of the lower-dose CT studies by scoring visualization of cranial structures, confidence of diagnosis and the need for more radiation dose. During the 30-month period, the lower-dose CT protocol had high compliance, with 2/137 studies performed with routine brain protocols. With the lower-dose CT protocol, volume CT dose index (CTDIvol) was 1.1 mGy for all patients (0-9 years old) and effective dose ranged from 0.06 to 0.22 mSv, comparable to a 4-view skull radiography examination. CTDIvol was reduced by 98% and effective dose was reduced up to 67-fold. Confidence in diagnosing craniosynostosis was high and more radiation dose was considered unnecessary in all studies (n=50) by both radiologists. Replacing the routine pediatric brain CT protocol with a lower-dose CT craniosynostosis protocol substantially reduced radiation exposure without compromising image quality or diagnostic confidence.


Fetal bradycardia without fetal distress: case presentation and review of the literature.
A case of a term pregnancy with a persistent fetal heart rate of 65 to 80 beats/min is presented. Initially this was presumed to be due to congenital heart block. Subsequent fetal ECG revealed blocked atrial extrasystoles. Review of the literature showed 31 previously reported cases of heart block diagnosed in utero. A review of this literature is discussed and the importance of differentiating bradycardia due to heart block from bradycardia due to fetal distress is emphasized.


A microwell assay for anchorage independent cell growth.
We describe modifications of the conventional assay for anchorage independent growth of fibroblasts that enable the assay to be carried out in microwell plates, as opposed to the conventional Petri dishes. The microwell assay is a good discriminator of final EGF concentrations in the range 10-100 picograms/ml, and can be used to detect absolute amounts of EGF below 2 pg. Addition of TGF beta to EGF enhances colony formation in the microassay in the usual manner. We describe the use of this microassay to identify and map local production of transforming growth factor activity by the component pieces of individual chick embryos. Transforming activity was identified in all the stages tested (Hamburger and Hamilton stages 13-23). Highest levels were found near the mid-line of the embryo. No clear differences in the cranio-caudal axis have so far been identified. This technique will enable the spatial and temporal distribution of transforming activity throughout vertebrate embryos to be completely mapped. It seems likely that this mapping process will help elucidate the normal role of transforming growth factors in embryos.


Population genetic analysis of 15 autosomal STRs loci in the central region of Argentina.
Allele frequencies, together with some parameters of forensic interest, for 15 STRs included in the Powerplex-16 System (CSF1PO, D3S1358, D5S818, D7S820, D8S1179, D13S317, D16S539, D18S51, D21S11, FGA, Penta D, Penta E, TH01, TPOX and VWA) were estimated from a sample set of 1368 unrelated individuals from three of the most densely populated provinces of Argentina. No deviations from Hardy-Weinberg equilibrium were observed using the Bonferroni correction for the number of loci analyzed. Comparative analyses between our population data and that of other Argentinean databases previously published are presented and discussed. The most informative loci in our data set is the Penta E Loci with discrimination power larger than 0.98 and typical paternity index larger than 4.3. Our results demonstrate that these loci are robust since different laboratories and sample sets provided highly consistent results. This observation underscores the usefulness of these markers systems for human identification and parentage testing.


Formulation and evaluation of microemulsion based delivery system for amphotericin B.
The present studies were designed to develop a formulation of amphotericin B in a lipid-based preparation as a microemulsion and to compare its toxicity with the commercial formulation Fungizone. The final product developed is a lyophilized amphotericin B, oil and surfactant blend for reconstitution in water to yield a microemulsion containing 5 mg/ml of the drug. Pseudoternary phase diagrams were constructed to identify areas of existence of microemulsion composed of Peceol (glyceryl monooleate) as oil phase and Mys 40 (polyethylene glycol 40 stearate) and Solutol HS 15 (polyethylene glycol 15 hydroxy stearate) as surfactants. Amphotericin B was co-evaporated with oil - surfactant mixture to produce a microemulsion pre-concentrate. The co-evaporate was diluted in water, filtered for sterilization and lyophilized to obtain the final product. The lyophilized as well as the reconstituted products were separately studied for stability and the latter was also characterized for various physicochemical aspects including droplet size of the dispersed phase, osmolarity and aggregation state of drug. The dispersion showed no evidence of precipitation of drug for 48 h, and resisted destabilization due to freeze-thaw cycles or centrifugation. The dispersed phase globules measured a mean size of 84 nm and uv-spectrophotometric studies indicated the presence of self-aggregated amphotericin B. The present formulation showed a 92% decrease in haemolysis of human RBC in vitro when compared with the commercially available Fungizone. The LD(50) in mice was estimated to be 3.4 mg/kg. The results indicate that the formulation holds promise for development as a safer and efficacious alternative for amphotericin B therapy.


