Identification, characterization, and mapping of Ecm1, a locus affecting extracellular matrix production and lesion size in Cochliobolus heterostrophus.
A mutant of Cochliobolus heterostrophus lacking the outer layer of extracellular matrix around its germ tubes and hyphae was obtained by mutagenizing protoplasts. The mutant not only lacks the outer matrix, but also produces much smaller lesions on corn leaves than nonmutant strains; the area of mutant lesions averages 0.6 mm2 compared with 5.8 mm2 for nonmutant lesions. Genetic analysis demonstrated that the failure to produce the outer matrix cosegregates with the reduced lesion size, indicating that the two traits are controlled by the same locus, designated Ecm1 (Extracellular Matrix Deficient). The mutant retains normal growth on media and normal abilities to germinate, form appressoria, and penetrate corn leaves. This indicates that the outer matrix is not necessary for infection prior to entrance of the fungus into the leaf. It also indicates that the pathogenicity defect in this mutant is manifested after penetration. To facilitate future tests of whether the pathogenicity defect is caused by the lack of the outer matrix, Ecm1 was mapped. Seven markers linked to Ecm1 were found by analysis of amplified fragment length polymorphisms. Ecm1 maps to chromosome 4; the closest markers to Ecm1 are 5 cM distant, which is estimated to represent about 115 kb.


Intelligent computer reporting 'lack of experience': a confidence measure for decision support systems.
The purpose of this study was to explore the feasibility of developing artificial neural networks that are able to provide confidence measures for their diagnostic advice. Computer-aided decision making can improve physician performance, but many physicians hesitate to use these 'black boxes'. If we are to rely upon decision support systems for such tasks as medical diagnosis it is essential that the computers indicate when the advice given is based on experience, i.e. give a confidence measure. An artificial neural network was trained to diagnose healed anterior myocardial infarction and to indicate 'lack of experience' when test electrocardiograms were different from the electrocardiograms of the training set. A database of 1249 electrocardiograms from patients who had undergone cardiac catheterization was used to train and test the neural network. Thereafter, the ability of the network to indicate 'lack of experience' was assessed using 100 left bundle branch block electrocardiograms, an electrocardiographic pattern that was excluded from the training set. The network indicated that 83% of the left bundle branch block electrocardiograms and 1% of the test electrocardiograms from catheterized patients were different from the electrocardiograms of the training set. All but one of the left bundle branch block electrocardiograms would otherwise be falsely classified as anterior myocardial infarction by the network. Artificial neural networks can be trained to indicate 'lack of experience', and this ability increases the possibility for neural networks to be accepted as reliable decision support systems in clinical practice.


Comparative analysis of HBV and HCV infection in hepatocellular carcinoma and chronic liver disease--an autopsy based study.
Hepatocellular carcinoma (HCC) is one of the common malignancies worldwide including Asian countries. Chronic viral hepatitis is implicated as an important etiological factor in carcinogenesis of liver. To study incidence of hepatitis B (HBV) and C (HCV) viruses in HCC and to compare the incidences with that of chronic liver disease. 40 cases each of HCC (group I) and chronic liver disease including cirrhotic liver (group II) who died of the liver disease. All cases were stained with HBsAg and HBcAb for HBV and RT-PCR for HCV RNA. Different groups were compared using student's t-paired and chi-square tests. Group I--HCC was seen in 37 cirrhotics and 3 non-cirrhotic cases. HBsAg was positive in 32 cases (80%), HBcAb in 22 cases (55%) and HCV in 23 cases (57.5%) (p<0.05). Dysplastic nodule (DN) was seen in 25 cases, HBsAg and HBcAg positivity were seen in 18 and 15 cases respectively. Group II--32 cases were cirrhotic and 8 were non-cirrhotics. HBsAg was positive in 28 (70%), HBcAb in 12 (30%) and HCV in 18 (45%) cases. DN was seen 24 cases, HBsAg and HBcAg postiviy were seen in 16 and 7 cases respectively. HBV and HCV co-infection was seen in 20 and 15 cases, and HCV with HBcAb positivity was seen in 13 and 9 cases in groups I and II respectively. Number of cells in each case showing positivity for HBcAb was also significantly higher in group I (p<0.01). Age and sex distribution did not show any distinctive differences between the two groups. the study highlights a high incidence ofHBVand HCV infection in cases of chronic liver disease and HCC. HBcAb positive state appears to be an independent risk factor for HCC.


Optimization of Citric Acid Production by Immobilized Cells of Novel Yeast Isolates.
Citric acid is a commercially valuable organic acid widely used in food, pharmaceutical, and beverage industries. In this study, 260 yeast strains were isolated from soil, bread, juices, and fruits wastes and preliminarily screened using bromocresol green agar plates for their ability to produce organic acids. Overall, 251 yeast isolates showed positive results, with yellow halos surrounding the colonies. Citric acid production by 20 promising isolates was evaluated using both free and immobilized cell techniques. Results showed that citric acid production by immobilized cells (30-40 g/L) was greater than that of freely suspended cells (8-19 g/L). Of the 20 isolates, two (KKU-L42 and KKU-L53) were selected for further analysis based on their citric acid production levels. Immobilized KKU-L42 cells had a higher citric acid production rate (62.5%), while immobilized KKU-L53 cells showed an ∼52.2% increase in citric acid production compared with free cells. The two isolates were accurately identified by amplification and sequence analysis of the 26S rRNA gene D1/D2 domain, with GenBank-based sequence comparison confirming that isolates KKU-L42 and KKU-L53 were Candida tropicalis and Pichia kluyveri, respectively. Several factors, including fermentation period, pH, temperature, and carbon and nitrogen source, were optimized for enhanced production of citric acid by both isolates. Maximum production was achieved at fermentation period of 5 days at pH 5.0 with glucose as a carbon source by both isolates. The optimum incubation temperature for citric acid production by C. tropicalis was 32 °C, with NH4Cl the best nitrogen source, while maximum citric acid by P. kluyveri was observed at 27 °C with (NH4)2 SO4 as the nitrogen source. Citric acid production was maintained for about four repeated batches over a period of 20 days. Our results suggest that apple and banana wastes are potential sources of novel yeast strains; C. tropicalis and P. kluyveri which could be used for commercial citric acid production.


Stromal cells in long-term cultures: keys to the elucidation of hematopoietic development?
Long-term bone marrow cultures mirror many aspects of in vivo mammalian hematopoiesis. Thus, these cultures have been used widely to analyze the complex interactions that regulate hematopoietic differentiation. Hematopoiesis in vivo and in vitro is dependent on stromal cells, a mixture of support cells. In the past years numerous clonal stromal cell lines derived from murine and human tissues have been isolated and characterized. The stromal cell lines have proved to be invaluable tools for the elucidation of the molecular and cellular signals that govern differentiation and self-renewal of hematopoietic cells. This review describes the salient features of arrow cultures with a focus on the isolation and characterization of stromal cell lines. We summarize how stromal cell lines have been crucial tools for the detection, isolation, and maintenance of rare pluripotent stem cells and B lineage cells. Intriguing questions about the nature of stromal cells, their requirements for growth and differentiation, and their histogenic origin remain areas for further investigation.


Novel functionally grafted pseudo-semi-interpenetrating networks constructed by reactive linear-dendritic copolymers.
This paper describes the synthesis of amphiphilic pseudo-semi-interpenetrating polymer networks (pseudo-semi-IPNs) containing linear poly(styrene) and poly(ethylene glycol) (PEG) cross-linked through monodendritic fragments. A unique feature of the synthetic strategy is the permanent attachment of the linear segment to the PEG network by a transesterification reaction between the hydroxyl groups at both ends of the PEG and peripheral ethyl ester moieties in the monodendron portion of a linear poly(styrene)-dendritic poly(benzyl ether) AB block copolymer. The proceeding of the reaction is monitored by (1)H NMR and size exclusion chromatography (SEC). The formation of an interlock structure between the linear block and the network matrix in the pseudo-semi-IPN is evidenced by the results from spectroscopic analyses and differential scanning calorimetry measurements. The accessibility of functional centers in the grafted semi-IPN is confirmed by model reactions with fluorescent markers, fluorescence spectroscopy, and NMR techniques and shows the potential of these novel materials as sequestering reagents for resin capture-release applications in parallel synthesis, combinatorial chemistry, and advanced drug design.


Ankle loading ameliorates bone loss from breast cancer-associated bone metastasis.
Breast cancer is a serious health problem that preferentially metastasizes to bone. We have previously shown that bone loss can be prevented by mechanical loading, but the efficacy of ankle loading for metastasis-linked bone loss has not been investigated. This study showed that body weight was decreased after inoculation of tumor cells, but ankle loading restored a rapid weight loss. The nonloading group exhibited a decrease in bone volume/tissue volume (BV/TV), trabecular thickness, and trabecular number (all P < 0.01) as well as an increase in trabecular separation (P < 0.001). However, ankle loading improved those changes (all P < 0.05). Furthermore, although the nonloading group increased the tumor bearing as well as expression of IL-8 and matrix metalloproteinase 9, ankle loading decreased them. Induction of tumor in the bone elevated the osteoclast number (P < 0.05) as well as the levels of nuclear factor of activated T-cells cytoplasmic 1, NF-κB ligand, cathepsin K, and serum tartrate-resistant acid phosphatase type 5b, but ankle loading reduced osteoclast activity and those levels (all P < 0.05). Tumor bearing was positively correlated with the osteoclast number (P < 0.01) and negatively correlated with BV/TV and the osteoblast number (both P < 0.01). Collectively, these findings demonstrate that ankle loading suppresses tumor growth and osteolysis by inhibiting bone resorption and enhancing bone formation.-Yang, S., Liu, H., Zhu, L., Li, X., Liu, D., Song, X., Yokota, H., Zhang, P. Ankle loading ameliorates bone loss from breast cancer-associated bone metastasis.


A lipid-based cell penetrating nano-assembly for RNAi-mediated anti-angiogenic cancer therapy.
Limited tumor tissue penetration is one of the key impeding factors retarding successful in vivo exploitations of anti-angiogenic cancer therapy. Herein we report on the design of a cell penetrating peptide-decorated lipid nano-assembly which, upon systemic administration, induces significant mouse tumor growth inhibition via enhanced tumor infiltration of encapsulated anti-angiogenic siRNA.


