Pangenome analysis and virulence profiling of Streptococcus intermedius.
Streptococcus intermedius, a member of the S. anginosus group, is a commensal bacterium present in the normal microbiota of human mucosal surfaces of the oral, gastrointestinal, and urogenital tracts. However, it has been associated with various infections such as liver and brain abscesses, bacteremia, osteo-articular infections, and endocarditis. Since 2005, high throughput genome sequencing methods enabled understanding the genetic landscape and diversity of bacteria as well as their pathogenic role. Here, in order to determine whether specific virulence genes could be related to specific clinical manifestations, we compared the genomes from 27 S. intermedius strains isolated from patients with various types of infections, including 13 that were sequenced in our institute and 14 available in GenBank. We estimated the theoretical pangenome size to be of 4,020 genes, including 1,355 core genes, 1,054 strain-specific genes and 1,611 accessory genes shared by 2 or more strains. The pangenome analysis demonstrated that the genomic diversity of S. intermedius represents an "open" pangenome model. We identified a core virulome of 70 genes and 78 unique virulence markers. The phylogenetic clusters based upon core-genome sequences and SNPs were independent from disease types and sample sources. However, using Principal Component analysis based on presence/ absence of virulence genes, we identified the sda histidine kinase, adhesion protein LAP and capsular polysaccharide biosynthesis protein cps4E as being associated to brain abscess or broncho-pulmonary infection. In contrast, liver and abdominal abscess were associated to presence of the fibronectin binding protein fbp54 and capsular polysaccharide biosynthesis protein cap8D and cpsB. Based on the virulence gene content of 27 S. intermedius strains causing various diseases, we identified putative disease-specific genetic profiles discriminating those causing brain abscess or broncho-pulmonary infection from those causing liver and abdominal abscess. These results provide an insight into S. intermedius pathogenesis and highlights putative targets in a diagnostic perspective.


Rhenium-catalyzed 1,3-isomerization of allylic alcohols: scope and chirality transfer.
The scope of the triphenylsilyl perrhennate (O3ReOSiPh3, 1) catalyzed 1,3-isomerization of allylic alcohols has been thoroughly explored. It was found to be effective for a wide variety of secondary and tertiary allylic alcohol substrates bearing aryl, alkyl, and cyano substituents. Two general reaction types were found which gave high levels of product selectivity: those driven by formation of an extended conjugated system and those driven by selective silylation of a particular isomer. The efficiency of chirality transfer with various substrates was investigated, and conditions were found in which secondary and tertiary allylic alcohols could be formed with high levels of enantioselectivity. Consideration of selectivity trends with respect to the nature of the substituents around the allylic system revealed that this is a reliable and predictable method for allylic alcohol synthesis.


The Synthesis of Bicyclo[4.2.1]nona-2,4,7-trienes by [6π + 2π]-Cycloaddition of 1-Substituted 1,3,5-Cycloheptatrienes Catalyzed by Titanium and Cobalt Complexes.
The [6π + 2π]-cycloaddition of alkynes to 1-methyl-, propyl-, benzyl-, and hydroxymethyl-substituted 1,3,5-cycloheptatrienes in the presence of catalytic systems Ti(acac)2Cl2-Et2AlCl and Co(acac)2(dppe)/Zn/ZnI2 was performed for the first time to give practically valuable bicyclo[4.2.1]nona-2,4,7-trienes in high yields (72-88%). The structures of the obtained bicyclic compounds were reliably proved by NMR methods and X-ray diffraction analysis. The newly synthesized bicycles have been investigated for their in vitro cytotoxic activity against Jurkat, K562, U937, and HL60 tumor and normal cell lines and induction of apoptosis.


Biological consequences of land use.
The primary goals of land-use planning are enunciated. A plea is made for consideration of the total biosphere and not just its separate components. The environmental impact statement process is reviewed and some suggestions made for its strengthening. Moves for international adoption of this process are noted, as well as the concept of eco-development currently under examination by UN agencies.


Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of anemia.
We studied 47 patients with sickle-cell anemia to determine the effect of alpha-thalassemia on the severity of their hemolytic anemia. We diagnosed alpha-thalassemia objectively by using alpha-globin-gene mapping to detect alpha-globin-gene deletions, studying 25 subjects with the normal four alpha-globin-genes, 18 with three, and four with two. The mean hemoglobin, hematocrit, and absolute reticulocyte levels (+/- S.D.) were 7.9 +/- 0.9 g per deciliter (4.9 +/- 0.6 mmol per liter), 22.9 +/- 2.9 per cent, and 501,000 +/- 126,000 per cubic millimeter, respectively, in the non-thalassemic group; 9.8 +/- 1.6 g per deciliter (6.1 +/- 1.0 mmol per liter), 29.0 +/- 5.0 per cent, and 361,000 +/- 51,000 per cubic millimeter in the group with three alpha-globin genes; and 9.2 +/- 1.0 g per deciliter (5.7 +/- 0.6 mmol per liter), 27.5 +/- 3.0 per cent, and 100,000 +/- 15,000 per cubic millimeter in the group with two alpha-globin genes. Deletion of alpha-globin genes was also accompanied by a decreased mean corpuscular hemoglobin concentration (MCHC) in post-reticulocyte erythrocytes and by increased hemoglobin F levels. The decreased intraerythrocytic hemoglobin S concentration and elevated hemoglobin F levels associated with alpha-thalassemia appear to diminish the degree of hemolytic anemia found in sickle-cell disease.


Structural and genetic basis of the in vivo immune response to TNP-LPS.
TNP-lipopolysaccharide (TNP-LPS) is a potent T-independent antigen in vivo, inducing a TNP-PFC response in T-depleted animals. The structural integrity of the lipid A-KDO portion of the LPS carrier molecule appears to be required since the haptenated LPS from Salmonella minnesota Re595 is immunogenic whereas the haptenated derivative of base hydrolyzed LPS is not. The immune response is not associated with any of the common histocompatiblity types, but does depend on the ability of the host strain to respond to LPS. C3H/HeJ mice are not killed by low doses of LPS and give a poor PFC response to TNP-LPS. Lethality and immunogenicity are dominant responses in hybrids of C3H/HeJ and responder mice. The structural and genetic requirements for the response to TNP-LPS suggest an active role for the carrier in the immunogenicity of this T-independent antigen.


In vitro release of betamethasone dipropionate from petrolatum-based ointments.
The purpose of this research was to develop new in vitro methodology for measuring release from petrolatum-based semisolids and to determine whether two ointments, both of which contained betamethasone dipropionate, 0.05%, but with different formulations, could be distinguished by release measurements. Several receptor media were explored to optimize the procedure utilizing Franz-type cells. Analysis was by HPLC. The release slope was 1.5 to 6 times greater from the ointment than the "augmented" ointment (which had greater clinical potency). Release was highest with a receptor consisting of a 5% solution of hexane in acetonitrile. Even so, it was necessary to subject samples of receptor from the augmented ointment to evaporation followed by reconstitution with a smaller volume of mobile phase to bring corticosteroid concentrations up to quantifiable levels. In another series of experiments, the HPLC mobile phase was used as the receptor and a relatively large volume (100 microliters) was injected onto the column. With the second approach, measured concentrations were lower but more reproducible. Quantifiable levels of betamethasone dipropionate were obtained for both formulations beginning from the first data point (at 1 hr), with satisfactory linearity of plots of amount released per unit area of membrane versus the square root of time. Using this methodology, it was possible to distinguish the effect of formulation differences in two ointments containing the same drug in the same concentration.