Cancer risk after breast proton therapy considering physiological and radiobiological uncertainties.
The reduced normal tissue dose burden from protons can reduce the risk of second cancer for breast cancer patients. Breathing motion and the impact of variable relative biological effectiveness (RBE) are however concerns for proton dose distributions. This study aimed to quantify the impact of these factors on risk predictions from proton and photon therapy. Twelve patients were planned in free breathing with protons and photons to deliver 50 Gy (RBE) in 25 fractions (assuming RBE = 1.1 for protons) to the left breast. Second cancer risk was evaluated with several models for the lungs, contralateral breast, heart and esophagus as organs at risk (OARs). Plans were recalculated on CT-datasets acquired in extreme phases to account for breathing motion. Proton plans were also recalculated assuming variable RBE for a range of radiobiological parameters. The OARs received substantially lower doses from protons compared to photons. The highest risks were for the lungs (average second cancer risks of 0.31% and 0.12% from photon and proton plans, respectively). The reduced risk with protons was maintained, even when breathing and/or RBE variation were taken into account. Furthermore, while the total risks from the photon plans were seen to increase with the integral dose, no such correlation was observed for the proton plans. Protons have an advantage over the photons with respect to the induction of cancer. Uncertainties in physiological movements and radiobiological parameters affected the absolute risk estimates, but not the general trend of lower risk associated with proton therapy.


Mechanical forces: The missing link between idiopathic pulmonary fibrosis and lung cancer.
Patients with idiopathic pulmonary fibrosis (IPF) have a high risk of developing lung cancer compared with the general population. The morbidity of lung cancer in IPF patient ranges from 3% to 22%, and in some cases exceeds 50%, and these patients have a reduced survival time. However, the mechanisms through which IPF increases the morbidity and mortality in lung cancer remain unclear. By carefully analyzing the pathological features of these two diseases, we uncovered that, first, similar to IPF, lung carcinomas are more frequently found in the peripheral area of the lungs and, second, lung cancers tend to develop from the honeycomb areas in IPF. In accordance with the above pathological features, due to the spatial location, the peripheral areas of the lung experience a high stretch force because the average distance between adjacent alveolar cells in this area tends to be larger than that at the central lung when inflated; furthermore, the honeycomb areas, comprised of condensed fibrous tissue, are characterized by increased stiffness. Both of these pathological features of lung cancer and IPF are coincidentally related to abnormal mechanical forces (stretch and tissue stiffness). Therefore, we believe that the aberrant mechanical forces that are generated in the lung with IPF may contribute to the onset and progression of lung cancer. In this review, we discuss the possible effects of mechanical forces that are generated in IPF on the initiation and progression of lung cancer from the perspective of the hallmarks of cancer, including proliferation, metastasis, angiogenesis, cancer stem cells, immunology, epigenetics, and metabolism, so as to advance our understanding of the pathogenesis of IPF-related lung cancer and to harness these concepts for lung cancer mechanotherapies.


A rapid separation procedure to analyse phosphorylation of two putative protein kinase C substrates in intact lymphocytes.
Activation of protein kinase C (PKC) has been implicated in the regulation of many biological processes including the regulation of T and B lymphocyte responses. A direct means of studying activation of this kinase is to analyse specific phosphorylation events of cellular substrates. In the present report we describe a fractionation method that allows quantitative analysis of phosphorylation of two distinct PKC substrates using normal human T cells and T-cell tumour lines. This method, which selectively visualizes PKC-dependent phosphorylation of both an 80- and a 19-kDa substrate, involves three simple fractionation steps and allows a large number of samples to be analysed simultaneously. Since specific antibodies to these cellular substrates are not commonly available, the present method provides an alternative approach which makes it feasible to use phosphorylation of the 19- and 80-kDa proteins as a sensitive marker for PKC activation. Finally, in a cellular system where PKC-mediated phosphorylation of these substrates can be studied without prior purification, the present method results in greatly improved resolution of these phosphorylation events.


Effects of concurrent sucralfate administration on pharmacokinetics of naproxen.
Sucralfate has been reported to protect the gastroduodenal mucosa against a variety of agents and is known to adsorb bile salts. Since gastrointestinal side effects can seriously compromise the efficacy of nonsteroidal anti-inflammatory drug therapy, and since it seems reasonable to assume that sucralfate may adsorb nonsteroidal anti-inflammatory drugs, the influence of sucralfate on the pharmacokinetic parameters of naproxen was assessed in 12 healthy volunteers. To do so, the pharmacokinetic profile of naproxen, administered alone or with sucralfate, singly or repeatedly (twice daily for five days), was compared. No significant difference was observed with any pharmacokinetic parameter between the single administration of naproxen alone or with sucralfate. However, a significantly lower maximum plasma concentration was attained with the repeated administration of naproxen in combination with sucralfate, compared with the repeated administration of naproxen alone. When single- and multiple-dose administration were compared, significant differences were observed in the maximum plasma concentration and the cumulative area under the curve. These results suggest an accumulation of naproxen after five days' administration. This accumulation, however, is not altered by the administration of sucralfate. The results of this study suggest that when naproxen is administered with sucralfate, only a delay in naproxen's absorption may occur, confirmed by a lower maximum plasma concentration, a longer time to reach the maximum plasma concentration, a similar elimination half-life, and equivalence in bioavailability. The clinical importance of such a delay has yet to be proved; however, it is unlikely that the clinical efficacy of naproxen will be altered, since the amount of drug absorbed remains the same.