Esophageal squamous cell carcinoma and gastric cardia adenocarcinoma shared susceptibility locus in PLCE1: a meta-analysis.
Two recent genome-wide association studies have identified a shared susceptibility variation PLCE1 rs2274223 for esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinomas (GCA). Subsequent case-control studies have reported this association in other populations. However, the findings were controversial and the effect remains undetermined. Our aim is to provide a precise quantification of the association between PLCE1 rs2274223 variation and the risk of ESCC and GCA. Studies were identified by a literature search in MEDLINE and EMBASE databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the association in allele, dominant, recessive, homozygous, and heterozygous models. Ten articles were identified, including 22156 ESCC cases and 28803 controls, 5197 GCA cases and 17613 controls. Overall, PLCE1 rs2274223 G allele (G vs. A: OR=1.26, 95% CI: 1.15-1.39 for ESCC; OR=1.51, 95% CI: 1.35-1.69 for GCA) and its carrier (GG +AG vs. AA: OR = 1.23; 95% CI =1.02-1.49 for ESCC; OR =1.62; 95% CI =1.15-2.29 for GCA) were significantly associated with the risk of ESCC and GCA. In stratified analysis by ethnicity, significant association of PLCE1 rs2274223 G allele and the risk of ESCC (OR=1.33, 95% CI 1.21-1.45) and GCA (OR =1.56, 95% CI: 1.47-1.64) was observed in Chinese population. Our meta-analysis results indicated that PLCE1 rs2274223 G allele significantly contributed to the risk of ESCC and GCA, especially in Chinese population.


Sound localization for a virtual sound source in cases of chronic otitis media.
Sound localization in subjects with chronic otitis media (COM) was examined before and soon after ear surgery by means of virtual sound presented by headphones, sound being synthesized based on the head-related transfer functions (HRTFs) in a normal subject. The localization ability in COM patients was usually worse than that in normal subjects, but was better than expected when compared with cases of acute loss. On the other hand, the effects of hearing improvement on localization ability observed in COM patients were smaller than those of simulated acute hearing loss achieved by earplugs in normal subjects. This seems to suggest that the localization cues in patients with chronic hearing loss are different from those under normal conditions.


Genotoxicity assessment of titanium dioxide nanoparticles using a standard battery of in vivo assays.
As one representative of nanometal oxides, titanium dioxide nanoparticles (TiO2-NPs) have been widely used, particularly in the food industry. The genotoxicity of TiO2-NPs has attracted great attention over the years. This study was undertaken to investigate the chromosome and DNA damage effects of TiO2-NPs (0, 50, 150, and 500 mg/kg BW) using rodent models. After a comprehensive characterization, we conducted a standard battery of in vivo genotoxicity tests, including the chromosomal aberration test (CA), micronucleus (MN) test, and the comet test. The results of all these tests were negative. There were no structural or numerical chromosomal abnormalities in mice bone marrow cells, no increase in the frequency of micronucleated polychromatic erythrocytes in mice bone marrow cells, and no elevation in % tail DNA in rat hepatocytes. This indicated that TiO2-NPs did not cause chromosomal damage or have a direct impact on DNA. These findings suggested that TiO2-NPs did not exhibit genotoxicity and provided valuable data for risk assessment purposes.


Thrombotic Microangiopathy, Podocytopathy, and Damage to the Renal Tubules with Severe Proteinuria and Acute Renal Dysfunction Induced by Lenvatinib.
Lenvatinib, a tyrosine kinase inhibitor (TKI), is a stronger inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptors 1 to 4, and platelet-derived growth factor receptor (PDGFR) than other TKIs. We herein report a 77-year-old Japanese woman who received the minimum dose of lenvatinib for treatment of hepatocellular carcinoma. Within one month of starting treatment, she developed severe proteinuria, hypertension, and renal dysfunction. A kidney biopsy showed drug-induced thrombotic microangiopathy, podocytopathy, and polar vasculosis. We also observed damage to the renal tubules, where PDGFR is located. To our knowledge, this is the first report of lenvatinib-induced damage to the renal tubules.


Identification of patients with cancer with a high risk to develop delirium.
Delirium deteriorates the quality of life in patients with cancer, but is frequently underdiagnosed and not adequately treated. In this study, we evaluated the occurrence of delirium and its risk factors in patients admitted to the hospital for treatment or palliative care in order to develop a prediction model to identify patients at high risk for delirium. In a period of 1.5 years, we evaluated the risk of developing delirium in 574 consecutively admitted patients with cancer to our academic oncology department with the Delirium Observation Screening Scale. Risk factors for delirium were extracted from the patient's chart. A delirium prediction algorithm was constructed using tree analysis, and validated with fivefold cross-validation. A total of 574 patients with cancer were acutely (42%) or electively (58%) admitted 1733 times. The incidence rate of delirium was 3.5 per 100 admittances. Tree analysis revealed that the predisposing factors of an unscheduled admittance and a metabolic imbalance accurately predicted the development of delirium. In this group the incidence rate of delirium was 33 per 100 patients (1:3). The AUC of the model was 0.81, and 0.65 after fivefold cross-validation. We identified that especially patients undergoing an unscheduled admittance with a metabolic imbalance do have a clinically relevant high risk to develop a delirium. Based on these factors, we propose to evaluate preventive treatment of these patients when admitted to the hospital in order to improve their quality of life.


Evolution of obesity prevalence in France: an age-period-cohort analysis.
A rapid increase in the prevalence of obesity has been reported in France since 1990. We investigated the impact of birth cohort on the changes in obesity prevalence after taking into account age and survey period. We analyzed data from 4 national surveys in 1997, 2000, 2003, and 2006. For each survey, self-reported data on weight and height were recorded on mailed questionnaires sent to a sample of 20,000 households, representative of the French population. Obesity was defined according to World Health Organization criteria as body mass index >or=30 kg/m. We modeled the prevalence of obesity using logistic regression with age, cohort, and period as explanatory variables. As these variables are linearly dependent, only nonlinear effects can be estimated uniquely and interpreted, after including specific chosen constraints in the models. There was a progressive increase in the prevalence of obesity between 1997 and 2006, attributable either to a period effect or to a cohort effect. There was a substantial departure from a linear trend for the cohort effect only, which seemed to be stronger in women: there was an acceleration in the prevalence of obesity with birth cohort for individuals born after the mid-1960s, in both sexes. Our results are consistent with previous studies in other countries. Compared with older generations, men and women born in the late 1960s may have been subject to early exposures that increased their lifelong susceptibility to obesity.


[Recent possibilities for the treatment of osteoporosis in the aged].
Treatment of idiopathic osteoporosis in the elderly presupposes exact radiological diagnosis, the exclusion of a primary illness as the cause of the pathological process and exact differential diagnosis from other metabolic osteopathies. We consider possible means of prevention of the immobilization of old people, and appropriate hormonal substitution in cases of previous illnesses which coincide with a disturbance of the gonadal function, as important prophylactic measures. In the case of manifest osteoporosis, if possible, an assignment of the disease to a manifestation with high or low bone turnover should be made, by means of biochemical adjuvants. In high bone turnover, the substitution of sex hormones or the administration of calcitonin is indicated, particularly if symptoms of pain are distinct. In osteoporosis with low bone turnover, fluoride in long-term therapy is the preferred medication. The latest studies show that a combination of fluoride and active vitamin D metabolites is preferable to monotherapy. All therapy for this disease, independent of the age of the patient, should be supported by isometric exercises, analgesics and appropriate dietary measures. Orthopaedic supporting measures should be applied only if conservative measures in acute vertebral fractures fail.


Microbial interactions during sugar cane must fermentation for bioethanol production: does quorum sensing play a role?
Microbial interactions represent important modulatory role in the dynamics of biological processes. During bioethanol production from sugar cane must, the presence of lactic acid bacteria (LAB) and wild yeasts is inevitable as they originate from the raw material and industrial environment. Increasing the concentration of ethanol, organic acids, and other extracellular metabolites in the fermentation must are revealed as wise strategies for survival by certain microorganisms. Despite this, the co-existence of LAB and yeasts in the fermentation vat and production of compounds such as organic acids and other extracellular metabolites result in reduction in the final yield of the bioethanol production process. In addition to the competition for nutrients, reduction of cellular viability of yeast strain responsible for fermentation, flocculation, biofilm formation, and changes in cell morphology are listed as important factors for reductions in productivity. Although these consequences are scientifically well established, there is still a gap about the physiological and molecular mechanisms governing these interactions. This review aims to discuss the potential occurrence of quorum sensing mechanisms between bacteria (mainly LAB) and yeasts and to highlight how the understanding of such mechanisms can result in very relevant and useful tools to benefit the biofuels industry and other sectors of biotechnology in which bacteria and yeast may co-exist in fermentation processes.


The major biotinyl protein from Pisum sativum seeds covalently binds biotin at a novel site.
Seeds of Pisum sativum contain a biotinyl polypeptide called SBP65 that behaves as a putative sink for the free vitamin, representing more than 90% of the total protein-bound biotin in mature seeds. A cDNA encoding SBP65 was cloned and sequenced. The deduced primary structure of the protein was confirmed by protein sequencing. Peptide sequencing also indicated binding of the biotin to lysine 103. The biotinylation domain of SBP65 differs markedly from that of presently known biotin enzymes. Molecular analysis of the protein sequence reveals an extremely hydrophilic protein containing several repeated motifs. These properties, as well as the temporal and spatial patterns of expression of this protein, suggest that SBP65 belongs to the LEA (late embryogenesis-abundant) group of proteins.


Safety of Procalcitonin Guided Early Discontinuation of Antibiotic Therapy among Children Receiving Cancer Chemotherapy and Having Low-Risk Febrile Neutropenia: A Randomized Feasibility Trial (ProFenC Study).
In low-risk febrile neutropenia (LR-FN), the safety of early discontinuation of empiric antibiotics without marrow recovery is not well established. This study aimed to evaluate the safety of procalcitonin (PCT) guided early discontinuation of antibiotics in LR-FN. In this trial, children with LR-FN with an afebrile period of at least 24 h, sterile blood culture, and negative/normalized PCT were randomized at 72 h of starting antibiotics into two groups: intervention arm and standard arm. The antibiotics were stopped in the intervention arm regardless of absolute neutrophil count (ANC), while in the standard arm, antibiotics were continued for at least 7 days or until recovery of ANC (>500/mm3). The primary objective was to determine the treatment failure rates, and the secondary objective was to compare the duration of antibiotics and all-cause mortality between the two arms. A total of 46 children with LR-FN were randomized to either the intervention arm (n = 23) or the standard arm (n = 23). Treatment failure was observed in 2/23 (8.7%) of patients in the intervention arm compared to 1/23 (4.3%) in the standard arm [RR: 2 (95% CI: 0.19-20.6); p = 0.55]. The median duration of antibiotics in the intervention arm and standard arm were 3 days vs 7 days (P= <0.001). There was no mortality in this study. PCT-guided early discontinuation of empirical antibiotics in LR-FN is feasible. There was no significant difference observed in treatment failure between the early discontinuation of antibiotics vs standard therapy. The total duration of antibiotic exposure was significantly lesser in the discontinuation arm. Further, larger multicenter studies are needed to confirm the finding of this study.