LATE-NIGHT SALIVARY CORTISOL IS UNALTERED IN PATIENTS WITH POLYCYSTIC OVARIAN SYNDROME (PCOS), IRRESPECTIVE OF DISEASE PHENOTYPE, AND IN OBESE WOMEN, IRRESPECTIVE OF THE PRESENCE OF PCOS.
To determine cutoff values of late-night salivary cortisol (LNSC) using an electrochemiluminescent immunoassay and investigate whether the diagnostic performance of the assay is influenced by the presence of obesity or polycystic ovary syndrome (PCOS). A total of 124 subjects comprising 25 patients with Cushing syndrome (CS), 44 with PCOS (22 nonobese and 22 obese), 21 with constitutional obesity (CO), and 34 healthy subjects (HS) were included in the study. Two consecutive LNSC samples were collected from all participants. The median LNSC levels of patients with CS were significantly higher than LNSC levels of HS, patients with CO, and obese and nonobese patients with PCOS, respectively (P<.01 for all). Healthy subjects, patients with CO, and obese and nonobese patients with PCOS did not differ in terms of median LNSC levels (P>.05 for all). The cutoff values and corresponding sensitivity and specificity were similar between the groups. The comparisons of the area under curve of the first LNSC (0.963; 95% confidence interval [CI], 0.910 to 0.989), second LNSC (0.954; 95% CI, 0.898 to 0.984), and the mean of two consecutive LNSC (mLNSC) values (0.962; 95% CI, 0.909 to 0.989) did not differ significantly (P>.05 for all). A cutoff value for mLNSC of 7.45 nmol/L yielded a sensitivity of 100% and specificity of 87.5% in HS. In conclusion, LNSC is a reliable test with high diagnostic accuracy in both HS and patients with PCOS and obesity. ACTH = adrenocorticotropic hormone AUC = area under the curve BMI = body mass index CO = constitutional obesity CS = Cushing syndrome E2 = estradiol ECLIA = electrochemiluminescent immunoassay FPG = fasting plasma glucose FSH = follicle-stimulating hormone HOMA-IR = homeostasis model assessment of insulin resistance HPA = hypothalamo-pituitary-adrenal HS = healthy subjects IQR = interquartile range LH = luteinizing hormone LNSC = late-night salivary cortisol LR = likelihood ratio mLNSC = mean of two consecutive LNSC samples PCOS = polycystic ovarian syndrome ROC = receiver operating characteristic UFC = urinary free cortisol WHR = waist-to-hip ratio.


Systematic Review and Network Meta-analysis of Idiopathic Pulmonary Fibrosis Treatments.
The antifibrotics pirfenidone and nintedanib are both approved for the treatment of idiopathic pulmonary fibrosis (IPF) by regulatory agencies and are recommended by health technology assessment bodies. Other treatments such as N-acetylcysteine are used in clinical practice but have not received regulatory approval. No head-to-head trials have been conducted to directly compare the efficacy of these therapies in IPF. To compare the efficacy of treatments for IPF. A systematic review was conducted up to April 2015. Phase II/III randomized controlled trials in adults with IPF were eligible. A Bayesian network meta-analysis (NMA) was used to compare pirfenidone, nintedanib, and N-acetylcysteine with respect to forced vital capacity (FVC) and mortality. Nine studies were included in the NMA. For change from baseline in FVC, the NMA indicated that pirfenidone and nintedanib were more effective than placebo after 1 year (pirfenidone vs. placebo: difference = 0.12 liter (L), 95% credible interval [CrI] = 0.03-0.21 L; nintedanib vs. placebo: difference = 0.11 L, 95% CrI = 0.00-0.22 L). There was no evidence that N-acetylcysteine had an effect on FVC compared with placebo (N-acetylcysteine vs. placebo: difference = 0.01 L, 95% CrI = -0.15-0.17 L). Patients treated with pirfenidone also had a lower risk of experiencing a decline in percent predicted FVC of ≥ 10% over 1 year (odds ratio [OR]: 0.58, 95% CrI = 0.40-0.88), whereas there was no conclusive evidence of a difference between nintedanib and placebo (OR: 0.65, 95% CrI = 0.42-1.02). The NMA indicated that pirfenidone reduced all-cause mortality relative to placebo over 1 year (hazard ratio [HR]: 0.52, 95% CrI = 0.28-0.92). There was no evidence of a difference in all-cause mortality between nintedanib and placebo (HR: 0.70, 95% CrI = 0.32-1.55), or N-acetylcysteine and placebo (HR: 2.00, 95% CrI=0.46-8.62). Our primary analysis of the available evidence indicates that over 1 year, pirfenidone and nintedanib are effective at reducing lung-function decline, and pirfenidone may reduce the odds of experiencing a decline in percent predicted FVC of ≥10% compared with placebo in the first year of treatment. The results of our analysis also suggest that pirfenidone improves survival. Fleetwood is an employee of Quantics Consulting. McCool and Glanville are employees of York Health Economics Consortium (YHEC). Quantics and YHEC received funding from F. Hoffmann-La Roche for conducting the systematic review and network meta-analysis reported in this paper. Edwards, Gsteiger, and Daigl are employees of F. Hoffmann-La Roche. Fisher was employed by InterMune UK, a wholly owned Roche subsidiary, until July 2015. He is currently employed by FIECON, which has received funding from F. Hoffmann-La Roche for consulting services. The systematic review and network meta-analysis reported in this paper were conducted by Fleetwood (Quantics Consulting) and McCool and Glanville (YHEC), funded by F. Hoffmann-La Roche. The original network analysis was funded by InterMune. Study concept and design were contributed by Edwards, Gsteiger, and Daigl, along with Fleetwood, McCool, and Glanville. Fleetwood, McCool, and Glanville collected the data, with assistance from Edwards, Gsteiger, and Daigl. Data interpretation was performed by Fleetwood and Fisher, with assistance from the other authors. The manuscript was written by Fleetwood, McCool, and Glanville, with assistance from Edwards, Daigl, and Fisher, and revised by all the authors.


Advances in inner ear gene therapy: exploring cochlear protection and regeneration.
To review the application of gene therapy in the inner ear. Gene delivery to the inner ear was first reported in 1996. Since then the field has progressed on multiple fronts. More diverse and sophisticated vectors are improving the efficiency of delivery to the inner ear. Research is transitioning from the delivery of marker genes to the delivery of therapeutic genes in animal models of inner ear disease. Three distinct areas of research are developing: (1) delivery of genes for protection of spiral ganglion neurons with potential application in cochlear implantation, (2) delivery of genes for protection of hair cells and hearing preservation in degenerative diseases and cochlear insults and (3) the use of gene therapy to transform cells from one phenotype to another and replace lost cells, potentially restoring lost function. Currently, no specific drugs are targeted at inner ear disease. The use of gene therapy in the inner ear is being applied in animal models of ototoxicity and ischemia reperfusion injury. Gene therapy can protect the inner ear from damage and even restore function through the regeneration of hair cells.


Analgesic and anti-inflammatory activities of Trigonella foenum-graecum (seed) extract.
Analgesic and anti-inflammatory effects were examined in a partially purified fraction (MTH) of the Trigonella foenum-graecum seed extract. The analgesic effects of graded doses of fraction (MTH in 10-40 mg/kg p.o.) were evaluated in mice against acetic acid induced writhing (chemically induced pain) and hot-plate method (thermally induced pain). The analgesia produced by MTH was compared with the standard analgesics pentazocine (PTZ, 5 mg/kg p.o.) and diclofenac sodium (DIS, 5 mg/kg p.o.). Acute anti-inflammatory activity of fraction (MTH) was also evaluated in carrageenan-induced rat paw edema model at the doses 10 and 20 mg/kg i.p. and compared with diclofenac sodium (5 mg/kg i.p.). In comparison to control group MTH showed highly significant, dose dependent analgesic activity against thermally as well as chemically induced pain (p < 0.001). MTH at the dose of 40 mg/kg has shown significant analgesic activity (p < 0.001) as compared to diclofenac sodium and pentazocine at the doses employed. In comparison to control, MTH at the employed doses produced marked acute anti-inflammatory activity in rats (p <0.001). The results suggest that the water soluble fraction (MTH) of herbal origin has significant analgesic and anti-inflammatory potential as reflected by the parameters investigated. Further investigations are, however, necessary to explore mechanism(s) of action involved in these pharmacological activities.