Genetic markers in renal adenocarcinoma.
The distribution of phenotypes and gene frequencies of the 3rd component of complement (C3), group-specific component (Gc), haptoglobin (Hp) and transferrin (Tf) were studied in 50 patients with renal adenocarcinoma. The statistical analysis of our findings in comparison to the frequency of these genes in the general population does not reveal any correlation between the distribution of the Hp and Tf phenotypes and the disease. On the contrary, a statistically significant association was found between renal adenocarcinoma and C3F and Gc2 genes. The relative risk incidence of this malignancy is 2.07 and 1.94 respectively for the carriers of these genes. These data indicate that genetic factors, possibly related to the immune mechanisms and calcium metabolism, play a role in the pathogenesis of renal adenocarcinoma.


Two-dimensional graphitic metal carbides: structure, stability and electronic properties.
Via first-principles computational modeling and calculations, we propose a new class of two-dimensional (2D) atomically thin crystals that contain metal-C3(MC3) moieties periodically distributed in a graphenic lattice, which we refer to as 2D graphitic metal carbides (g-MCs). Most g-MCs are dynamically stable as verified by the calculated phonon spectra. Our detailed chemical bonding analyzes reveal that the high stability of g-MCs can be attributed to a unique bonding feature, which manifests as the carbon-backbone-mediated metal-metal interactions. These analyzes provide new insights for understanding the stability of 2D materials. It is found that the calculated electronic band gaps and magnetic moments (per unit cell) of g-MCs can range from 0 to 1.30 eV and 0 to 4.40μB, respectively. Highly tunable electronic properties imply great potential of 2D g-MCs in various applications. As an example, we show that 2D g-MnC can be an excellent electrocatalyst towards CO2reductive reaction for the formation of formic acid with an exceptionally high loading of Mn atoms (∼43 wt%). We expect this work to simulate new experiments for fabrication and applications of g-MCs.


Activation of ATF3 via the Integrated Stress Response Pathway Regulates Innate Immune and Autophagy Processes to Restrict Zika Virus.
Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that can have devastating health consequences. The developmental and neurological effects from a ZIKV infection arise in part from the virus triggering cellular stress pathways and perturbing transcriptional programs. To date, the underlying mechanisms of transcriptional control directing viral restriction and virus-host interaction are understudied. Activating Transcription Factor 3 (ATF3) is a stress-induced transcriptional effector that modulates the expression of genes involved in a myriad of cellular processes, including inflammation and antiviral responses, to restore cellular homeostasis. While ATF3 is known to be upregulated during ZIKV infection, the mode by which ATF3 is activated and the specific role of ATF3 during ZIKV infection is unknown. In this study, we show via inhibitor and RNA interference approaches that ZIKV infection initiates the integrated stress response pathway to activate ATF4 which in turn induces ATF3 expression. Additionally, by using a CRISPR-Cas9 system to deplete ATF3, we found that ATF3 acts to limit ZIKV gene expression in A549 cells. In particular, the ATF3-dependent anti-ZIKV response occurred through regulation of innate immunity and autophagy pathways. We show that ATF3 differentially regulates the expression of innate immune response genes and suppresses the transcription of autophagy related genes to influence autophagic flux. Our study therefore highlights an important role for the integrated stress response pathway and ATF3 in establishing an antiviral effect during ZIKV infection.


Antiplatelet agents in patients undergoing percutaneous coronary intervention: how many and how much?
Antiplatelet agents play a major role in patients undergoing percutaneous coronary intervention (PCI). Stent thrombosis and the demand for improved clinical outcomes have driven the need for aggressive antiplatelet and anticoagulant regimens and newer, more efficacious, therapies. The benefits of intravenous glycoprotein (GP) IIb/IIIa antagonists and clopidogrel in high-risk patients undergoing PCI appear complementary. In low- to intermediate-risk patients, clopidogrel pre-treatment and a maintenance dose of aspirin + clopidogrel for at least 1 year after PCI are supported by the data, although the optimal duration of clopidogrel treatment beyond 1 year remains hotly contested. The next generation of clinical trials will examine the benefits of antiplatelet and antithrombotic agents as adjunctive therapy with drug-eluting stents. A better understanding of our patients' overall risk will add to procedural success and more durable outcomes.


Perspectives on diagnostic strategies for HIP-dealing with the barriers and challenges: USA.
Gestational diabetes (GDM) affects up to 7-18% of pregnant women and is associated with several maternal and perinatal morbidities. International organizations suggest several different recommendations regarding how to screen and to manage hyperglycemia in pregnancy (HIP). We aimed to analyze the most important and employed guidelines about screening and management of HIP and we investigated existing related literature. We found several different criteria for screening for HIP, with the main difference being between non-USA-based IADPSG (One-step) approach, and the USA-based (Two-step) approach. The use of IADPSG approach (One-step) is associated with an increase in the incidence of GDM, improvement of several maternal and perinatal outcomes, and cost-effectiveness, compared to the USA-based Two-step criteria. As the One-Step approach endorsed by IADPSG, WHO, and FIGO is associated with maternal and perinatal benefits, it should be preferred to the Two-Step approach currently endorsed by the USA-based societies such as ACOG and SMFM. The hope is to approve universal screening guidelines based on the One-step approach to improve health care and reduce costs and adverse outcomes for women with GDM.