Worldwide variation of dialysis-associated peritonitis in children.
Peritonitis is the most common cause of dialysis failure in children on chronic peritoneal dialysis. We performed a prospective study of 501 peritonitis episodes in 44 pediatric dialysis centers located in 14 countries that examined peritonitis etiology, efficiency of opinion-based management guidelines, and final outcomes. Culture-negative incidence varied significantly from 11% in North America to 67% in Mexico. Argentina and North America had the highest rate of Gram-negative episodes. Pseudomonas-based peritonitis was eightfold more common in the United States than in Europe, and correlated with the frequency of exit site cleansing and topical mupirocin administration. Significant regional variation in antibiotic susceptibility was noted for the first generation cephalosporins and aminoglycosides. Initial response rates to standardized empiric antibiotic treatment did not differ between regions; however, final outcomes were significantly less favorable in Eastern Europe. The wide regional variation in culture-negative peritonitis, and the distribution and antibiotic susceptibilities of causative bacteria needs to be taken into consideration when the guidelines for empiric therapy of pediatric dialysis-associated peritonitis are revised.


Colonoscopic Perforations.
Colonoscopy is the gold standard for colon cancer screening. It has led to a decrease in the incidence of colorectal cancer mortality. Colon perforation is a feared complication of this procedure with high morbidity and substantial mortality. Due to the high volume of colonoscopies performed, the absolute number of colonoscopic perforations is relatively high. It leads to a substantial cost to the patient and the health system. Understanding the mechanisms and the risk factors may help in preventing perforation. Traditionally, a laparotomy with creation of a stoma was used to address this complication. However, minimally invasive techniques such as laparoscopy and endoluminal repairs are being used more commonly now. More surgeons are favoring primary anastomosis (with or without a diverting loop ileostomy) than a Hartmann procedure.


Tc-99m DTPA uptake in extramedullary plasmacytoma of the retroperitoneum.
A case is presented in which uptake of Tc-99m DTPA has been demonstrated in an extramedullary plasmacytoma of the retroperitoneum. Because Ga-67 citrate does not concentrate in the same areas as Tc-99m DTPA, a radionuclide-specific uptake mechanism may be present. Extramedullary plasmacytoma should be included in the list of possible causes if extrarenal or extracentral nervous system uptake of Tc-99m DTPA occurs.


Increased hydraulic conductance of human articular cartilage and subchondral bone plate with progression of osteoarthritis.
Osteoarthritis (OA) is characterized by progressive degeneration of articular cartilage and remodeling of the subchondral bone plate, comprising calcified cartilage and underlying subchondral bone. Calcified cartilage remodeling due to upward invasion by vascular canals or to calcified cartilage erosion may contribute to biomechanical alteration of the osteochondral tissue and its subchondral bone plate component. The study hypothesis was that hydraulic conductance of osteochondral tissue and subchondral bone plate increases with structural changes indicative of increasing stages of OA. Osteochondral cores were harvested from the knees of cadaveric tissue donors and from discarded fragments from patients with OA undergoing knee surgery. The osteochondral cores from tissue donors were macroscopically normal, and the cores from patients with OA had partial-thickness or full-thickness erosion to bone. The cores were perfusion-tested to determine the hydraulic conductance, or ease of fluid flow, in their native state and after enzymatic removal of cartilage. Adjacent portions were analyzed by 3-dimensional histology for calcified cartilage, subchondral bone, and subchondral bone plate thickness and vascular canal density. Hydraulic conductance of native osteochondral tissue and subchondral bone plate was higher (2,700-fold and 3-fold, respectively) in fully eroded samples than in normal samples. The calcified cartilage layer was thicker (1.5-fold) in partially eroded samples than in normal samples but thinner and incomplete in fully eroded samples. Subchondral bone plate vascularity was altered with increasing stages of OA. During joint loading, increased hydraulic conductance of the osteochondral tissue and subchondral bone plate could have deleterious biomechanical consequences for cartilage. Increased fluid exudation from overlying and opposing cartilage, increased fluid depressurization, and increased cartilage tissue strains could lead to chondrocyte death and cartilage damage.


Highly functionalized alkenes produced from base-free organocatalytic Wittig reactions: (E)-3-benzylidenepyrrolidine-2,5-dione, (E)-3-benzylidene-1-methylpyrrolidine-2,5-dione and (E)-3-benzylidene-1-tert-butylpyrrolidine-2,5-dione.
The Wittig reaction is a fundamental transformation for the preparation of alkenes from carbonyl compounds and phosphonium ylides. The ylides are prepared prior to the olefination step from the respective phosphonium salts by deprotonation utilizing strong bases. A first free-base catalytic Wittig reaction for the preparation of highly functionalized alkenes was based on tributylphosphane as the catalyst. Subsequently we developed a system employing a phospholene oxide as a pre-catalyst and trimethoxysilane as reducing agent which operates under milder conditions. The title compounds, (E)-3-benzylidenepyrrolidine-2,5-dione, C11H9NO2, (I), the methylpyrrolidine derivative, C12H11NO2, (II), and the tert-butylpyrrolidine derivative, C15H17NO2, (III), have been synthesized by base-free catalytic Wittig reactions. In the crystal of (I), molecules are linked into centrosymmetric dimers via pairs of N-H...O hydrogen bonds. Furthermore, in the crystal structure of (III), there are two molecules in the asymmetric unit, whereas in (I) and (II), only one molecule is present.


Alternation of the Autonomic Nervous System Is Associated With Pulmonary Sequelae in Patients With COVID-19 After Six Months of Discharge.
Previous studies suggest that autonomic dysfunction is associated with disease severity in acute phase in patients with coronavirus disease 2019 (COVID-19). However, the association between autonomic dysfunction and pulmonary sequelae in patients with COVID-19 is unknown. We conducted a prospective study to investigate the association between autonomic dysfunction and pulmonary sequelae in patients with COVID-19 discharged for 6 months. We included 40 eligible participants and collected the following indicators: heart rate variability (HRV), pulmonary function tests (PFTs), lung X-ray computed tomography (CT), routine blood parameters, liver function parameters, and lymphocyte subsets. We found that at 6 months post-discharge, HRV still had a tight correlation with pulmonary fibrosis. There was a significant difference in HRV between patients with and without diffusion dysfunction, but HRV did not differ between patients with or without ventilatory dysfunction. Diffusion dysfunction and pulmonary fibrosis were tightly associated, and HRV index changes in patients with diffusion dysfunction had the same trend as that of patients with pulmonary fibrosis. They had a lower standard deviation of NN intervals (SDNN), the standard deviation of the average NN intervals (SDANN), and the triangular index, but a higher ratio between LF and HF power (LF/HF). In addition, WBC, neutrophils, and CD4/CD8 were correlated with pulmonary fibrosis and HRV. We concluded that autonomic dysfunction is closely associated with pulmonary fibrosis and diffusion dysfunction, and immune mechanisms may potentially contribute to this process.


Nuclear factor 90 mediates activation of the cellular antiviral expression cascade.
Viral infection triggers a cascade of interferon response genes, but the mechanisms that prime such innate antiviral defenses are poorly understood. Among candidate cellular mediators of the antiviral response are the double-stranded RNA (dsRNA)-binding proteins. Here we show that a C-terminal variant of the ubiquitous dsRNA-binding protein, nuclear factor 90 (NF90ctv), can activate the interferon response genes in the absence of viral infection. NF90ctv-expressing cells were infected with the syncytium-inducing HIV-1 strain NL4-3 and were shown to inhibit viral replication. To gain insight into this mechanism of protection, we analyzed the expression profiles of NF90ctv-positive cells as compared with parental cells transduced with the empty vector. Of the 5600 genes represented on the expression arrays, 90 displayed significant (4-fold or more) changes in mRNA levels in NF90-expressing cells. About 50% are known interferon alpha/beta-stimulated genes. The microarray expression data were confirmed by quantitative reverse transcriptase-polymerase chain reaction analysis of six representative interferon-inducible genes. Electrophoretic mobility shift assays showed that the biological response is mediated by the activation of transcription factors in NF90ctv-expressing cells. Functional significance of the activated transcription complex was evaluated by transfection assays with luciferase reporter constructs driven by the interferon-inducible promoter from the 2'-5'-oligoadenylate synthetase (p69) gene. Resistance to HIV-1, caused by the expression of NF90ctv in the cell culture system, appears to be mediated in part by the induction of interferon response genes. This leads to a hypothesis as to the mechanism of action of NF90 in mediating endogenous antiviral responses.


Kinematic coupling of the glenohumeral and scapulothoracic joints generates humeral axial rotation.
Glenohumeral and scapulothoracic motion combine to generate humerothoracic motion, but their discrete contributions towards humerothoracic axial rotation have not been investigated. Understanding their contributions to axial rotation is important to judge the effects of pathology, surgical intervention, and physiotherapy. Therefore, the purpose of this study was to investigate the kinematic coupling between glenohumeral and scapulothoracic motion and determine their relative contributions towards axial rotation. Twenty healthy subjects (10 M/10F, ages 22-66) were previously recorded using biplane fluoroscopy while performing arm elevation in the coronal, scapular, and sagittal planes, and external rotation in 0° and 90° of abduction. Glenohumeral and scapulothoracic contributions towards axial rotation were computed by integrating the projection of glenohumeral and scapulothoracic angular velocity onto the humeral longitudinal axis, and analyzed using one dimensional statistical parametric mapping and linear regression. During arm elevation, scapulothoracic motion supplied 13-20° (76-94%) of axial rotation, mainly via scapulothoracic upward rotation. The contribution of scapulothoracic motion towards axial rotation was strongly correlated with glenohumeral plane of elevation during arm elevation. During external rotation, scapulothoracic motion contributed 10° (8%) towards axial rotation in 0° of abduction and 15° (15%) in 90° of abduction. The contribution of scapulothoracic motion towards humerothoracic axial rotation could explain the simultaneous changes in glenohumeral plane of elevation and axial rotation associated with some pathologies and surgeries. Understanding how humerothoracic motion results from the functional coupling of scapulothoracic and glenohumeral motions may inform diagnostic and treatment strategies by targeting the source of movement impairments in clinical populations.