The effects of tobacco smoke on plasma alpha- and gamma-tocopherol levels in passive and active cigarette smokers.
Tobacco smoke is one of the causes of oxidative stress that is leading to attenuation of the antioxidative body protective barrier by means of decreasing the levels of intra- and extracellular antioxidants. The effect of tobacco smoke on plasma levels of two main forms of Vitamin E, alpha- and gamma-tocopherol, in passive smokers (urinary cotinine concentration 50-500 microg/L) and active smokers (urinary cotinine concentration >500 microg/L) were studied. Slight, but statistically significant decreases in plasma alpha-tocopherol level in passive and active smokers in comparison with non-smokers (by 5.7% and 9.2%, respectively) were found. The plasma gamma-tocopherol levels remained unchanged. The Pearson's correlation coefficient for the plasma alpha-tocopherol level and the urinary cotinine concentration in passive and active smokers was -0.431, P = 0.004 and -0.534, P < 0.001, respectively, and for gamma-tocopherol in similar conditions -0.190, P = 0.217 and 0.346, P = 0.027, respectively. The obtained results indicate the secondary role that alpha- and gamma-tocopherol play in the process of tobacco smoke free radical scavenge, or they may also reflect the body increased anti-oxidative mobilization in response to oxidative stress evoked by tobacco smoke.


Inhibition of Langerhans cell ATPase and contact sensitization by lanthanides--role of T-suppressor cells.
Lanthanides are rare earths, elements 55-71 in the periodic table, that are of interest in biologic systems as isomorphic competitors for calcium binding sites. Lanthanides were tested for their inhibitory influence on the Ca++/Mg(++)-dependent ATPase of epidermal langerhans cells in vitro, and on the immunologic function of Langerhans cells in vivo. The trivalent ions of lanthanides, lanthanum, and cerium completely inhibited the ATPase staining of Langerhans cells in vitro. When mice were sensitized with dinitrofluorobenzene on skin sites pretreated with topical lanthanum chloride, and challenged on untreated ear skin, a markedly reduced contact hypersensitivity response was observed. This hyporesponsiveness was found to be antigen specific, and could be passively transferred to naive syngeneic animals recipients by CD4-CD8+ spleen cells. These results suggest that inhibition of the epidermal Langerhans cell surface ATPase by application of topical lanthanum and the induction of antigen-specific immunologic tolerance may be related events.


Association of objectively measured sedentary behavior and physical activity with cardiometabolic risk markers in older adults.
The aim of this study was to examine the associations between sedentary behavior and different intensities of physical activity with cardiometabolic risk, and to analyze the simultaneous effect of excess sedentary behavior and recommended levels of physical activity on cardiometabolic risk markers in older adults. We conducted a population-based cross-sectional study on a sample of older adults (60+) living in Florianopolis, Brazil. The objectively measured predictors were sedentary time, light physical activity and moderate to vigorous physical activity, and the outcomes were markers of cardiometabolic risk. Data were considered valid when the participant had used the accelerometer for at least four days per week. The sample included 425 older adults (59.8% women), with a mean age of 73.9 years (95%CI: 73.5-74.4). Sedentary behavior was associated with lower systolic blood pressure levels (β = -0.03; 95%CI: -0.05; -0.01) and lower HDL cholesterol (β = -0.02; 95%CI: -0.02; -0.01). Light physical activity was not associated with any cardiovascular risk markers after adjustment. Each minute spent in moderate to vigorous physical activity was associated with lower waist circumference (β = -0.15; 95%CI: -0.24; -0.05), systolic blood pressure (β = -0.18; 95%CI: -0.32; -0.04) and plasma glucose (β = -0.18; 95%CI: -0.33;-0.02), and with higher HDL cholesterol (β = 0.10; 95%CI: 0.01; 0.18). Moreover, physically inactive and sedentary individuals had a greater mean waist circumference and lower HDL cholesterol than physically active and non-sedentary subjects. The results suggest that moderate to vigorous physical activity have a positive impact on cardiometabolic risk markers in older adults. Light physical activity does not appear to have a beneficial effect on the cardiometabolic markers, and despite the benefits provided by the different intensities of physical activity, the simultaneous presence of sedentary behavior and low physical activity level was associated with poor cardiometabolic risk markers.


Metformin Use and Kidney Cancer Survival Outcomes: A Systematic Review and Meta-Analysis.
Metformin has been associated with improved survival outcomes in various malignancies. However, studies in kidney cancer are conflicting. We performed a systematic review and meta-analysis to evaluate the association between metformin and kidney cancer survival. We searched Medline and EMBASE databases from inception to June 2017 to identify studies evaluating the association between metformin use and kidney cancer survival outcomes. We evaluated risk of bias with the Newcastle-Ottawa scale. We pooled hazard ratios (HRs) for recurrence-free, progression-free, cancer-specific, and overall survival using random effects models, and explored heterogeneity with metaregression. We evaluated publication bias through Begg's and Egger's tests, and the trim and fill procedure. We identified 9 studies meeting inclusion criteria, collectively involving 7426 patients. Five studies were at low risk of bias. The direction of association for metformin use was toward benefit for recurrence-free survival (HR, 0.99; 95% confidence interval [CI], 0.36-2.74), progression-free survival (pooled HR, 0.84; 95% CI, 0.66-1.07), cancer-specific (pooled HR, 0.72; 95% CI, 0.48-1.09), and overall survival (pooled HR, 0.73; 95% CI, 0.50-1.09), though none reached statistical significance. Metaregression found no study-level characteristic to be associated with the effect size, and there was no strong evidence of publication bias for any outcome. There is no evidence of a statistically significant association between metformin use and any survival outcome in kidney cancer. We discuss the potential for bias in chemoprevention studies and provide recommendations to reduce bias in future studies evaluating metformin in kidney cancer.


Independent Optical Control of Microfluidic Valves Formed from Optomechanically Responsive Nanocomposite Hydrogels.
Independent optical control of microfluidic valves formed from optomechanically responsive nanocomposite hydrogels is achieved using strongly absorbing Au nanoparticles or nanoshells embedded within a thermally responsive polymer. Valves formed from composites with different nanoparticles could be independently controlled by changing the illumination wavelength.


The importance of a preclinical trial: a selected injury intervention program for pediatric trauma centers.
Trauma centers are an ideal site to conduct screening and intervention programs that target risk taking behaviors. We hypothesized that a parent/child-centered intervention is a feasible method of injury prevention for a level one pediatric trauma center. The study was conducted in children aged 7 years to 17 years at two level one pediatric trauma centers. The high-risk behaviors targeted were (i) not always using a seat belt, (ii) not always using a bicycle helmet, or (iii) placing children under 12 in the front seat of the car. Those patients who had a positive screening test underwent a brief intervention. Experimental end points included accrual rates, acceptability of protocol by patients and medical staff, knowledge retention. Eighty-eight of the 101 families approached participated. The mean age was 13.3 +/- 2.8 years. The time to consent and screen was 2.7 +/- 0.2 minutes and 9.5 +/- 0.54 minutes. Fifty-three of 88 (60%) children had a positive screening test to one or more of the high risk behaviors. It took 11.5 +/- 1.2 minutes for intervention. Ninety-two percent of healthcare professionals felt that program fit into the trauma center routine. Forty-nine of the 53 families who had a positive screen were successfully contacted 3 months after the intervention. Ninety-seven percent of the follow-up group remembered talking about how seat belts and helmets save lives and about placing children in the back seat of a car. Seventy-nine percent of the families found the information helpful, 53% felt they learned something from the intervention. Screening and brief intervention is a well-accepted and operationally practical injury prevention intervention. Further controlled injury intervention trials are justified.