Highly Selective Recovery of Lanthanides by Using a Layered Vanadate with Acid and Radiation Resistance.
It is of vital importance to capture lanthanides (nuclear fission products) from waste solutions for radionuclide remediation owing to their hazards. The effective separation of lanthanides are achieved by an acid/base-stable and radiation-resistant vanadate, namely, [Me2 NH2 ]V3 O7 (1). It exhibits high adsorption capacities for lanthanides (qm Eu =161.4 mg g-1 ; qm Sm =139.2 mg g-1 ). And high adsorption capacities are maintained over a pH range of 2.0-6.9 (qm Eu =75.1 mg g-1 at low pH of 2.5). It displays high selectivity for Eu3+ (simulant of An3+ ) against a large excess of interfering ions. It can efficiently separate Eu3+ and Cs+ (or Sr2+ ) with the highest separation factor SFEu/Cs of 156 (SFEu/Sr of 134) to date. The adsorption mechanism is revealed by calculations and XPS, EXAFS, Raman, and elemental analyses. These merits combined with facile synthesis and convenient elution makes the title vanadate a promising lanthanide scavenger for environmental remediation.


Physical aspects of precision in genetic regulation.
The process by which transcription factors (TFs) locate specific DNA binding sites is stochastic and as such, is subject to a considerable level of noise. TFs diffuse in the three-dimensional nuclear space, but can also slide along the DNA. It was proposed that this sliding facilitates the TF molecules arriving to their binding site, by effectively reducing the dimensionality of diffusion. However, the possible implications of DNA sliding on the accuracy by which the nuclear concentration of TFs can be estimated were not examined. Here, we calculate the mean and the variance of the number of TFs that bind to their binding site in reduced and partially reduced diffusion dimensionality regimes. We find that a search process which combines three-dimensional diffusion in the nucleus with one-dimensional sliding along the DNA can reduce the noise in TF binding and in this way enables a better estimation of the TF concentration inside the nucleus.


Potential value of radionuclide cisternography in diagnosis and management planning of spontaneous intracranial hypotension.
Spontaneous intracranial hypotension (SIH) is caused by spontaneous spinal cerebrospinal fluid (CSF) leaks. However, there is debate regarding clinical indication of radionuclide cisternography (RNC) for identification of the actual site of a CSF leak. We therefore investigated the potential value of RNC in SIH. RNC was performed on 30 patients with SIH. Patients were managed with conservative management only or epidural blood patches (EBPs) according to clinical conditions and RNC findings. RNC revealed direct signs of spinal CSF leaks in 80% of patients. Of this group, complete resolution of headache was obtained in 12 (71%) of 17 patients who received EBP vs. 1 (14%) of 7 patients treated with conservative management only (p=0.02). Complete headache relief with conservative management only was seen in one (14%) patient with direct signs of spinal CSF leaks compared to five (83%) patients without direct signs (p=0.03). RNC is useful for diagnosis and better management planning of SIH.


Effects of PACAP(1-27) on the canine endocrine pancreas in vivo: interaction with cholinergic mechanism.
The aim of the present study was to characterize the effects of pituitary adenylate cyclase activating polypeptide (PACAP) on the endocrine pancreas in anesthetized dogs. PACAP(1-27) and a PACAP receptor (PAC(1)) blocker, PACAP(6-27), were locally administered to the pancreas. PACAP(1-27) (0.005-5 microg) increased basal insulin and glucagon secretion in a dose-dependent manner. PACAP(6-27) (200 microg) blocked the glucagon response to PACAP(1-27) (0.5 microg) by about 80%, while the insulin response remained unchanged. With a higher dose of PACAP(6-27) (500 microg), both responses to PACAP(1-27) were inhibited by more than 80%. In the presence of atropine with an equivalent dose (128.2 microg) of PACAP(6-27) (500 microg) on a molar basis, the insulin response to PACAP(1-27) was diminished by about 20%, while the glucagon response was enhanced by about 80%. The PACAP(1-27)-induced increase in pancreatic venous blood flow was blocked by PACAP(6-27) but not by atropine. The study suggests that the endocrine secretagogue effect of PACAP(1-27) is primarily mediated by the PAC(1) receptor, and that PACAP(1-27) may interact with muscarinic receptor function in PACAP-induced insulin and glucagon secretion in the canine pancreas in vivo.