[New Developments in CKD-MBD. The present state and problem of CKD-MBD treatment in Japan].
When considering the CKD-MBD treatment of our country, we should take account of clinical background, such as a high ratio of long-term hemodialysis patients, a small number of renal transplantation surgeries, etc. Furthermore, insurance systems differ from country to country and the universal public insurance system will also have some influences on medical circumstances in Japan. Re-considering the CKD-MBD treatment of Japan from these perspectives, there remain some issues to be addressed ; a choice of which phosphate binder is the best, a selection of treatment for severe secondary hyperparathyroidism, cinacalcet or surgery. The issues about native vitamin D agent and the treatment for osteoporosis in CKD patients should be also resolved. This article argues the present situation of CKD-MBD treatment and considers new issues and problems for more sophisticated CKD-MBD therapy in Japan.


Three cases of fetal ascites with successful outcome and seven year evaluation of NIHF: 1981-1987.
Three pregnant women with fetal ascites were admitted to our hospital at 30, 32 and 33 weeks of gestation on diagnosis by sonogram. On sonogram, all the fetuses were initially with marked ascites but without any pleural or pericardial effusion or subcutaneous edema. Under observation by sonogram and cardiotocogram, obstetrical intervention was performed by cesarean section in all 3 cases; at 31 weeks of gestation due to notably increased ascites, at 32 weeks due to fetal distress and at 35 weeks due to development of subcutaneous edema, respectively, and the subsequent courses were uneventful. On the other hand, in our precious experience with 21 cases of NIHF over a period of 7 years, only 2 babies with NIHF have been born alive. We think fetal ascites should be considered an initial sign of NIHF and the successful outcome of these three cases were due to early diagnosis by frequent sonographic examination.


Cerebral dominance for consciousness.
In a prospective study we evaluated the relationship of level of consciousness to hemispheric side of lesion following acute cerebrovascular injury. Fifty-seven percent of patients with left hemispheric lesions had initial impairment of consciousness, in contrast to 25% with right-sided damage.


Effects of concomitant temozolomide and radiation therapies on WT1-specific T-cells in malignant glioma.
Immunotherapy targeting the Wilms' tumour 1 gene product has been proven safe and effective for treating malignant glioma in a phase II clinical study. Currently, radiation/temozolomide therapy is the standard treatment with only modest benefit. Whether combining radiation/temozolomide therapy with WT1 immunotherapy will have a negating effect on immunotherapy is still controversial because of the significant lymphocytopaenia induced by the former therapy. To address this issue, we investigated the changes in frequency and number of WT1-specific T-cells in patients with malignant gliomas. Twenty-two patients with newly diagnosed malignant glioma who received standard radiation/temozolomide therapy were recruited for the study. Blood samples were collected before treatment and on the sixth week of therapy. The frequencies and numbers of lymphocytes, CD8(+) T-cells, WT1-specific T-cells, regulatory T-cells, natural killer cells and natural killer T-cells were measured and analysed using T-tests. Analysis of the frequency of T lymphocytes and its subpopulation showed an increase in regulatory T-cells, but no significant change was noted in the populations of T-cells, WT1-specific T-cells, NK cells and NKT cells. Reductions in the total numbers of T-cells, WT1-specific T-cells, NK cells and NKT cells were mainly a consequence of the decrease in the total lymphocyte count. Radiation/temozolomide therapy did not significantly affect the frequency of WT1-specific T-cells, suggesting that the combination with WT1 immunotherapy may be possible, although further assessment in the clinical setting is warranted.


Specificity of experience-dependent pitch representation in the brainstem.
Crosslanguage comparisons of brainstem-evoked potentials have revealed experience-dependent plasticity in pitch representation for curvilinear f0 contours representative of Mandarin tones. To assess the tolerance limits of this experience-dependent selectivity, we evaluated cross-linguistically (Chinese, English) the pitch strength and tracking accuracy of linear rising and falling f0 ramps representative of Mandarin tones 2 and 4. No crosslanguage differences in pitch strength or accuracy were observed for either tone, indicating that stimuli with linear rising/falling ramps elicit homogeneous pitch representations at the level of the brainstem regardless of language experience. We conclude that pitch extraction at the brainstem level is critically dependent on specific dimensions of pitch contours that native speakers have been exposed to in natural speech contexts.


Microanatomy of lymphocyte-endothelial interactions at the high endothelial venules of lymph nodes.
Lymphocyte trafficking into lymph nodes and Peyer's patches is mediated primarily by specifically differentiated venules, called high endothelial venules (HEVs), located in the tissue parenchyma. HEVs have a unique morphology and phenotype, which enables them to interact with circulating lymphocytes efficiently. That is, the HEV endothelial cells have a tall and plump appearance, and constitutively express multiple adhesion molecules and chemokines on their surface. These molecules can interact with cognate receptors on circulating lymphocytes, thereby mediating the stepwise and sequential lymphocyte adhesion and transendothelial migration (TEM) at the HEV endothelial luminal surface. This review summarizes the fine morphological aspects of the unique HEV endothelial cells, with special reference to the spatial distribution of the adhesion molecules and chemokines that regulate lymphocyte migration.


Pharmacokinetics of flavanone glycosides after ingestion of single doses of fresh-squeezed orange juice versus commercially processed orange juice in healthy humans.
Orange juice is a rich source of flavonoids considered beneficial to cardiovascular health in humans. The objective of this study was to analyze the pharmacokinetics of the main flavanone glycosides, hesperidin and narirutin, in humans after the consumption of two styles of orange juice, fresh-squeezed (FOJ) and commercially processed (POJ), differing in their amounts of soluble and insoluble forms of these compounds. Healthy human subjects consumed 11.5 mL/kg body weight of FOJ, and after an interval of 30 days, consumed the same quantity of POJ. The results showed that there were no significant differences in the Tmax of the pharmacokinetic curves for the metabolites of hesperidin and narirutin following the consumption of the two styles of juices, and corrected for differences in doses in the POJ and FOJ, there were also no significant differences in the AUC and Cmax values and percent absorption of these compounds.


Liquor landscapes: Does access to alcohol outlets influence alcohol consumption in young adults?
Few longitudinal studies have examined the impact of liquor licences on alcohol consumption, and none in young adults, the life stage when alcohol intake is at its highest. We examined associations between liquor licences (i.e., general licences, on-premise licences, liquor stores, and club licences) and alcohol consumption at 20-years (n=988) and 22-years (n=893), and whether changes in the licences between time-points influenced alcohol consumption (n=665). Only general licences were associated with alcohol consumption at 20-years (p=0.037), but by 22-years, all licences types were positively associated with alcohol consumption (p<0.05). Longitudinal analyses showed that for each increase in liquor stores over time, alcohol consumption increased by 1.22g/day or 8% (p=0.030), and for each additional club licence, consumption increased by 0.90g/day or 6% (p=0.007). Limiting liquor licences could contribute to a reduction in young adults' alcohol intake.


Electrophoretic processing of chitosan based composite scaffolds with Nb-doped bioactive glass for bone tissue regeneration.
Bioactive glasses (BGs), due to their ability to influence osteogenic cell functions, have become attractive materials to improve loaded and unloaded bone regeneration. BG systems can be easily doped with several metallic ions (e.g., Ag, Sr, Cu, Nb) in order to confer antibacterial properties. In particular, Nb, when compared with other metal ions, has been reported to be less cytotoxic and possess the ability to enhance mineralization process in human osteoblast populations. In this study, we co-deposited, through one-pot electrophoretic deposition (EPD), chitosan (CS), gelatin (GE) and a modified BG containing Nb to obtain substrates with antibacterial activity for unloaded bone regeneration. Self-standing composite scaffolds, with a defined porosity (15-90 μm) and homogeneous dispersion of BGs were obtained. TGA analysis revealed a BG loading of about 10% in the obtained scaffolds. The apatite formation ability of the scaffolds was evaluated in vitro in simulated body fluid (SBF). SEM observations, XRD and FT-IR spectra showed a slow (21-28 days) yet effective nucleation of CaP species on BGs. In particular, FT-IR peak around 603 cm-1 and XRD peak at 2θ = 32°, denoted the formation of a mineral phase after SBF immersion. In vitro biological investigation revealed that the release of Nb from composite scaffolds had no cytotoxic effects. Interestingly, BG-doped Nb scaffolds displayed antibacterial properties, reducing S. lutea and E. coli growth of ≈60% and ≈50%, respectively. Altogether, the obtained results disclose the produced composite scaffolds as promising materials with inherent antibacterial activity for bone tissue engineering applications.


Ghana's herbal medicine industry: prospects, challenges and ways forward from a developing country perspective.
The herbal medicine industry is one of the fastest growing industries in the world. However, no detailed assessments have been undertaken on how to achieve the benefits of this industry for developing countries. This study examined the herbal medicine industry in Ghana, with a particular focus on its prospects, challenges and ways forward. The prospects of the medicinal plant trade are huge, and include reducing the national health budget, being a source of foreign and domestic income, as well as creation of employment and poverty reduction. However, the industry is currently inundated with several challenges, such as registration of herbal medicine products and practitioners, a lack of clinical trials for herbal products, standards and quality control issues, shortage of raw plant materials for production, and insufficient scientific research to support traditional claims on the pharmacological effects of medicinal plants. I propose a number of interventions to address these challenges: increased government support, capacity building initiatives, improved regulation of herbal medicines, application of modern technology in the manufacturing of herbal products, large-scale cultivation of medicinal plants, and improved packaging and branding for herbal medicines. Both the national government and the private sector have crucial roles to deliver in the development of the herbal medicine industry in a country like Ghana.


Resection and Primary Closure of Edematous Glossoepiglottic Mucosa in a Dog Causing Laryngeal Obstruction.
An approximately 22 mo old male neutered English bulldog was evaluated for acute onset of dyspnea with suspected brachycephalic obstructive airway syndrome (BOAS). Laryngoscopic exam revealed diffuse, severe edema and static displacement of redundant glossoepiglottic (GE) mucosa causing complete obstruction of the larynx and epiglottic entrapment. Static displacement of the GE mucosa was observed and determined to be the overriding component of dyspnea in this patient with BOAS. Resection and primary closure with two separate, simple continuous sutures of the GE mucosa were performed. Resection and primary closure of the GE mucosa resolved the acute onset of dyspnea in this patient. Surgical correction of the stenotic nares, elongated soft palate, and everted laryngeal saccules were performed under the same anesthetic procedure. Static displacement of the GE mucosa may occur in patients with BOAS. Surgical resection and closure of the GE mucosa resolved this patient's dyspnea and is recommended in airway obstruction. It remains to be determined if primary closure and subsequent tensioning or scar tissue of the GE mucosa results in further complications related to restricted epiglottic movement.