Correction of Hallux Abducto Valgus Deformity Using Closing Base Wedge Osteotomy: A Study of 101 Patients.
Hallux abducto valgus is a functionally disabling deformity with lateral deviation of the hallux and medial prominence of the first metatarsal head. Various surgical techniques have been used in the treatment of this deformity. In this retrospective review, we assess the outcomes of proximal closing base wedge osteotomy (CBWO). A single-surgeon database was reviewed for patients who underwent proximal CBWO between January 1, 2012, and December 31, 2017. A total of 101 patients were identified with a mean age of 49 years (range 13 to 80) and mean body mass index of 29 kg/m2 (range 19 to 53). The medical records were reviewed for smoking status, time to heal, rates of nonunion, shortening of the first metatarsal, intermetatarsal angle, hallux valgus angle, elevatus, mean loss of correction, complication rates, and pain scores. Pre- and postoperative variables were compared using Student's t test for continuous variables. The mean pre- and postoperative intermetatarsal angles were 15.46° (range 10° to 21°) and 3.77° (range 0° to 10°; p < .05). The mean pre- and postoperative hallux abductus valgus angles were 34.57° (range 12° to 60°) and 9.24° (range, 0° to 30°;p < .05). The mean metatarsal length shortening was 3.72 mm, and the mean postoperative elevatus was 2.73 mm. We have demonstrated excellent outcomes of CBWO with correction of intermetatarsal and hallux valgus angles. This procedure allows for superior reduction of moderate to severe intermetatarsal angles in rigid first rays. The mean postoperative elevatus of 2.73 did not result in any adverse sequelae.


Role of Twist1 Phosphorylation in Angiogenesis and Pulmonary Fibrosis.
Idiopathic pulmonary fibrosis is a chronic and progressive lung disease in which microvessel remodeling is deregulated. However, the mechanism by which deregulated angiogenesis contributes to the pathogenesis of pulmonary fibrosis remains unclear. Here we show that a transcription factor, Twist1, controls angiogenesis through the angiopoietin-Tie2 pathway, and that deregulation of this mechanism mediates pathological angiogenesis and collagen deposition in a bleomycin-induced mouse pulmonary fibrosis model. Twist1 knockdown decreases Tie2 expression and attenuates endothelial cell sprouting in vitro. Angiogenesis is also inhibited in fibrin gel implanted on Tie2-specific Twist1 conditional knockout (Twist1fl/fl/Tie2-cre) mouse lung in vivo. Inhibition of Twist1 phosphorylation at the serine 42 (Ser42) residue by treating endothelial cells with a mutant construct (Twist1S42A) decreases Tie2 expression and attenuates angiogenesis compared with full-length Twist1 in vitro and in vivo. Bleomycin challenge up-regulates Twist1 Ser42 phosphorylation and Tie2 expression, increases blood vessel density, and induces collagen deposition in the mouse lung, whereas these effects are attenuated in Twist1fl/fl/Tie2-cre mice or in mice treated with Twist1S42A mutant construct. These results indicate that Twist1 Ser42 phosphorylation contributes to the pathogenesis of bleomycin-induced pulmonary fibrosis through angiopoietin-Tie2 signaling.


Development of oral cancer vaccine using recombinant Bifidobacterium displaying Wilms' tumor 1 protein.
Several types of vaccine-delivering tumor-associated antigens (TAAs) have been developed in basic and clinical research. Wilms' tumor 1 (WT1), identified as a gene responsible for pediatric renal neoplasm, is one of the most promising TAA for cancer immunotherapy. Peptide and dendritic cell-based WT1 cancer vaccines showed some therapeutic efficacy in clinical and pre-clinical studies but as yet no oral WT1 vaccine can be administrated in a simple and easy way. In the present study, we constructed a novel oral cancer vaccine using a recombinant Bifidobacterium longum displaying WT1 protein. B. longum 420 was orally administered into mice inoculated with WT1-expressing tumor cells for 4 weeks to examine anti-tumor effects. To analyze the WT1-specific cellular immune responses to oral B. longum 420, mice splenocytes were isolated and cytokine production and cytotoxic activities were determined. Oral administrations of B. longum 420 significantly inhibited WT1-expressing tumor growth and prolonged survival in mice. Immunohistochemical study and immunological assays revealed that B. longum 420 substantially induced tumor infiltration of CD4+T and CD8+T cells, systemic WT1-specific cytokine production, and cytotoxic activity mediated by WT1-epitope specific cytotoxic T lymphocytes, with no apparent adverse effects. Our novel oral cancer vaccine safely induced WT1-specific cellular immunity via activation of the gut mucosal immune system and achieved therapeutic efficacy with several practical advantages over existing non-oral vaccines.


[Falling in geriatrics. Diagnosis and treatment].
Falls are among the most frequent adverse events in the life of an older person. Accident and emergency units, outpatient services and internal medicine wards should have a diagnostic concept for falls and fall-related injuries and implement an evidence-based risk management for fall prevention. The recently published Reviews of the Cochrane Collaboration and the revised guidelines of the Anglo-American medical societies are a proper basis to plan these steps. This, of course, has to be adapted for the needs of each institution. Currently, it is probable that at least 30% of all falls are preventable. A structured fall history and multifactorial assessment is not part of the routine of outpatient and inpatient services in Germany. The planned revision of the German nursing guideline on fall prevention and the current activities of the Aktionsbündnis Patientensicherheit will also lead to a legal dilemma for those institutions that have not implemented an adequate workup.


Platelet microparticle number is associated with the extent of myocardial damage in acute myocardial infarction.
Activated platelets generate microparticles. Increased platelet microparticles occur in acute myocardial infarction (AMI) and contribute to intracoronary thrombosis and subsequent myocardial injury. This study aimed to investigate the impact of platelet microparticles on intracoronary thrombosis by assessing the relationship between platelet microparticles and the extent of myocardial damage in AMI. This was a cross sectional study. The subjects were patients with acute coronary syndrome (ACS). Forty-one consecutive subjects with ACS admitted to intensive cardiovascular care unit were enrolled. The clinical spectrum of ACS comprised AMI (n = 26), both ST-elevation AMI (STEMI) and non-ST-elevation AMI (NSTEMI), and unstable angina (n = 15). Platelet microparticles were isolated from peripheral venous blood and detected with anti-CD42b-PE by the flow cytometry method. The extent of myocardial damage was determined by measuring the peak level of serial cardiac enzymes within 24 h of admission. Subjects with AMI had a significantly higher number of platelet microparticles than those with unstable angina (4855 ±4509/µl vs. 2181 ±1923/µl respectively; p = 0.036). Subjects with STEMI had the highest number of platelet microparticles, but no significant difference was detected as compared to those with NSTEMI (5775 ±5680/µl vs. 3601 ±1632/µl). The number of platelet microparticles in AMI was positively associated with the extent of myocardial damage (peak CK-MB: r = 0.408, p = 0.019 and peak GOT: r = 0.384, p = 0.026). The number of platelet microparticles was increased in AMI as compared to unstable angina and associated with the extent of myocardial damage.