Disulfide bonds convert small heat shock protein Hsp16.3 from a chaperone to a non-chaperone: implications for the evolution of cysteine in molecular chaperones.
Molecular chaperones mainly function in assisting newly synthesized polypeptide folding and protect non-native proteins from aggregation, with known structural features such as the ability of spontaneous folding/refolding and high conformational flexibility. In this report, we verified the assumption that the lack of disulfide bonds in molecular chaperones is a prerequisite for such unique structural features. Using small heat shock protein (one sub-class of chaperones) Hsp16.3 as a model system, our results show the following: (1) Cysteine-free Hsp16.3 wild type protein can efficiently exhibit chaperone activity and spontaneously refold/reassemble with high conformational flexibility. (2) Whereas Hsp16.3 G89C mutant with inter-subunit disulfide bonds formed seems to lose the nature of chaperone proteins, i.e., under stress conditions, it neither acts as molecular chaperone nor spontaneously refolds/reassembles. Structural analysis indicated that the mutant exists as an unstable molten globule-like state, which incorrectly exposes hydrophobic surfaces and irreversibly tends to form aggregates that can be suppressed by the other molecular chaperone (alpha-crystallin). By contrast, reduction of disulfide bond in the Hsp16.3 G89C mutant can significantly recover its character as a molecular chaperone. In light of these results, we propose that disulfide bonds could severely disturb the structure/function of molecular chaperones like Hsp16.3. Our results might not only provide insights into understanding the structural basis of chaperone upon binding substrates, but also explain the observation that the occurrence of cysteine in molecular chaperones is much lower than that in other protein families, subsequently being helpful to understand the evolution of protein family.


Fascioliasis and other plant-borne trematode zoonoses.
Fascioliasis and other food-borne trematodiases are included in the list of important helminthiases with a great impact on human development. Six plant-borne trematode species have been found to affect humans: Fasciola hepatica, Fasciola gigantica and Fasciolopsis buski (Fasciolidae), Gastrodiscoides hominis (Gastrodiscidae), Watsonius watsoni and Fischoederius elongatus (Paramphistomidae). Whereas F. hepatica and F. gigantica are hepatic, the other four species are intestinal parasites. The fasciolids and the gastrodiscid cause important zoonoses distributed throughout many countries, while W. watsoni and F. elongatus have been only accidentally detected in humans. Present climate and global changes appear to increasingly affect snail-borne helminthiases, which are strongly dependent on environmental factors. Fascioliasis is a good example of an emerging/re-emerging parasitic disease in many countries as a consequence of many phenomena related to environmental changes as well as man-made modifications. The ability of F. hepatica to spread is related to its capacity to colonise and adapt to new hosts and environments, even at the extreme inhospitality of very high altitude. Moreover, the spread of F. hepatica from its original European range to other continents is related to the geographic expansion of its original European lymnaeid intermediate host species Galba truncatula, the American species Pseudosuccinea columella, and its adaptation to other lymnaeid species authochthonous in the newly colonised areas. Although fasciolopsiasis and gastrodiscoidiasis can be controlled along with other food-borne parasitoses, fasciolopsiasis still remains a public health problem in many endemic areas despite sustained WHO control programmes. Fasciolopsiasis has become a re-emerging infection in recent years and gastrodiscoidiasis, initially supposed to be restricted to Asian countries, is now being reported in African countries.


Do medication prescription patterns follow guidelines in a cohort of women with interstitial cystitis/bladder pain syndrome?
To describe prescription prevalence of oral bladder pain medications among women with interstitial cystitis/bladder pain syndrome (IC/BPS) and to compare with current treatment guidelines. We sampled female patients with an ICD-9/10 diagnosis of IC/BPS (595.1/N30.10) by querying active users of the Veterans Health Administration. Medical records were reviewed to determine whether patients met IC/BPS diagnostic criteria. A cohort of women with other pelvic pain disorders was identified. Prescription prevalence of typical non-narcotic oral bladder pain medications was compared between the two groups and healthy controls. Prescription prevalence was also compared before and after the diagnosis of IC/BPS was made using Poisson regression. There were 641 women who met criteria for IC/BPS and 197 women with "Other pelvic pain" disorders. Women with IC/BPS were prescribed a pain medication more often than those with "Other pelvic pain" (77% vs. 59%, p < 0.0001). Of the women with IC/BPS, 44% tried three or more pain medications. Of women with a diagnosis of IC/BPS, only 67% were prescribed an American Urological Association-recommended medication. Prescription prevalence increased after diagnosis for both pentosan polysulfate (10%-29%, p < 0.0001) and hydroxyzine (17%-40%, p < 0.0001), but not for amitriptyline or cimetidine. Amitriptyline was prescribed to 223 women with IC/BPS, only 125 of which (56%) had a documented history of depression. Many women with IC/BPS required multiple bladder prescriptions, highlighting the difficulty in finding an effective treatment for IC/BPS. Pentosan polysulfate and hydroxyzine were preferred IC/BPS medications. Our next step will be to analyze treatment patterns in those patients who did not receive medications.


[Physical bases of blister formation. II. A study of the total osmotic pressure in the blister fluid of suction blisters and of "naturally" occurring blisters as well as in the serum].
Total osmotic pressure does not differ significantly in suction blister fluid or in serum of healthy persons from blister fluid, suction blister fluid or serum of patients with dermatitis herpetiformis, bullous contact dermatitis and pemphigus vulgaris. The average values reach about 293 mOsmol/kg. This results from direct measurement of total osmolality with an electronic semimicroosmometer based on the principle of freezing point reduction. In opposite to colloid osmotic pressure the total osmotic pressure does not take part in blister formation of human skin in spite of the different concentrations of the single electrolytes in the fluids of various blisters.