Characterization of superlighting polymer-DNA aggregates: a fluorescence and light scattering study.
The massive amplification of fluorescence signal observed upon hybridization of as few as five DNA molecules into self-assembled structures formed between a cationic polymer and DNA oligonucleotides is investigated. These superlighting polymer-DNA aggregates were studied by fluorescence spectroscopy, static and dynamic light scattering, and zeta potential measurements in order to characterize the aggregation behavior and to understand the processes involved during DNA detection. Multi-angle laser light scattering was also used to obtain the weight-average aggregate mass (AM), the aggregation number (Nagg), the radius of gyration (Rg), and the dissymmetry ratio (z). These results have been used, together with TEM imaging, to propose a suitable physical model for the aggregates.


The effect of flight-related behaviour on the risk of venous thrombosis after air travel.
In a case-control study including 11,033 participants (The Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study) on risk factors of venous thrombosis, we studied the effect of flight-related behaviour on the risk of venous thrombosis after air travel. Patients and control subjects received a questionnaire on risk factors for venous thrombosis, including recent travel history and details of their last flight. From this population, 80 patients and 108 control subjects were selected who had recently (<8 weeks) travelled for more than 4 h by aeroplane. Window seating compared to aisle seating increased the risk twofold [odds ratio (OR) 2.2; 95% confidence interval (CI): 1.1-4.4], particularly in those who were obese (OR 6.1; 95% CI: 0.5-76.2). Anxiety (OR 2.5; 95% CI: 0.9-7.0) and sleeping (OR 1.5; 95% CI: 0.7-3.1) may increase the risk slightly. The risk was not affected by alcohol consumption (OR 1.1; 95% CI: 0.5-2.4). Flying business class may lower the risk (OR 0.7; 95% CI: 0.2-1.8). We did not find a protective effect for several measures currently part of standard advice from airlines and clinicians, i.e. drinking non-alcoholic beverages, exercising or wearing stockings. The effect of behavioural factors during flying on the risk of venous thrombosis after air travel is limited. Current advice on prevention of travel-related thrombosis may have to be reconsidered.


[Extensive small bowel resections].
Bowel resections of at least 70% of the total length give rise to nutritional and metabolic disorders. The consequences are also related to the site of the resection itself, to the causative disease and thus to the patient's morphological and functional adaptation capacity. Over the past 20 years we have operated on 32 patients for vascular disorders, Crohn's disease, intestinal volvulus, actinic enteritis, and ileo-caecal carcinoma. In all patients total parenteral nutrition was started and followed by enteral nutrition and oral feeding after variable periods of time. The postoperative course, in terms of adaptation and stabilisation, was regular on most cases: only in the patients operated on for Crohn's disease was symptom and nutritional remission belated or incomplete. The perioperative mortality was 34% (11 patients). The extent of the resection was often conditioned by the topography of irreversible anatomico-pathological lesions and only in one case did a colic resection prove necessary. In more extensive resections, involving a longer adaptation time, enteral nutrition was supplemented with total parenteral nutrition for lengthier periods.


The origin of cerebrospinal fluid somatostatin: hypothalamic or disperse central nervous system secretion?
The present study deals with the origin of somatostatin in cerebrospinal fluid. Two groups of experiments were performed: (1) Diagnostic lumbar puncture was performed in 37 patients admitted for various neurological diseases. Immunological determination of albumin and gamma-globulin, and radioimmunological analysis of somatostatin in successive cerebrospinal fluid taps demonstrated that while the protein concentration was approximately 20% lower in the 11th ml compared to the 1st ml drawn, the somatostatin concentration was constant. (2) Intravenous arginine infusion (30 G/30 min) induced identical patterns of plasma growth hormone in 8 patients with multiple sclerosis in relapse, in 6 patients with multiple sclerosis in the stable phase, and in 7 patients in whom no neurological disease was eventually diagnosed. Cerebrospinal fluid somatostatin was significantly lower in the patients with multiple sclerosis in relapse than in the two other groups, while cerebrospinal fluid growth hormone concentration was identical. There was no correlation between basal or arginine provoked plasma growth hormone and the cerebrospinal fluid content of somatostatin. The results indicate that cerebrospinal fluid somatostatin is released dispersely from the central nervous system including the spinal cord - and that it offers no indication of the activity or tone of hypothalamic growth hormone release inhibiting control of the pituitary gland.


[Perioperative outcomes after endovascular versus open repair of abdominal aortic aneurysms: a single center experience].
To evaluate the outcomes of endovascular repair (EVAR) versus open repair (OR) in the patients with abdominal aortic aneurysm (AAA) and compare their perioperative rates of morbidity and mortality. The clinical data of 371 AAA patients from January 2006 to January 2011 were collected and analyzed. Endovascular (n = 174) and open (n = 197) repairs were performed. The relevant parameters included preoperative status, intraoperative blood loss, procedure time, intensive care unit (ICU) stay length, ventilatory support time, postoperative fasting time and duration of postoperative hospital stay and anesthesia methods. The perioperative rates of morbidity and mortality were presented. The patients of EVAR group were elder than those of OR group [(72 ± 8) vs (60 ± 14) years old, P = 0.000]. The comorbidity rate of chronic obstructive pulmonary disease (COPD) in EVAR group was higher than that in OR group (31.0% vs 21.8%, P = 0.045). As compared with OR group, the EVAR group had less blood loss [(125 ± 43) vs (858 ± 602) ml, P = 0.000], a lower rate of blood transfusion (0 vs 71.1%, P = 0.000), shorter ICU stay length [(15 ± 5) vs (31 ± 11) h, P = 0.000], shorter postoperative fasting time [(7 ± 4) vs (90 ± 32) h, P = 0.000], shorter procedure time [(146 ± 39) vs (210 ± 24) min, P = 0.000] and shorter ventilatory support time [(90 ± 23) vs (220.0 ± 132.0) min, P = 0.000]. In EVAR group, general (88, 50.6%), epidural (52, 30.0%) and local (34, 19.4%) anesthesia were used. General anesthesia was used for all OR group patients. The duration of postoperative hospital stay was similar in two groups (9.1 ± 2.7) d vs (9.2 ± 2.6) d (P = 0.798). The perioperative complication rate was lower in EVAR group (12.6% vs 27.0%, P = 0.001). And the 30-day mortality rate was 1.15% in EVAR group and 2.0% in OR group. Endovascular repair is less-invasive in AAA patients and offers significant advantages over open surgery. Especially it is indicated for those patients non-suitable for open surgery. And a long-term survival rate is expected.


Beauty, symmetry, and magnetocaloric effect—four-shell keplerates with 104 lanthanide atoms.
The hydrolysis of Ln(ClO4)3 in the presence of acetate leads to the assembly of the three largest known lanthanide-exclusive cluster complexes, [Nd104(ClO4)6(CH3COO)60(μ3-OH)168(μ4-O)30(H2O)112]·(ClO4)18·(CH3CH2OH)8·xH2O (1, x ≈ 158) and [Ln104(ClO4)6(CH3COO)56(μ3-OH)168(μ4-O)30(H2O)112]·(ClO4)22·(CH3CH2OH)2·xH2O (2, Ln = Nd; 3, Ln = Gd; x ≈ 140). The structure of the common 104-lanthanide core, abbreviated as Ln8@Ln48@Ln24@Ln24, features a four-shell arrangement of the metal atoms contained in an innermost cube (a Platonic solid) and, moving outward, three Archimedean solids: a truncated cuboctahedron, a truncated octahedron, and a rhombicuboctahedron. The magnetic entropy change of ΔS(m) = 46.9 J kg(-1) K(-1) at 2 K for ΔH = 7 T in the case of the Gd104 cluster is the largest among previously known lanthanide-exclusive cluster compounds.


Free latissimus dorsi muscle flap with skin graft for treatment of traumatic chronic bony wounds.
Based on this review of 35 cases of chronic bony wounds, it would appear that the free-muscle flap method of wound closure and nourishment after thorough dead bone debridement is an attractive and successful alternative to local skin flaps, staged skin flaps, or extend skin-muscle flaps in areas where reliable muscle flaps are not available. It would also seem that the latissimus dorsi muscle flap with skin graft is an ideal donor-muscle transfer with features allowing a favorable and contoured surface in the recipient site and minimal aesthetic and functional deformity in the donor site.


Myofibroblastic contraction in spontaneous regression of multiple congenital mesenchymal hamartomas.
Subcutaneous nodules from a newborn boy with "multiple fibromatosis" involving the head, neck, trunk, and all four extremities were studied by light microscopy, transmission electron microscopy, and immunofluorescent techniques. Light microscopy suggested a hamartomatous process with fibroblastic adipose, vasoformative and apparent smooth muscle components. The principal cell population combined ultrastructural characteristics of both fibroblasts and smooth muscle cells. Immunofluorescent studies revealed binding of human anti-smooth muscle antibody to the cytoplasm of the spindle cell population of the subdermal nodules but not to fibroblasts of the overlying un-involved skin. The ultrastructural and immunofluorescent studies revealed the previously underscribed fact that fibrous hamartoma of infancy is principally a proliferation of myofibroblasts. At age 8 months, there was complete spontaneous regression of all subcutaneous nodules not previously altered by excisional biopsy. The authors conclude that myofibroblasts are fibrocontractile cells, which play a role in shrinkage and eventual disappearance of these subdermal hamartomas.


Research and Development of Preclinical Overhauser-Enhanced Magnetic Resonance Imaging.
Significance: Imaging free radicals, including reactive oxygen species and reactive nitrogen species, can be useful for understanding the pathology of diseases in animal disease models, as they are related to various physiological functions or diseases. Among the methods used for imaging free radicals, Overhauser-enhanced magnetic resonance imaging (OMRI) has a short image acquisition time and high spatial resolution. Therefore, OMRI is used to obtain various biological parameters. In this study, we review the methodology for improving the biological OMRI system and its applications. Recent Advances: The sensitivity of OMRI systems has been enhanced significantly to allow the visualization of various biological parameters, such as redox state, partial oxygen pressure, and pH, in different body parts of small animals, using spin probes. Furthermore, both endogenous free radicals and exogenous free radicals present in drugs can be visualized using OMRI. Critical Issues: To acquire accurate biological parameters at a high resolution, it is essential to increase the electron paramagnetic resonance (EPR) excitation efficiency and achieve a high enhancement factor. In addition, the size and magnetic field strength also need to be optimized for the measurement target. Future Directions: The advancement of in vivo OMRI techniques will be useful for understanding the pathology, diagnosis, and evaluation of therapeutic effects of drugs in various disease models. Antioxid. Redox Signal. 37, 1094-1110.