Identification of New Biomarkers Associated With IDH Mutation and Prognosis in Astrocytic Tumors Using NanoString nCounter Analysis System.
Isocitrate dehydrogenase (IDH) mutations have been reported as biomarkers associated with tumorigenesis and prognosis in gliomas. However, genes affected by these mutations are still under investigation. The purpose of this study is to identify new molecular biomarkers associated with IDH mutation and prognosis in astrocytic tumors, which account for the largest proportion of gliomas. NanoString analysis was conducted on 40 astrocytic tumors. In total, 69 genes and 6 fusion genes were selected for screening. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to validate the selected discriminatory genes. Kaplan-Meier survival curves and log-rank test were used to analyze the overall survival and progression-free survival. mRNA levels of NTRK3, ERCC1, JAK2, AXL, BCL2, ESR1, HSP90AB1, TUBB3, RET, and ABCG2 were elevated in the IDH mutant group, whereas levels of POSTN and ERBB2 were elevated in the IDH wild-type group. Genes more highly expressed in the better prognosis group included NTRK3, ERCC1, ROS1, ERBB4, BCL2, CDKN2A, AXL, PI3KCA, HSP90AB1, ABCG2, JAK2, and RET. In the worse prognosis group, TIMP1, POSTN, and ERBB2 showed increased expressions. The elevated expression of HSP90AB1 was correlated with IDH mutation, long survival, and secondary glioblastomas. Elevated TIMP1 expression was related to high tumor grade and short patient survival. The results of NanoString were confirmed with quantitative real-time polymerase chain reaction and immunohistochemistry. HSP90AB1 is related to IDH mutation and the expressions of HSP90AB1 and TIMP1 can predict prognosis in astrocytic tumors. The NanoString analysis system is a precise and reliable method to detect mRNA expression in formalin-fixed paraffin-embedded samples.


A proposed Primary Health Early Warning Score (PHEWS) with emphasis on early detection of sepsis in the elderly.
There are several secondary care early warning scores which alert for severe illness including sepsis. None are specifically adjusted for primary care. A Primary Health Early Warning Score (PHEWS) is proposed which incorporates practical parameters from both secondary and primary care.


Antimicrobial peptide LL-37 produced by HSV-2-infected keratinocytes enhances HIV infection of Langerhans cells.
Herpes simplex virus (HSV)-2 shedding is associated with increased risk for sexually acquiring HIV. Because Langerhans cells (LCs), the mucosal epithelium resident dendritic cells, are suspected to be one of the initial target cell types infected by HIV following sexual exposure, we examined whether and how HSV-2 affects HIV infection of LCs. Although relatively few HSV-2/HIV-coinfected LCs were detected, HSV-2 dramatically enhanced the HIV susceptibility of LCs within skin explants. HSV-2 stimulated epithelial cell production of antimicrobial peptides (AMPs), including human β defensins and LL-37. LL-37 strongly upregulated the expression of HIV receptors in monocyte-derived LCs (mLCs), thereby enhancing their HIV susceptibility. Culture supernatants of epithelial cells infected with HSV-2 enhanced HIV susceptibility in mLCs, and this effect was abrogated by blocking LL-37 production. These data suggest that HSV-2 enhances sexual transmission of HIV by increasing HIV susceptibility of LCs via epithelial cell production of LL-37.


[3D Collagen Hydrogel Culture of Rat Calvarial Osteoblasts].
To establish a collagen hydrogel three-dimensional culture model with rat calvarial osteoblasts (ROBs). ROBs were obtained through enzyme digestion of segregated neonatal SD rat skull. The collagen hydrogel three-dimensional culture model was established by mixing ROBs with different concentrations of type I rat tail collagen (collagen concentration of 1, 2, 3 mg/mL), DMEM medium and NaOH under adjusted PH and a temperature of 37 degrees C. Cell viability and activity were detected by FDA/PI staining and CCK-8 3 d after cell culture. The optimal culture method of 3D collagen hydrogel was identified. Cell distribution was observed using scanning electron microscopy and HE staining. ROBs collagen was formed firmly at 2 mg/mL, which had significantly higher levels of cell viability and activity than those at 1 mg/mL and 3 mg/mL. Scanning electron microscopy and HE staining showed that cells under the 2 mg/mL collagen culture system adhered with collagen tightly and distributed homogeneously. A collagen hydrogel 3D culture model was established successfully by mixing ROBs with collagen at 2 mg/mL.


The paradoxical effects of nutrient ratios and supply rates on an outbreaking insect herbivore, the Australian plague locust.
1. The Australian plague locust, Chortoicetes terminifera, develops following rainfall in an environment dominated by two host plants, the annual Dactyloctenium radulans and the perennial Astrebla lappacea. This simple system provides an ideal opportunity to explore the relationship between plant quality, individual herbivore performance and population responses. 2. We compared the two grasses chemically and structurally, and the behavioural, physiological and developmental responses of locust nymphs to these diets. 3. The grasses appeared to be of similar nutritional quality in terms of their chemical composition, although they differed in their physical properties. Early instar nymphs performed equally well on both grasses. However, older nymphs consuming D. radulans developed faster, survived better and attained a higher body weight compared with those consuming A. lappacea. 4. The differences in performance by the older nymphs related to the rate and ratio of supply of carbohydrate and protein from the two grasses, with less carbohydrate being assimilated from A. lappacea than D. radulans per unit of protein assimilated. Experiments showed that these differences arose as a direct result of the physical barrier to nutrient extraction provided by cell walls and indirectly through the amount of water contained within each cell. Paradoxically, nitrogen did not limit performance in the traditional sense through shortage,but rather its relative excess in A. lappacea appeared to impede intake and assimilation of adequate carbohydrate. 5. As a consequence, we predict that the length of time D. radulans remains available following rainfall will influence plaguing dynamics, although not for the reasons previously thought. 6. The results highlight the need to consider nutrient balance and actual rates of supply (rather than simply measuring the chemical composition of the plant) when attempting to understand herbivore nutritional ecology.


Establishment of an effective nursing team against COVID-19-a COVID-19 treatment center experience.
Novel coronavirus disease 2019 (COVID-19) is a serious infectious respiratory disease widespread worldwide. Nurses are the front-line staff in contact with infected patients and play a key role in treating patients and controlling the epidemic. The purpose of this study was to share our nursing team's experience in the treatment of COVID-19 and provide clinical guidance. Detail nursing system arrangement was laid down: (I) reasonable division of ward channel was built; (II) effectively arranged human nursing resources and establishing special groups, including Training group, Critical patients nursing group, Quality control group, Epidemic preventive measures group, and Logistics support group; (III) optimize nursing workflow and establish various rules and regulations; (IV) scientific scheduling and humanized management; (V) pay attention to psychological support and adopt humanized management. The pre-job preparation, treatment results, and medical staff infection number were recorded. Fifty-four intensive care nurses all passed the training with an average score of 99.75±0.13. One patient was dead, and 22 patients were discharged smoothly. The average length of stay was 9.12 days. The medical staff was not infected. The treatment center was set up and functioning rapidly, safely, and orderly by implementing an emergency management strategy. The goal of a high rescue rate, low mortality, and no medical staff infection was achieved. This nursing system could be applied in COVID-19 patient treatment.