Developmental time course of the sympathetic postganglionic innervation of the rat eye.
The time course of the innervation of the rat iris by sympathetic postganglionic axons from the superior cervical ganglion (SCG) has been studied in postnatal rats. A retrogradely transported fluorescent dye, Fast blue (FB) was injected bilaterally into the anterior eye chamber of rats within 3 h of birth or at 7 or 14 days postnatal. Littermates were killed at 24 h intervals, both SCG removed, fixed and sectioned. A substantial number of sympathetic neurones were labelled retrogradely from the eye at birth. The number of labelled cells tripled over the first postnatal week to reach proportions equivalent to those labelled in 3-week-old rats. The degree of sympathetic fibre ingrowth to the iris was examined at 3 postnatal ages, using fluorescence histochemistry. This method showed a small proportion of catecholamine-containing fibres in the iris at birth with a more extensive fibre density over the iris by 7 days after birth. A further increase in fibre density had occurred by the end of the 3rd postnatal week even though the number of cells projecting to the iris at these two ages was similar. This difference in fibre density may arise from ramification of fibres which have reached the iris by 7 days postbirth.


LncRNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism.
The Hippo pathway plays essential roles in organ size control and cancer prevention via restricting its downstream effector, Yes-associated protein (YAP). Previous studies have revealed an oncogenic function of YAP in reprogramming glucose metabolism, while the underlying mechanism remains to be fully clarified. Accumulating evidence suggests long noncoding RNAs (lncRNAs) as attractive therapeutic targets, given their roles in modulating various cancer-related signaling pathways. In this study, we report that lncRNA breast cancer anti-estrogen resistance 4 (BCAR4) is required for YAP-dependent glycolysis. Mechanistically, YAP promotes the expression of BCAR4, which subsequently coordinates the Hedgehog signaling to enhance the transcription of glycolysis activators HK2 and PFKFB3. Therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 attenuated YAP-dependent glycolysis and tumor growth. The expression levels of BCAR4 and YAP are positively correlated in tissue samples from breast cancer patients, where high expression of both BCAR4 and YAP is associated with poor patient survival outcome. Taken together, our study not only reveals the mechanism by which YAP reprograms glucose metabolism, but also highlights the therapeutic potential of targeting YAP-BCAR4-glycolysis axis for breast cancer treatment.


Sulfonylurea-stimulated glucose transport association with diacylglycerollike activation of protein kinase C in BC3H1 myocytes.
The extrapancreatic effects of sulfonylurea drugs include increased glucose uptake by certain peripheral tissues. To study this effect, we used BC3H1 myocytes, which are reported to respond to these drugs. Within 30 min, tolbutamide and glyburide increased [3H]-2-deoxyglucose uptake in a dose-dependent manner. The inactive analogue carboxytolbutamide had no effect on glucose transport. Because increases in glucose transport may be mediated by activation of the diacylglycerol-protein kinase C signaling system, we examined the effects of these drugs on lipid metabolism and protein kinase C activity. Unlike insulin, tolbutamide and glyburide failed to increase [3H]glycerol labeling of diacylglycerol or labeling of phospholipids by 32P. After 30 min of treatment with tolbutamide or glyburide, however, membrane-associated and cytosolic protein kinase C activity were each increased. When cells were treated with 12-O-tetradecanoylphorbol-13-acetate (TPA) for 48 h to deplete certain isoforms of protein kinase C, glyburide, tolbutamide, and acute TPA treatment failed to increase glucose uptake, suggesting that TPA and sulfonylureas operate through activation of a common pathway. The effect of glyburide was additive to TPA in stimulating glucose uptake at low but not high TPA concentrations. As with insulin and TPA, extracellular Ca2+ was not essential for sulfonylurea-stimulated glucose uptake. Staurosporine, a protein kinase C inhibitor, blocked glyburide-, tolbutamide-, and insulin-stimulated glucose uptake. In intact cells, glyburide stimulated the phosphorylation of both 80,000-Mr and 40,000-Mr proteins, which are markers for protein kinase C activation. Addition of sulfonylureas directly to the protein kinase C assay system in vitro provoked dioleinlike effects, in that sensitivity of the enzyme to Ca2+ was increased.(ABSTRACT TRUNCATED AT 250 WORDS)


Myopericytoma: A Series of 5 Cases Affecting the Nervous System.
Myopericytomas are benign vascular tumors composed of perivascular myoid cells that usually arise in superficial soft tissues of the extremities. We here report on 5 cases of myopericytoma, malignant myopericytoma, and glomangiopericytoma arising from subcutaneous, paraspinal, orbital, and sellar regions that secondarily involved the nervous system. Patients experienced orbital swelling, progressing neuropathic pain, dermatoma specific pain, and oculomotor paresis. Mean age at diagnosis was 56.8 years (range, 38-74 years). After a mean follow-up of 38 months, no recurrence was detected. All tumors were unencapsulated but relatively well-circumscribed lesions, showing typical histologic and immunohistochemical features of soft-tissue myopericytoma, including one malignant case. We conclude that myopericytoma may affect the nervous system and for prognostic and therapeutic reasons, needs to be differentiated from other vascular tumors.