Short communication: Use of fecal starch concentration as an indicator of dry feed digestion in preweaned dairy calves.
Fecal starch (FS) has been used as a tool to evaluate starch and diet digestibility in lactating dairy cows and feedlot steers. Some on-farm advisors also use FS to evaluate calf starter digestibility in preweaned dairy calves. Our objective was to evaluate the influence of starter intake (SI), starch and organic matter digestibility, milk replacer (MR) feeding rate, and age on FS concentrations in preweaned dairy calves. Male Holstein calves (43 ± 2.9 kg of body weight; n = 35) from a single farm were fed different amounts of MR ranging from 0.44 to 1.10 kg of dry matter (DM) daily (27% crude protein, 17% fat) and weaned by 7 wk of age. Starter ingredient composition was 37% whole corn, 20% whole oats, 35% protein pellet, and 3% molasses and contained 43 ± 1.9% starch. Fecal grab samples were taken at 3 (n = 20), 6 (n = 20), and 8 wk (n = 35) of age. Twelve fecal samples per calf were taken via rectal palpation over a 5-d period each week, frozen daily, combined on an equal wet-weight basis, and subsampled for analysis. Chromic oxide was used as an external digestibility marker at 3 and 6 wk (included in MR), whereas acid-insoluble ash was used as an internal marker at 8 wk. Milk replacer and starter intakes (offered and refused) were recorded daily during collection periods. Multiple and linear regression of organic matter digestibility (% of DM), total-tract starch digestibility (TTSD; % of DM), MR intake (kg/d), SI (kg/d), and age (week) versus FS (% of fecal DM) were determined using PROC REG of SAS (version 9.2, SAS Institute Inc., Cary, NC). Prior to weaning, SI, age, and MR rate explained 89% of the variation in TTSD, where TTSD = [19.7 × SI (±4.25)] + [3.8 × age (±0.79)] - [24.8 × MR (±3.19)] + 56.2 (±3.39). At 3 wk of age, TTSD increased (coefficient of determination = 0.53) and SI decreased (coefficient of determination = 0.20) with increasing FS. At 6 wk of age, TTSD and SI were unrelated to FS. In 8-wk-old calves (with 2 trials), SI, MR rate, FS, and trial explained 92% of the variation in TTSD, where TTSD = -[2.6 × SI (±0.67)] - [2.4 × MR (±0.56)] - [0.6 × FS (±0.04)] + [1.1 × trial (±0.33)] + 100.4 (±1.02). Postweaning, TTSD decreased linearly as FS increased (coefficient of determination = 0.86), whereas FS and SI were unrelated, a relationship in contrast to the previously observed result in calves still consuming milk replacer. In the current study, FS was not a good estimate of TTSD or dry feed intake in the preweaned calf, but has potential for evaluating TTSD in calves after weaning.


RNA Regulation of Lipotoxicity and Metabolic Stress.
Noncoding RNAs are an emerging class of nonpeptide regulators of metabolism. Metabolic diseases and the altered metabolic environment induce marked changes in levels of microRNAs and long noncoding RNAs. Furthermore, recent studies indicate that a growing number of microRNAs and long noncoding RNAs serve as critical mediators of adaptive and maladaptive responses through their effects on gene expression. The metabolic environment also has a profound impact on the functions of classes of noncoding RNAs that have been thought primarily to subserve housekeeping functions in cells-ribosomal RNAs, transfer RNAs, and small nucleolar RNAs. Evidence is accumulating that these RNAs are also components of an integrated cellular response to the metabolic milieu. This Perspective discusses the different classes of noncoding RNAs and their contributions to the pathogenesis of metabolic stress.


Perivascular expression and potent vasoconstrictor effect of dynorphin A in cerebral arteries.
Numerous literary data indicate that dynorphin A (DYN-A) has a significant impact on cerebral circulation, especially under pathophysiological conditions, but its potential direct influence on the tone of cerebral vessels is obscure. The aim of the present study was threefold: 1) to clarify if DYN-A is present in cerebral vessels, 2) to determine if it exerts any direct effect on cerebrovascular tone, and if so, 3) to analyze the role of κ-opiate receptors in mediating the effect. Immunohistochemical analysis revealed the expression of DYN-A in perivascular nerves of rat pial arteries as well as in both rat and human intraparenchymal vessels of the cerebral cortex. In isolated rat basilar and middle cerebral arteries (BAs and MCAs) DYN-A (1-13) and DYN-A (1-17) but not DYN-A (1-8) or dynorphin B (DYN-B) induced strong vasoconstriction in micromolar concentrations. The maximal effects, compared to a reference contraction induced by 124 mM K(+), were 115±6% and 104±10% in BAs and 113±3% and 125±9% in MCAs for 10 µM of DYN-A (1-13) and DYN-A (1-17), respectively. The vasoconstrictor effects of DYN-A (1-13) could be inhibited but not abolished by both the κ-opiate receptor antagonist nor-Binaltorphimine dihydrochloride (NORBI) and blockade of G(i/o)-protein mediated signaling by pertussis toxin. Finally, des-Tyr(1) DYN-A (2-13), which reportedly fails to activate κ-opiate receptors, induced vasoconstriction of 45±11% in BAs and 50±5% in MCAs at 10 µM, which effects were resistant to NORBI. DYN-A is present in rat and human cerebral perivascular nerves and induces sustained contraction of rat cerebral arteries. This vasoconstrictor effect is only partly mediated by κ-opiate receptors and heterotrimeric G(i/o)-proteins. To our knowledge our present findings are the first to indicate that DYN-A has a direct cerebral vasoconstrictor effect and that a dynorphin-induced vascular action may be, at least in part, independent of κ-opiate receptors.


Molecular characterization of a unique variant of avian infectious bronchitis virus in Tunisia.
Avian infectious bronchitis virus (IBV) is responsible of significant economic losses for poultry industry around the world, through evolution of its pathogenicity, inadequacy of vaccines, and virus evasion. Such evasion is related to the unstable nature of its RNA, in particular the S glycoprotein encoding gene, which raises great challenges with regard to the control of the disease, along with the lack of proof reading mechanisms of the RNA polymerase. The emergence of new variants might be a reason for the endemic outbreaks that are being reported in Tunisia, in addition to poor vaccination techniques and ineffective prophylactic programs. In the present study, partial nucleotide sequences of the S1 glycoprotein gene and the 3'-untranslated region (UTR) of 2 Tunisian isolates, TN1011/16 and TN1012/16, identified in 2016, were determined. Specific mutations were found in S1 gene as well as in 3'UTR region. Phylogenetic analysis of the S1 nucleotide sequences showed that both isolates are closely related to the Algerian strains, and formed a common cluster within the genotype I. In addition, these isolates were non-recombinant ones, confirming that they are unique variants. Based on their S1 gene sequences, TN1011/16 and TN1012/16 strains were distant from the H120 vaccine strain, commercially used in Tunisia along with the variant vaccine 793B type (4/91). A comparison between nucleotide sequences of their 3'UTR region and S1 gene showed a difference in IBV classification. The obtained results have confirmed that the IBVsequence continues to drift and brings valuable information in relation with its evolution, vaccine development and better control of the disease.


Phase I combination trial of lenalidomide and azacitidine in patients with higher-risk myelodysplastic syndromes.
Lenalidomide and azacitidine are active in patients with lower- and higher-risk myelodysplastic syndromes (MDS). These agents may complement each other by targeting both the bone marrow microenvironment and hypomethylating action on the malignant clone. This phase I trial explored the safety of combination therapy in patients with higher-risk MDS. Response and characterization of molecular and methylation status of responders were secondary objectives. Patients were enrolled using a 3 + 3 dose escalation. Cycles lasted 28 days, and patients received a maximum of seven cycles. Of 18 patients enrolled, median age was 68 years (range, 52 to 78 years), interval from diagnosis was 5 weeks (range, 2 to 106 weeks), and follow-up was 7 months (range, 1 to 26 months). International Prognostic Scoring System categories were intermediate 1 (n = 2), intermediate 2 (n = 10), and high (n = 6). No dose-limiting toxicities occurred, and a maximum-tolerated dose was not reached. Grades 3 to 4 nonhematologic toxicities (> 1) included febrile neutropenia (n = 5), cardiac (n = 2), and CNS hemorrhage (n = 2). Median absolute neutrophil count decrease was 26%, and platelet decrease was 1% (mean, 24%). The overall response rate was 67%: eight patients (44%) had a complete response (CR); three patients (17%) had hematologic improvement; one patient (6%) had marrow CR. Patients achieving CR were more likely to have normal cytogenetics and lower methylation levels. The combination of lenalidomide and azacitidine is well tolerated with encouraging clinical activity. The go-forward dose is azacitidine 75 mg/m(2) on days 1 through 5 and lenalidomide 10 mg on days 1 through 21.


Phycomycosis of the bronchus.
A case of phycomycosis of the bronchus in a 29-year-old diabetic man is reported. The interval between infection and death was not less than 35 days. Infection of the bronchus appears to have been direct. The diagnosis of phycomycosis could have been made before death.


Sequential activation of a segmented ground pad reduces skin heating during radiofrequency tumor ablation: optimization via computational models.
Radiofrequency (RF) ablation has become an accepted treatment modality for unresectable tumors. The need for larger ablation zones has resulted in increased RF generator power. Skin burns due to ground pad heating are increasingly limiting further increases in generator power, and thus, ablation zone size. We investigated a method for reducing ground pad heating in which a commercial ground pad is segmented into multiple ground electrodes, with sequential activation of ground electrode subsets. We created finite-element method computer models of a commercial ground pad (14 x 23 cm) and compared normal operation of a standard pad to sequential activation of a segmented pad (two to five separate ground electrode segments). A constant current of 1 A was applied for 12 min in all simulations. Time periods during sequential activation simulations were adjusted to keep the leading edge temperatures at each ground electrode equal. The maximum temperature using standard activation of the commercial pad was 41.7 degrees C. For sequential activation of a segmented pad, the maximum temperature ranged from 39.3 degrees C (five segments) to 40.9 degrees C (two segments). Sequential activation of a segmented ground pad resulted in lower tissue temperatures. This method may reduce the incidence of ground pad burns and enable the use of higher power generators during RF tumor ablation.