Can nutrient pathways and biotic interactions control eutrophication in riverine ecosystems? Evidence from a model driven mesocosm experiment.
Ecological theory predicts that the relative importance of benthic to planktonic primary production usually changes along the rivers' continuum from a predomination of benthic algae in lower stream orders to a predomination of planktonic algae at higher orders. Underlying mechanisms driving the interaction between algae in these habitats, its controlling factors and consequences for riverine ecosystems are, however, only partly understood. We present a mechanistic analysis of the governing ecological processes using a simplified, numerical model and examine how abiotic factors and biotic interactions influence benthic and planktonic algae by changing resource competition. We compare the outcome of the model with the results of a factorial mesocosm experiment mimicking the parameter spaces of the model. The results show a remarkable similarity with regard to the temporal development of benthic and pelagic algal biomass and shifting dominance patterns. In particular we analyse the effects of the pathways of nutrient supply (upwelling from the hyporheic zone, direct supply to the surface water, or via both pathways) and grazing in a gradient of river depths. Our results show that detachment of benthic algae, sinking of planktonic algae and the pathway of nutrient supply are key processes determining the respective algal biomass distributions particularly in shallow and intermediate deep systems. Increasing nutrient supply increases algal biomasses, but does not change the general pattern of the interactions. Decreasing light supply decreases the dominance of planktonic algae, but increases dissolved nutrients. At intermediate to high grazing rates algal biomass can be controlled by grazers, but however, at high grazing rates, dissolved nutrients accumulate in the surface water. Our results indicate that nutrient pathways, resource competition and internal control by grazing need to be considered explicitly for the understanding and explanation of eutrophication phenomena in riverine ecosystems. As a consequence, ecologically effective eutrophication management of running water systems has to go beyond the control of nutrient emissions or the achievement of limiting threshold values in the receiving waters, but requires the consideration of the nutrient pathways (surface water versus groundwater) and the shifting biological controls from lower to higher order stream ecosystems.


Prognostic consequences of borderline dysnatremia: pay attention to minimal serum sodium change.
To assess the prevalence of dysnatremia, including borderline changes in serum sodium concentration, and to estimate the impact of these dysnatremia on mortality after adjustment for confounders. Observational study on a prospective database fed by 13 intensive care units (ICUs). Unselected patients with ICU stay longer than 48 h were enrolled over a 14-year period were included in this study. Mild to severe hyponatremia were defined as serum sodium concentration < 135, < 130, and < 125 mmol/L respectively. Mild to severe hypernatremia were defined as serum sodium concentration > 145, > 150, and > 155 mmol/L respectively. Borderline hyponatremia and hypernatremia were defined as serum sodium concentration between 135 and 137 mmol/L or 143 and 145 respectively. A total of 11,125 patients were included in this study. Among these patients, 3,047 (27.4%) had mild to severe hyponatremia at ICU admission, 2,258 (20.3%) had borderline hyponatremia at ICU admission, 1,078 (9.7%) had borderline hypernatremia and 877 (7.9%) had mild to severe hypernatremia. After adjustment for confounder, both moderate and severe hyponatremia (subdistribution hazard ratio (sHR) 1.82, 95% CI 1.002 to 1.395 and 1.27, 95% CI 1.01 to 1.60 respectively) were associated with day-30 mortality. Similarly, mild, moderate and severe hypernatremia (sHR 1.34, 95% CI 1.14 to 1.57; 1.51, 95% CI 1.15 to 1.99; and 2.64, 95% CI 2.00 to 3.81 respectively) were independently associated with day-30 mortality. One-third of critically ill patients had a mild to moderate dysnatremia at ICU admission. Dysnatremia, including mild changes in serum sodium concentration, is an independent risk factor for hospital mortality and should not be neglected.


Aggressive behavior in two different group-housing systems for pregnant sows.
The study housed 120 pregnant sows from Day 29 of pregnancy to 1 week before parturition either in groups of 10 with trickle feeding (TRICKLE) or in groups of 20 with an unprotected electronic sow feeding (FITMIX). The study recorded aggressive interaction on 11 nonconsecutive days. Frequency of aggressive interactions was higher in FITMIX (p < .05); yet, intense physical contact was unusual in both systems (3% of the total interactions). Conflicts in FITMIX centered largely on the feeder (83% vs. 23% for FITMIX and TRICKLE, respectively [p < .05]); in TRICKLE, they occurred mainly in the resting area (13% vs. 48% for FITMIX and TRICKLE, respectively [p < .05]). Forty-six percent of the FITMIX sows (mostly gilts and subordinates) needed assistance to adapt to the feeding system. Eventually, 8.3% of the FITMIX sows failed to adapt and had to be removed. In conclusion, although aggressive interactions were mainly of low intensity, sequential feeding appeared to make FITMIX a more competitive feeding system.


Effect of amino acid substitutions in a potential metal-binding site of AnfA on expression from the anfH promoter in Azotobacter vinelandii.
AnfA, an activator required for transcription of the structural genes encoding nitrogenase 3 (anfHDGK) in Azotobacter vinelandii, has a potential metal-binding site [(S19)H(C21)FTGE(C26)R] in its N terminus. Growth studies and expression of an anfH-lacZ fusion in mutants containing amino acid substitutions in this site indicate that Ser-19 is not required for AnfA activity whereas Cys-21 and Cys-26 are required. Residual expression of the anfH-lacZ fusion in AnfA- mutants was found to be due to activation by VnfA, the activator required for expression of genes encoding nitrogenase 2.


Pollen and mold spores. An atmospheric and field survey in Los Angeles.
A two-year survey of pollen and mold spores by the gravity slide method revealed that there are no clear-cut tree, grass or weed pollen seasons in California. Pollen counts should be correlated with field studies to distinguish the various plants whose pollen have a similar appearance. Spores of Alternaria and Hormodendrum, whose importance in allergic disease of the respiratory tract has been well established for many years, were found all during the year. More hormodendrum spores were collected than the total of all other pollens combined.


[Dry hands (irritative contact dermatitis) in housewives which is not alleviated on cessation of domestic work: clinical varieties].
There are three types of hand dermatitis in housewives. The most usual are cured when housework is stopped. Another type is that of housewife contact dermatitis which appears on pre-existing endogenous lesions such as dyshidrosis or nummular eczema. The third form is housewife hand contact dermatitis which appears, or coexists with, localized endogenous lesions of the hands. The last two forms are not cured when housework is stopped. In some cases the three forms may coexist or appear one after another. It is not usual for a person suffering from typical flexural atopic dermatitis to present with one of the described three forms of hand dermatitis. Nevertheless, without having some relationship to atopic diathesis no woman could suffer from any of these three forms of dermatitis. In spite of the lack of analytical data, everyday clinical facts (one example being these different forms of housewife hand dermatitis) suggest the need to accept a subgroup of cutaneous atopic diathesis.


The interplay of SARS-CoV-2 evolution and constraints imposed by the structure and functionality of its proteins.
The unprecedented pace of the sequencing of the SARS-CoV-2 virus genomes provides us with unique information about the genetic changes in a single pathogen during ongoing pandemic. By the analysis of close to 200,000 genomes we show that the patterns of the SARS-CoV-2 virus mutations along its genome are closely correlated with the structural and functional features of the encoded proteins. Requirements of foldability of proteins' 3D structures and the conservation of their key functional regions, such as protein-protein interaction interfaces, are the dominant factors driving evolutionary selection in protein-coding genes. At the same time, avoidance of the host immunity leads to the abundance of mutations in other regions, resulting in high variability of the missense mutation rate along the genome. "Unexplained" peaks and valleys in the mutation rate provide hints on function for yet uncharacterized genomic regions and specific protein structural and functional features they code for. Some of these observations have immediate practical implications for the selection of target regions for PCR-based COVID-19 tests and for evaluating the risk of mutations in epitopes targeted by specific antibodies and vaccine design strategies.