Correction to: Thickness profiles of the corneal epithelium along the steep and flat meridians of astigmatic corneas after orthokeratology.
An amendment to this paper has been published and can be accessed via the original article.


Merging of the Case 2 Regional Coast Colour and Maximum-Peak Height chlorophyll-a algorithms: validation and demonstration of satellite-derived retrievals across US lakes.
Water quality monitoring is relevant for protecting the designated, or beneficial uses, of water such as drinking, aquatic life, recreation, irrigation, and food supply that support the economy, human well-being, and aquatic ecosystem health. Managing finite water resources to support these designated uses requires information on water quality so that managers can make sustainable decisions. Chlorophyll-a (chl-a, µg L-1) concentration can serve as a proxy for phytoplankton biomass and may be used as an indicator of increased anthropogenic nutrient stress. Satellite remote sensing may present a complement to in situ measures for assessments of water quality through the retrieval of chl-a with in-water algorithms. Validation of chl-a algorithms across US lakes improves algorithm maturity relevant for monitoring applications. This study compares performance of the Case 2 Regional Coast Colour (C2RCC) chl-a retrieval algorithm, a revised version of the Maximum-Peak Height (MPH(P)) algorithm, and three scenarios merging these two approaches. Satellite data were retrieved from the MEdium Resolution Imaging Spectrometer (MERIS) and the Ocean and Land Colour Instrument (OLCI), while field observations were obtained from 181 lakes matched with U.S. Water Quality Portal chl-a data. The best performance based on mean absolute multiplicative error (MAEmult) was demonstrated by the merged algorithm referred to as C15-M10 (MAEmult = 1.8, biasmult = 0.97, n = 836). In the C15-M10 algorithm, the MPH(P) chl-a value was retained if it was > 10 µg L-1; if the MPH(P) value was ≤ 10 µg L-1, the C2RCC value was selected, as long as that value was < 15 µg L-1. Time-series and lake-wide gradients compared against independent assessments from Lake Champlain and long-term ecological research stations in Wisconsin were used as complementary examples supporting water quality reporting requirements. Trophic state assessments for Wisconsin lakes provided examples in support of inland water quality monitoring applications. This study presents and assesses merged adaptations of chl-a algorithms previously reported independently. Additionally, it contributes to the transition of chl-a algorithm maturity by quantifying error statistics for a number of locations and times.


An accurate and explainable ensemble learning method for carotid plaque prediction in an asymptomatic population.
The identification of carotid plaque, one of the most crucial tasks in stroke screening, is of great significance in the assessment of subclinical atherosclerosis and preventing the onset of stroke. However, traditional ultrasound examination is not prevalent or cost-effective for asymptomatic people, particularly low-income individuals in rural areas. Thus, it is necessary to develop an accurate and explainable model for early identification of the risk of plaque prevalence that can help in the primary prevention of stroke. We developed an ensemble learning method to predict the occurrence of carotid plaques. A dataset comprising 1440 subjects (50% with plaques and 50% without plaques) and ten-fold cross-validation were utilized to evaluate the model performance. Four machine learning methods (extreme gradient boosting (XGBoost), gradient boosting decision tree, random forest, and support vector machine) were evaluated. Subsequently, the interpretability of the XGBoost model, which provided the best performance, was analyzed from three aspects: feature importance, feature effect on prediction model, and feature effect on prediction decision for a specific subject. The XGBoost algorithm provided the best performance (sensitivity: 0.8678, specificity: 0.8592, accuracy: 0.8632, F1 score: 0.8621, area under the curve: 0.8635) in carotid plaque prediction and also had excellent performance under missing data circumstances. Further, interpretability analysis showed that the decisions of the XGBoost model were highly congruent with clinical knowledge. The model results are superior to those of state-of-the-art methods. Thus, it is a promising carotid plaque prediction tool that could be used in the primary prevention of stroke.


Investigating the SecY plug movement at the SecYEG translocation channel.
Protein translocation occurs across the energy-conserving bacterial membrane at the SecYEG channel. The crystal structure of the channel has revealed a possible mechanism for gating and opening. This study evaluates the plug hypothesis using cysteine crosslink experiments in combination with various allelic forms of the Sec complex. The results demonstrate that the SecY plug domain moves away from the center of the channel toward SecE during polypeptide translocation, and further show that the translocation-enhancing prlA3 mutation and SecG subunit change the properties of channel gating. Locking the plug in the open state preactivates the Sec complex, and a super-active translocase can be created when combined with the prlA4 mutation located in the pore of the channel. Dimerization of the Sec complex, which is essential for translocase activity, relocates the plug toward the open position. We propose that oligomerization may result in SecYEG cooperative interactions important to prime the translocon function.