Synchronous pulsed flowering: analysis of the flowering phenology in Juncus (Juncaceae).
The timing of flowering within and among individuals is of fundamental biological importance because of its influence on total seed production and, ultimately, fitness. Traditional descriptive parameters of flowering phenology focus on onset and duration of flowering and on synchrony among individuals. These parameters do not adequately account for variability in flowering across the flowering duration at individual and population level. This study aims to analyse the flowering phenology of wind-pollinated Juncus species that has been described as temporally highly variable ('pulsed flowering'). Additionally, an attempt is made to identify proximate environmental factors that may cue the flowering, and ultimate causes for the flowering patterns are discussed. Flowering phenology was examined in populations of nine Juncus species by estimating flowering synchrony and by using the coefficient of variation (CV) to describe the temporal variation in flowering on individual and population levels. Phenologies were compared with null models to test which patterns deviate from random flowering. All parameters assessed were compared with each other and the performance of the parameters in response to randomization and varying synchrony was evaluated using a model population. Flowering patterns were correlated with temperature and humidity. Most flowering patterns of Juncus were best described as synchronous pulsed flowering, characterized as population-wide concerted flowering events separated by days with no or few open flowers. Flowering synchrony and variability differed from a random pattern in most cases. CV values in combination with a measure of synchrony differentiated among flowering patterns found. Synchrony varied among species and was independent from variability in flowering. Neither temperature nor humidity could be determined as potential cues for the flowering pulses. The results indicate that selection may act independently on synchrony and variability. We propose that synchronous pulsed flowering in Juncus is an evolved strategy that provides selective benefits by increasing outcrossing and by spreading the risk of reproductive failure.


Altered serum levels of type I collagen turnover indicators accompanied by IL-6 and IL-8 release in stable COPD.
COPD, characterized by chronic inflammation and airway remodeling, has significant pathological alterations in composition and deposition of the extracellular matrix. The expression of procollagen 1 C-terminal peptide (PICP) and collagen type 1 C-terminal telopeptide (ICTP), two major by-products in the synthesis and degradation of collagen, was shown to be positively correlated with inflammatory mediator levels in previous studies. In this study, we investigated whether the serum concentrations of PICP and ICTP were associated with the inflammation level for patients with stable COPD. We collected serum samples from 25 control subjects and 20 patients with stable COPD from December 2011 to October 2012 in Shanghai Zhongshan Hospital and Shanghai Dahua Hospital. We determined concentrations of PICP, ICTP, C-reactive protein (CRP), IL-6, IL-8, and tumor necrosis factor (TNF)-α by using enzyme-linked immunosorbent assay methods. Demographic characteristics were comparable between the two groups. In patients with stable COPD, serum levels of CRP, IL-6, IL-8, and TNF-α were all elevated compared to control subjects, but only changes of IL-6 achieved statistical significance. Serum concentration of PICP was significantly elevated in patients with COPD, and level of ICTP was slightly decreased. Moreover, serum concentrations of PICP were positively correlated with the levels of both IL-6 and IL-8. The increased levels of serum PICP in COPD might indicate the condition of airway remodeling, and IL-6 and/or IL-8 might play an important role in stimulating collagen synthesis.


A dodecanuclear metallamacrocycle having a multidentate bridging ligand in two different binding modes.
The reaction of Mn(OAc)2 x 4H2O with 2,6-dimethoxybenzoylsalicylhydrazide (H3dmbshz) leads to a dodecanuclear manganese metallamacrocycle [Mn12(dmbshz)12(EtOH)6], 1. The successive manganese centers are connected by the hydrazide N-N groups of the ligands in an alternating pentadentate binding mode, hexadentate binding mode. The alternation results in two alternating chelation modes around the metal centers, a tridentate-tridentate chelation mode and a bidentate-tridentate chelation mode. The metal ions in 1 are in a (A(A)Delta(B)C(A)Lambda(B))(A(A)Delta(B)C(A)Lambda(B)) chiral sequence, the alternation of the chiralities expanding the cyclic ring system to a 36-membered dodecanuclear manganese metallamacrocyclic ring system with S6 point group symmetry.


The (Parental) Whole Is Greater Than the Sum of Its Parts: A Multifactorial Model of Parent Factors in Pediatric Chronic Pain.
Parents play a critical role in children's experience of, and recovery from, chronic pain. Although several parental factors have been linked to child pain and functioning, these factors are typically examined in isolation or as moderators or mediators. Structural equation modeling affords the opportunity to examine the extent to which parental factors are interrelated, and if there are differential associations among parental factors and child outcomes. Based on extant literature, a unified model of parental factors, including chronic pain status, physical functioning, responses to child pain, and psychological factors, and their effect on child pain and functioning, was conceptualized. This model was evaluated using structural equation modeling based on data from 146 dyads recruited from a multidisciplinary pain clinic. Modifications to model iterations were made based on theoretical and statistical justification. The final model revealed associations among all parental factors, with significant loadings on child pain and functioning. Findings indicated the conceptual model was supported, with the exception of parent responses to child pain. Findings support the inclusion of parent chronic pain status and physical and psychological functioning as part of a comprehensive assessment of youth with chronic pain and may inform new parental intervention targets to improve child outcomes. PERSPECTIVE: A unified structural equation model indicated parents' own chronic pain characteristics and physical and psychological functioning represent important factors associated with child pain and functioning. Current family-based interventions that often primarily focus on parent responses to child pain may need to be adapted to more comprehensively address parental factors.


Regional left atrial coagulation and fibrinolytic activities in patients with mitral stenosis.
Systemic thromboembolism is a major complication of mitral stenosis (MS), especially in those patients having atrial fibrillation (AF). Recent evidence has suggested that regional left atrial coagulation activity may be increased in MS and may contribute to the pathophysiology of left atrial thrombus. However, the relation of left atrial coagulation activity to factors that predispose to left atrial thrombus formation is unknown. Also, the relations between left atrial and systemic coagulation activity, fibrinolysis, and platelet activation remain unresolved. Left atrial and peripheral venous levels of fibrinogen, antithrombin III, factor VII and factor VIII for coagulation, D-dimer, tPA and PAI-I, plasmin and antiplasmin for fibrinolysis, and platelet factor 4 and vWF for platelet activation, and endothelial dysfunction were measured in 46 patients with MS and normal clotting times who were undergoing percutaneous mitral valvuloplasty. Left atrial tPA, plasmin, PAI-I, antiplasmin, PF4, and vWF levels exceeded the corresponding peripheral venous levels (P < 0.05) in patients with MS, being more significant in the AF subgroup. There were no significant differences between left atrial and peripheral venous levels of fibrinogen, D-dimer, factor VII, and factor VIII within the patient group (P > 0.05). The results suggest that there are significant variations in the indices of coagulation, fibrinolytic system and platelet activation, and endothelial dysfunction between left atrial and peripheral venous blood samples of patients with MS that may be due to limited spillover from the left atrium to the systemic circulation.


Racial-ethnic background and specialty choice: a study of U.S. medical school graduates in 1987.
This study used two Association of American Medical Colleges' questionnaires to determine whether there was a relationship between the racial-ethnic backgrounds and the specialty choices of a 1987 cohort of 11,136 U.S. medical school seniors, both prior to entering medical school and as they prepared for residency training. Their specialty preferences as premedical students were shown by their responses to the Premedical Student Questionnaire, administered when they registered for the Medical College Admission Test; their specialty choices at the end of their medical school training were shown by their responses to the Medical Student Graduation Questionnaire, which they completed shortly before graduation. Racial-ethnic backgrounds, self-recorded, were classified into black, other underrepresented minorities, Asian, other non-underrepresented minorities, and white. Specialties were clustered into primary care, medical specialties, surgical specialties, and supporting services. Before entering medical school, the students had similar specialty preferences regardless of background. As seniors in medical school, there was even greater convergence of specialty choices among the students of all backgrounds. Racial-ethnic background in itself appears not to have been a major factor influencing the senior medical students' specialty choices.


Overexpression of Populus trichocarpa CYP85A3 promotes growth and biomass production in transgenic trees.
Brassinosteroids (BRs) are essential hormones that play crucial roles in plant growth, reproduction and response to abiotic and biotic stress. In Arabidopsis, AtCYP85A2 works as a bifunctional cytochrome P450 monooxygenase to catalyse the conversion of castasterone to brassinolide, a final rate-limiting step in the BR-biosynthetic pathway. Here, we report the functional characterizations of PtCYP85A3, one of the three AtCYP85A2 homologous genes from Populus trichocarpa. PtCYP85A3 shares the highest similarity with AtCYP85A2 and can rescue the retarded-growth phenotype of the Arabidopsis cyp85a2-2 and tomato dx mutants. Constitutive expression of PtCYP85A3, driven by the cauliflower mosaic virus 35S promoter, increased the endogenous BR levels and significantly promoted the growth and biomass production in both transgenic tomato and poplar. Compared to the wild type, plant height, shoot fresh weight and fruit yield increased 50%, 56% and 43%, respectively, in transgenic tomato plants. Similarly, plant height and stem diameter increased 15% and 25%, respectively, in transgenic poplar plants. Further study revealed that overexpression of PtCYP85A3 enhanced xylem formation without affecting the composition of cellulose and lignin, as well as the cell wall thickness in transgenic poplar. Our finding suggests that PtCYP85A3 could be used as a potential candidate gene for engineering fast-growing trees with improved wood production.


Autoimmune Disease-Related Hub Genes are Potential Biomarkers and Associated with Immune Microenvironment in Endometriosis.
Endometriosis, a common gynecological condition, can cause symptoms such as dysmenorrhea, infertility, and abnormal bleeding, which can negatively affect a woman's quality of life. In the current study, the pathophysiological mechanisms of endometriosis are unknown, but this study suggests that endometriosis is associated with dysregulation of the autoimmune system. This study identify hub genes involved in the prevalence, identification and diagnostic value of endometriosis and autoimmune diseases, and explore the central genes and immune infiltrates, the diagnosis of endometriosis provides a new sight of thinking about diagnosis and treatment. The relevant datasets for endometriosis GSE141549, GSE7305 and autoimmune disease-related genes (AIDGs) were downloaded from online database. Using the "limma" package and WGCNA to screen out the autoimmune disease related genes and endometriosis related genes, the autoimmune disease gene-related differential genes (AID-DEGs) progressive GO, KEGG enrichment analysis, and then using the protein interaction network and Cytoscape software to select hub genes (CXCL12, PECAM1, NGF, CTGF, WNT5A), using the "pROC" package to analyze the hub genes for the diagnostic value of endometriosis. The difference in the importance of hub genes for the diagnosis of endometriosis was analyzed by machine learning random forest, and the combined diagnostic value of hub genes was analyzed by using the Support Vector Machine (SVM) algorithm. The eutopic (EU) and ectopic endometrium (EC) immune microenvironment of endometriosis was evaluated using CIBERSORT, the correlation of hub genes to the immune microenvironment was analyzed. The hub genes associated with AIDGs are differentially expressed in EC and EU of endometriosis and possess important value for the diagnosis of endometriosis. The hub genes have a very important impact on the immune microenvironment of endometriosis, which is important for exploring the connection between endometriosis and autoimmune diseases and provides a new insight for the subsequent study of immunotherapy and diagnosis of endometriosis.


Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies.
Kidney transplantation is considered the favored treatment for patients suffering from end-stage renal disease, since successful transplantation is associated with longer survival and improved quality of life compared to dialysis. Alloreactive immune responses against the donor kidney may lead to acute rejection of the transplant. The current diagnosis of renal allograft rejection mainly relies on clinical monitoring, including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the kidney transplant biopsy. These parameters have their limitations. Identification and validation of biomarkers, which correlate with or predict the presence of acute rejection, and which could improve therapeutic decision making, are priorities for the transplantation community. There is a need for alternative, less invasive but sensitive markers to diagnose acute graft rejection. Here, we provide an overview of the current status on research of biomarkers of acute kidney transplant rejection in blood and urine. We specifically discuss relatively novel research strategies in biomarker research, including transcriptomics and proteomics, and elaborate on donor-derived cell-free DNA as a potential biomarker.


Prenatal diagnosis of exstrophy of the cloaca.
While screening for neural tub defects, three cases of exstrophy of the cloaca were found through elevated second-trimester maternal serum alphafetoprotein levels. Measurement of amniotic fluid alphafetoprotein and examination of the structure of rapidly adhering cells confirmed the abnormalities, and the pregnancies were terminated. Subsequent studies of cholinesterase isozymes by acrylamide electrophoresis showed an abnormal acetylcholinesterase band in each of the three amniotic fluids. During the same period, two more cases of exstrophy of the cloaca were identified in spontaneous abortions and another one in a stillbirth. It is suggested that the condition is more common than has been previously suspected and is often misclassified as omphalocele.


Floquet Topological Order in Interacting Systems of Bosons and Fermions.
Periodically driven noninteracting systems may exhibit anomalous chiral edge modes, despite hosting bands with trivial topology. We find that these drives have surprising many-body analogs, corresponding to class A, which exhibit anomalous charge and information transport at the boundary. Drives of this form are applicable to generic systems of bosons, fermions, and spins, and may be characterized by the anomalous unitary operator that acts at the edge of an open system. We find that these operators are robust to all local perturbations and may be classified by a pair of coprime integers. This defines a notion of dynamical topological order that may be applied to general time-dependent systems, including many-body localized phases or time crystals.


Toward Realistic Dosimetry In Vitro: Determining Effective Concentrations of Test Substances in Cell Culture and Their Prediction by an In Silico Mass Balance Model.
Nominal concentrations (CNom) in cell culture media are routinely used to define concentration-effect relationships in the in vitro toxicology. The actual concentration in the medium (CMedium) can be affected by adsorption processes, evaporation, or degradation of chemicals. Therefore, we measured the total and free concentration of 12 chemicals, covering a wide range of lipophilicity (log KOW -0.07-6.84), in the culture medium (CMedium) and cells (CCell) after incubation with Balb/c 3T3 cells for up to 48 h. Measured values were compared to predictions using an as yet unpublished in silico mass balance model that combined relevant equations from similar models published by others. The total CMedium for all chemicals except tamoxifen (TAM) were similar to the CNom. This was attributed to the cellular uptake of TAM and accumulation into lysosomes. The free (i.e., unbound) CMedium for the low/no protein binding chemicals were similar to the CNom, whereas values of all moderately to highly protein-bound chemicals were less than 30% of the CNom. Of the 12 chemicals, the two most hydrophilic chemicals, acetaminophen (APAP) and caffeine (CAF), were the only ones for which the CCell was the same as the CNom. The CCell for all other chemicals tended to increase over time and were all 2- to 274-fold higher than CNom. Measurements of CCytosol, using a digitonin method to release cytosol, compared well with CCell (using a freeze-thaw method) for four chemicals (CAF, APAP, FLU, and KET), indicating that both methods could be used. The mass balance model predicted the total CMedium within 30% of the measured values for 11 chemicals. The free CMedium of all 12 chemicals were predicted within 3-fold of the measured values. There was a poorer prediction of CCell values, with a median overprediction of 3- to 4-fold. In conclusion, while the number of chemicals in the study is limited, it demonstrates the large differences between CNom and total and free CMedium and CCell, which were also relatively well predicted by the mass balance model.


Cumulative incidence of first recurrence after curative treatment of stage I-III colorectal cancer. Competing risk analyses of temporal and anatomic patterns.
Updated knowledge about the rates of recurrence and time to recurrence following curative treatment of colorectal cancer is essential to secure better patient information on prognosis, to serve as a premise in the discussion on adjuvant chemotherapy, and help to properly scale the intensity and length of follow-up. This is a population-based study investigating aspects on first recurrence after radical treatment of clinical stages I-III of colorectal cancer in Central-Norway during 2001-2015. To reveal any time-trends, data were stratified by the time periods 2001-2005, 2006-2010 and 2011-2015. The cumulative incidence of first recurrence was calculated, treating death of unrelated causes as a competing event. Multivariable Cox analyses were done to calculate cause specific hazard ratios (HR) for risk of recurrence. At a minimum follow-up of six years, a first recurrence was detected in 1,113/5,556 patients at risk (20.0%). The recurrence rate was reduced from 23.6% in the first time period, through 20.0% in the second, and to 17.2% in the last, p < 0.001. The reduction applied to all tumor locations, to pathological disease stages II and III, to both gender, across different tumor differentiations, and to both elective and emergency surgery. In multivariable analyses time period, gender, disease stage, and tumor differentiation were significant determinants for risk of recurrence. The rate of first recurrence after curative surgery for colorectal cancer was substantially reduced from 2001 to 2015. The reason for the reduction could not be attributed to a single factor only. A combined effect of several incremental improvements, such as an increased use of preoperative radiation for rectal cancers, improved adjuvant chemotherapy for colon cancer, and a reduced proportion of emergency surgery, is suggested.


Association of Postprocedural Left Atrial Volume and Reservoir Function with Outcomes in Patients with Atrial Fibrillation Undergoing Catheter Ablation.
The value of left atrial (LA) volume and reservoir function (ResF) after ablation for atrial fibrillation for predicting overall outcomes needs further investigation, particularly in large cohorts. The aim of this study was to test the hypothesis that abnormal LA volume and ResF after ablation are associated with adverse outcomes. Patients who underwent primary atrial fibrillation ablation between 2007 and 2016 and had available measurements of maximum LA volume index (LAVImax) and minimum LA volume index (LAVImin) and LA ResF (LA emptying fraction and LA expansion index) at 3-month echocardiographic examination after ablation were included in this analysis. The primary endpoint was the composite of cardiac hospitalization for heart failure or acute ischemic events, stroke or transient ischemic attack, and all-cause death; secondary endpoints were cardiac hospitalization and all-cause death. A total of 792 patients were studied (mean age, 60 ± 10 years). Over a median of 7.5 years (interquartile range, 3.0-9.7 years) of follow-up, 96 patients experienced adverse events. After adjustment for several parameters, including age, comorbidities, and left ventricular structure and function, increased LA volumes and impaired ResF were each independently associated with the primary endpoint (LAVImax > 34 mL/m2: adjusted hazard ratio [HR], 2.37 [95% CI, 1.49-3.76; P = .0003]; LAVImin ≥ 20.5 mL/m2: adjusted HR, 3.21 [95% CI, 1.97-5.24; P < .0001]; LA emptying fraction < 40%: adjusted HR, 2.00 [95% CI, 1.29-3.10; P = .002]; LA expansion index < 66%: adjusted HR, 1.91 [95% CI, 1.22-2.98; P = .005]) as well as with the secondary endpoints of cardiac hospitalization (P < .05 for adjusted HR for all LA parameters) and all-cause death (P < .05 for adjusted HR for LAVImin, LA emptying fraction and LA expansion index). ResF measures were incremental to LAVImax (P < .05 for all), but not to LAVImin. In patients with normal LA (LAVImax ≤ 34 mL/m2; n = 403), those with higher LAVImin (≥17 mL/m2) were at 4 times higher risk for primary endpoint events (age-adjusted HR, 4.32; 95% CI, 1.90-9.81; P = .0005). All these findings were independent of atrial tachyarrhythmia recurrence. Enlarged left atrium and impaired ResF at 3 months after ablation for atrial fibrillation are strongly associated with long-term outcomes, independent of left ventricular function or cardiac rhythm at follow-up. LAVImin showed the strongest associations and even identified a high-risk subgroup among patients with nondilated left atria.


Challenges in Wireless System Integration as Enablers for Indoor Context Aware Environments.
The advent of fully interactive environments within Smart Cities and Smart Regions requires the use of multiple wireless systems. In the case of user-device interaction, which finds multiple applications such as Ambient Assisted Living, Intelligent Transportation Systems or Smart Grids, among others, large amount of transceivers are employed in order to achieve anytime, anyplace and any device connectivity. The resulting combination of heterogeneous wireless network exhibits fundamental limitations derived from Coverage/Capacity relations, as a function of required Quality of Service parameters, required bit rate, energy restrictions and adaptive modulation and coding schemes. In this context, inherent transceiver density poses challenges in overall system operation, given by multiple node operation which increases overall interference levels. In this work, a deterministic based analysis applied to variable density wireless sensor network operation within complex indoor scenarios is presented, as a function of topological node distribution. The extensive analysis derives interference characterizations, both for conventional transceivers as well as wearables, which provide relevant information in terms of individual node configuration as well as complete network layout.


Apnea management during WATCHMAN device deployment with apneic oxygenation: A case report of three cases.
WATCHMAN is a percutaneous left atrial appendage closure device that is implanted in patients who are unsuitable for anticoagulation therapy for atrial fibrillation. During WATCHMAN implantation, inducing apnea in the patient is preferable to allow stable deployment. We present three cases in which apneic oxygenation was employed to maintain oxygenation during apnea, and oxygen reserve index (ORiTM) was measured to evaluate its safety and efficacy. Oxygen was administered continuously via the endotracheal tube during apnea. During all four apneic events in three patients (mean duration of 356 seconds), the ORi values maintained above 0.24, which is generally considered the threshold of partial pressure of arterial oxygen (PaO2) > 100 mmHg. Transcutaneous oxygen saturation and PaO2 remained above 99% and 300 mmHg, respectively. There were no respiratory or circulatory complications during or after the surgery.