Effects of vitamin C stimulation on rehabilitation of dysphagia after stroke: a randomized trial.
Stroke is a clinical syndrome of localized or global brain dysfunction caused by cerebrovascular disease. The aim of this study was to explore the effect of vitamin C acid stimulation on the rehabilitation process, Nourishment State Index and immune function indicators of stroke patients with dysphagia. This is a prospective cohort study. This study was conducted at our hospital. We analyzed stroke patients with dysphagia. A total of 120 stroke patients with dysphagia were randomly divided into a routine group and a test group, with 60 cases in each group. Routine swallowing training was performed in the routine group, and the test group was stimulated with vitamin C acid. The water swallow test (WST) and video fluoroscopic swallowing study (VFSS) were used to compare the rehabilitation of dysphagia in the two groups. Nourishment State Index was evaluated by BMI, serum albumin, total serum protein and hemoglobin. Immune Function Index was evaluated by IgA, IgM and IgG. Compared with the control group, the WST level of patients treated with vitamin C acid stimulation intervention were significantly reduced, and the VFSS score were significantly increased. Serum levels of hemoglobin, albumin, total protein, IgA, IgM and IgG in the vitamin C acid stimulation group were remarkably increased than those in the control group. Vitamin C acid stimulation exhibits a good application effect in patients with dysphagia after stroke. Moreover, vitamin C acid stimulation can further improve the nutritional status and immune function after stroke and promote postoperative recovery of patients. Therefore, we believe that vitamin C stimulation therapy can be widely used in stroke rehabilitation management. Vitamin C acid stimulation significantly improves rehabilitation of stroke patients with dysphagia and ameliorates the nutritional status and immune function of patients.


Exploring potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy.
The negative impact of long COVID on social life and human health is increasingly prominent, and the elevated risk of cardiovascular disease in patients recovering from COVID-19 has also been fully confirmed. However, the pathogenesis of long COVID-related inflammatory cardiomyopathy is still unclear. Here, we explore potential biomarkers and therapeutic targets of long COVID-associated inflammatory cardiomyopathy. Datasets that met the study requirements were identified in Gene Expression Omnibus (GEO), and differentially expressed genes (DEGs) were obtained by the algorithm. Then, functional enrichment analysis was performed to explore the basic molecular mechanisms and biological processes associated with DEGs. A protein-protein interaction (PPI) network was constructed and analyzed to identify hub genes among the common DEGs. Finally, a third dataset was introduced for validation. Ultimately, 3,098 upregulated DEGs and 1965 downregulated DEGs were extracted from the inflammatory cardiomyopathy dataset. A total of 89 upregulated DEGs and 217 downregulated DEGs were extracted from the dataset of convalescent COVID patients. Enrichment analysis and construction of the PPI network confirmed VEGFA, FOXO1, CXCR4, and SMAD4 as upregulated hub genes and KRAS and TXN as downregulated hub genes. The separate dataset of patients with COVID-19 infection used for verification led to speculation that long COVID-associated inflammatory cardiomyopathy is mainly attributable to the immune-mediated response and inflammation rather than to direct infection of cells by the virus. Screening of potential biomarkers and therapeutic targets sheds new light on the pathogenesis of long COVID-associated inflammatory cardiomyopathy as well as potential therapeutic approaches. Further clinical studies are needed to explore these possibilities in light of the increasingly severe negative impacts of long COVID.


The minimum transition hypothesis for intermittent hierarchical motor control.
In intermittent control, instead of continuously calculating the control signal, the controller occasionally changes this signal at certain sparse points in time. The control law may include feedback, adaptation, optimization, or any other control strategies. When, where, and how does the brain employ intermittency as it controls movement? These are open questions in motor neuroscience. Evidence for intermittency in human motor control has been repeatedly observed in the neural control of movement literature. Moreover, some researchers have provided theoretical models to address intermittency. Even so, the vast majority of current models, and I would dare to say the dogma in most of the current motor neuroscience literature involves continuous control. In this paper, I focus on an area in which intermittent control has not yet been thoroughly considered, the structure of muscle synergies. A synergy in the muscle space is a group of muscles activated together by a single neural command. Under the assumption that the motor control is intermittent, I present the minimum transition hypothesis (MTH) and its predictions with regards to the structure of muscle synergies. The MTH asserts that the purpose of synergies is to minimize the effort of the higher level in the hierarchy by minimizing the number of transitions in an intermittent control signal. The implications of the MTH are not only for the structure of the muscle synergies but also to the intermittent and hierarchical nature of the motor system, with various predictions as to the process of skill learning, and important implications to the design of brain machine interfaces and human robot interaction.


Generating the cerebral cortical area map.
The view that the cortical primordium is initially patterned in similar ways to the rest of the embryo has been a conceptual breakthrough. We now have a new starting point for understanding how the cortical area map is established and how maps may change and evolve. Here we review findings that signaling molecules secreted from distinct cortical signaling centers establish positional information in the cortical primordium and regulate regional growth. In other embryonic systems, positional signals would regulate the patterned expression of transcription factors, leading, in a gene regulatory cascade, to the patterned differentiation of the tissue. We discuss candidate transcription factors with respect to such a model of cortical patterning. Finally, embryonic structures interact to pattern one another. We review data suggesting that the thalamus and cortex are patterned independently then interact to generate the final cortical area map.


4Children for parents and for midwives.
This article outlines the launch of a new website which will bring together the rich, but sometimes difficult to access, body of best practice, research and evidence, that parents and professionals need when dealing with children aged from birth-five. The article sets out the scale, type and quality of information that is available, highlights what midwives could helpfully share with parents to help them deal with their children's developments, and what they could access themselves to develop their practice and ensure they remain as up to date as possible with early years developments.


Early echo-guided percutaneous aspiration of peripheral lung abscesses in children: report of two cases.
A 9 year-old boy and a 7 year-old girl suffered from fever and chest pains before they were brought to Chang Gung Children's Hospital. Chest radiographs and computed tomography scans showed lung abscesses with pleural attachment, and using echo-guidance, percutaneous aspirations were done which confirmed the growth of Fusobacterium sp, and Veillonella parvula respectively, both of which are susceptible to penicillin G. The fever and chest pains subsided within 24 hours after the procedure. We suggest using early percutaneous aspiration of peripheral located lung abscesses soon after admission, rather than after a 10-14 day trial of antibiotic therapy: it can be a safe and cost-effective procedure to shorten the duration of the parenteral antibiotic treatment and hospitalization.


Study of the frequency and reasons for discontinuation of different lines of treatment in patients with multiple myeloma.
The availability of new agents for the treatment of multiple myeloma has allowed the use of multiple lines of treatment, but a percentage of patients do not reach to receive this combination because of toxicity and early death. In this regard, a cross-sectional European study evaluated the management of different lines and discontinuation of treatment in 7635 patients from seven countries in routine clinical practice, finding that 39% of European patients do not receive a second line and that only 4% of patients reach third line in Spain, a figure that is striking when comparing with the rest of the countries. We analyze the frequency and causes of treatment discontinuation in a series of 108 patients from a Spanish University hospital showing that the main reason for permanent treatment discontinuation after finishing first line was to have a response, while death due to disease progression accounted for the main reason in subsequent lines of therapy, with its frequency increasing according to the number of lines received. Additionally, in our longitudinal study, we estimated, using a competitive risk analysis, that 22% of patients would not receive a second line of therapy at 60 months and 47% would not reach third line, also at 60 months, showing a marked discrepancy with the results reported in the cross-sectional European study. Although based on limited data, our results suggest the convenience of validating the findings of cross-sectional studies conducted in large cohorts.


Regulation of pancreatic microRNA-7 expression.
Genome-encoded microRNAs (miRNAs) provide a posttranscriptional regulatory layer, which is important for pancreas development. Differentiation of endocrine cells is controlled by a network of pancreatic transcription factors including Ngn3 and NeuroD/Beta2. However, how specific miRNAs are intertwined into this transcriptional network is not well understood. Here, we characterize the regulation of microRNA-7 (miR-7) by endocrine-specific transcription factors. Our data reveal that three independent miR-7 genes are coexpressed in the pancreas. We have identified conserved blocks upstream of pre-miR-7a-2 and pre-miR-7b and demonstrated by functional assays that they possess promoter activity, which is increased by the expression of NeuroD/Beta2. These data suggest that the endocrine specificity of miR-7 expression is governed by transcriptional mechanisms and involves members of the pancreatic endocrine network of transcription factors.