Lung function in simple complete transposition after intracardiac repair.
Pulmonary function was measured in 35 patients (mean age 11.6 years) with simple complete transposition 4.4 years after intracardiac repair. A disturbance in the lung function (greater than 2 SD from the normal value) was found in 88% of the patients. A marked increase in static recoil pressure (P less than 0.001) was most frequent (in 66%). Static lung compliance was only 75.1% of the predicted values. Values of mean vital and total lung capacity were decreased (P less than 0.01 and 0.001). Residual volume, the ratios of functional residual versus total lung capacity and residual volume versus total capacity were all increased. The signs of decreased patency of the airways were found in only 4 patients. A negative correlation was detected between the indices of lung stiffness and the age of assessment of lung function. A positive correlation was found between the ratios between functional residual and total capacity and pulmonary blood flow. No other correlation between lung function data and pulmonary arterial pressure or flow was proved. Increased lung stiffness, restriction of lung volume and hyperinflation could influence unfavorably the long-term results in successfully treated patients with simple complete transposition.


DNA-abnormality in hairy cell leukemia.
Spleen and light density peripheral blood leukocytes of 10 hairy cell leukemia (HCL) patients and total leukocytes of one patient and blood donor cells were stained quantitatively for cellular DNA. The DNA content of single cells was measured by flow cytometry (FC) and compared to the DNA content of sheep cells admixed as an internal control. Eight of eleven patients (72 per cent) showed deviations from blood donor DNA content. Two female patients showed increased cellular DNA content, the six male patients had hypodiploid cells. Chromosomal aberrations are therefore likely to exist in the majority of HCL patients. Separation of HCL cells into sheep erythrocyte rosette and non rosette forming cells revealed similar DNA abnormalities in both cell populations, suggesting that the leukemia encompasses cells with B and with T markers.


Combining Deep Eutectic Solvents with TEMPO-based Polymer Electrodes: Influence of Molar Ratio on Electrode Performance.
For sustainable energy storage, all-organic batteries based on redox-active polymers promise to become an alternative to lithium ion batteries. Yet, polymers contribute to the goal of an all-organic cell as electrodes or as solid electrolytes. Here, we replace the electrolyte with a deep eutectic solvent (DES) composed of sodium bis(trifluoromethanesulfonyl)imide (NaTFSI) and N-methylacetamide (NMA), while using poly(2,2,6,6-tetramethylpiperidin-1-yl-oxyl methacrylate) (PTMA) as cathode. The successful combination of a DES with a polymer electrode is reported here for the first time. The electrochemical stability of PTMA electrodes in the DES at the eutectic molar ratio of 1 : 6 is comparable to conventional battery electrolytes. More viscous electrolytes with higher salt concentration can hinder cycling at high rates. Lower salt concentration leads to decreasing capacities and faster decomposition. The eutectic mixture of 1 : 6 is best suited uniting high stability and moderate viscosity.


Ion specificity of rat chorda tympani fibers to chemical and electrical tongue stimulations.
Responses of rat single chorda tympani fibers to ionic chemical stimuli and anodal tongue stimulations with ionic bathing solutions were examined. Fourteen out of 30 fibers showed the highest sensitivities to NaCl for both chemical and electrical stimulations, whereas the remaining 16 fibers showed almost no ion specificity for electrical stimulation even though most of them have the highest sensitivities to HCl for chemical stimulation. Ion specificity for electrical stimulation was significantly smaller than that for chemical stimulation.


Early neuropsychological detection and the characteristics of Parkinson's disease associated with mild dementia.
Parkinson's disease (PD) may exhibit patterns of cognitive deficits, yet physicians are currently lacking operational criteria to define the clinical boundaries between PD and PD dementia (PDD). Therefore, we investigated the characteristics of the cognitive impairments in mild PDD. We recruited 30 PDD, 20 PD-MCI (PD with mild cognitive impairment without dementia) and 33 controls. All subjects were evaluated with detailed neuropsychological tests. Our results showed that visual memory, visuospatial functions, naming and calculation displayed more marked impairment than that of the other domains. Thus we suggest that adding cognitive dysfunctions of cortical type to the early cognitive deficits of PD-MCI can help predict the development of dementia.


Niobium-doped conductive TiO-TiO2 heterostructure supported bifunctional catalyst for efficient and stable zinc-air batteries.
The development of highly active and durable nonprecious metal-based bifunctional electrocatalysts for oxygen reduction/evolution reaction (ORR/OER) is important for rechargeable zinc-air batteries. Herein, a three-dimensional conductive niobium-doped TiO-TiO2 heterostructure supported ZIF-67-derived Co-NC bifunctional catalyst was fabricated. In the Co-NC@Nb-TiOx catalyst, the Nb doping promoted the formation of TiO-TiO2 heterojunction support, enhanced its conductivity and stability and provided strong electron metal-support interaction between Co-NC and Nb-TiOx. Also, the supported Co-NC nanoparticles provided abundant active sites with excellent ORR/OER activity. Experimental analysis reveals that the high OER activity of Co-NC@Nb-TiOx can be attributed to the in-situ generated CoOOH species. It exhibits excellent ORR activity, as shown by its onset potential (0.95 V vs. RHE) and half-wave potential (0.86 V vs. RHE). Its OER overpotential at 10 mA cm-2 is 480 mV. The zinc-air battery realizes outstanding cycling stability over 225 h cycles tested at 10 mA cm-2. This work demonstrates the importance of designing highly stable metal oxide-supported catalysts in electrochemical energy conversion devices.