Inflammatory changes induced by transplanted neural precursor cells in a multiple sclerosis model.
Recent studies on neural precursor cell (NPC) transplantation in multiple sclerosis animal models reveal that these cells exert their therapeutic effect mainly because of immunomodulation rather than cell replacement. In this study intraventricularly transplanted NPCs in mice, induced experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis, improved the clinical symptoms and suppressed inflammation in the brain by enhancing the apoptosis of inflammatory cells. However, the same treatment failed to reduce significantly the inflammatory cells in the spinal cord, the pathology of which predominantly determines the clinical manifestation of experimental autoimmune encephalomyelitis. Our findings suggest that immunosuppression is rather a local phenomenon and thus, bystander neuroprotective mechanisms triggered by NPC intraventricular transplantation should be accountable for their therapeutic effect.


Presbycusis: a human temporal bone study of individuals with flat audiometric patterns of hearing loss using a new method to quantify stria vascularis volume.
The purpose of this study was to determine the prevalence of stria vascularis atrophy in individuals with presbycusis and flat audiometric patterns of hearing loss. Individuals with presbycusis have historically been categorized by the shape of their audiograms, and flat audiometric thresholds have been reported to be associated with atrophy of the stria vascularis. Stria vascularis volume was not measured in these studies. Retrospective case review. Archival human temporal bones from individuals with presbycusis were selected on the basis of strict audiometric criteria for flat audiometric thresholds. Six temporal bones that met these criteria were identified and compared with 10 temporal bones in individuals with normal hearing. A unique quantitative method was developed to measure the stria vascularis volume in these temporal bones. The hair cell and spiral ganglion cell populations also were quantitatively evaluated. Only one of the six individuals with presbycusis and flat audiometric thresholds had significant atrophy of the stria vascularis. This individual with stria vascularis atrophy also had reduced inner hair cell, outer hair cell, and ganglion cell populations. Three of the individuals with presbycusis had spiral ganglion cell loss, three individuals had inner hair cell loss, and all six individuals had outer hair cell loss. The results of this investigation suggest that individuals with presbycusis and flat audiometric patterns of hearing loss infrequently have stria vascularis atrophy. Outer hair cell loss alone or in combination with inner hair cell or ganglion cell loss may be the cause of flat audiometric thresholds in individuals with presbycusis.


Iron-sulfur cluster N5 is coordinated by an HXXXCXXCXXXXXC motif in the NuoG subunit of Escherichia coli NADH:quinone oxidoreductase (complex I).
NADH:quinone oxidoreductase (complex I) plays a central role in cellular energy metabolism, and its dysfunction is found in numerous human mitochondrial diseases. Although the understanding of its structure and function has been limited, the x-ray crystal structure of the hydrophilic part of Thermus thermophilus complex I recently became available. It revealed the localization of all redox centers, including 9 iron-sulfur clusters and their coordinating ligands, and confirmed the predictions mostly made by Ohnishi et al. (Ohnishi, T., and Nakamaru-Ogiso, E. (2008) Biochim. Biophys. Acta 1777, 703-710) based on various EPR studies. Recently, Yakovlev et al. (Yakovlev, G., Reda, T., and Hirst, J. (2007) Proc. Natl. Acad. Sci. U. S. A. 104, 12720-12725) claimed that the EPR signals from clusters N4, N5, and N6b were misassigned. Here we identified and characterized cluster N5 in the Escherichia coli complex I whose EPR signals had never been detected by any group. Using homologous recombination, we constructed mutant strains of H101A, H101C, H101A/C114A, and cluster N5 knock-out. Although mutant NuoEFG subcomplexes were dissociated from complex I, we successfully recovered these mutant NuoCDEFG subcomplexes by expressing the His-tagged NuoCD subunit, which had a high affinity to NuoG. The W221A mutant was used as a control subcomplex carrying wild-type clusters. By lowering temperatures to around 3 K, we finally succeeded in detecting cluster N5 signals in the control for the first time. However, no cluster N5 signals were found in any of the N5 mutants, whereas EPR signals from all other clusters were detected. These data confirmed that, contrary to the misassignment claim, cluster N5 has a unique coordination with His(Cys)(3) ligands in NuoG.


Age-related language characteristics of children and adolescents with fragile X syndrome.
In addition to moderate-to-severe mental retardation (MR), the fragile X [fra(X)] mutation produces significant impediments in speech and language. Severe delays in speech and language have been demonstrated in both adult males and young individuals with the fra(X) mutation. Having observed longitudinal declines in IQ scores in young males with fra(X) and given the relationship between cognitive ability and language skill, we wanted to determine whether speech-language deficits in young males with fra(X) were age-related in ways comparable with those observed in cognitive deficits. We examined a small sample (n = 16) of children and adolescents, ages 6-17 years, using the Clinical Evaluation of Language Fundamental-Preschool (CELF-P). The CELF-P is used to evaluate language deficits in preschool children and assesses receptive and expressive language ability. It is standardized for children ages 3-7 years and provides age-normed standard scores. To evaluate changes in language scores, we converted raw scores into age-equivalents. Results indicate that males with fra(X) have significantly lower age equivalent scores compared with females. A cross-sectional analysis of males' age-equivalent scores reveals that a plateau is reached at approximately 48 months. Our findings suggest that, as with IQ and adaptive behavior scores, language development in young, fully mutated fra(X) individuals appears to reach a plateau as they age.


Interplay between the RNA Chaperone Hfq, Small RNAs and Transcriptional Regulator OmpR Modulates Iron Homeostasis in the Enteropathogen Yersinia enterocolitica.
Iron is both essential for and potentially toxic to bacteria, so the precise maintenance of iron homeostasis is necessary for their survival. Our previous study indicated that in the human enteropathogen Yersinia enterocolitica, the regulator OmpR directly controls the transcription of the fur, fecA and fepA genes, encoding the ferric uptake repressor and two transporters of ferric siderophores, respectively. This study was undertaken to determine the significance of the RNA chaperone Hfq and the small RNAs OmrA and RyhB1 in the post-transcriptional control of the expression of these OmpR targets. We show that Hfq silences fur, fecA and fepA expression post-transcriptionally and negatively affects the production of FLAG-tagged Fur, FecA and FepA proteins. In addition, we found that the fur gene is under the negative control of the sRNA RyhB1, while fecA and fepA are negatively regulated by the sRNA OmrA. Finally, our data revealed that the role of OmrA results from a complex interplay of transcriptional and post-transcriptional effects in the feedback circuit between the regulator OmpR and the sRNA OmrA. Thus, the expression of fur, fecA and fepA is subject to complex transcriptional and post-transcriptional regulation in order to maintain iron homeostasis in Y. enterocolitica.


[Clinical experience with bromperidol in chronic psychoses].
Bromperidol therapeutic efficacy, and tolerance was studied by means of a 3-month open trial on 25 chronic psychotic female inpatients from a room at San Juan ward for medium to extensive length of stay, The Braulio A. Moyano National Psychiatric Hospital, Buenos Aires. This drug was administered orally on a single 10- to 35 mg night dose. No effect whatsoever was observed on periodic catatonia. However, its being well-tolerated and effective on chronic psychotic patients, coupled to the "bonus" of a single daily dose, turns BP into a suitable alternative drug for Haloperidol when dealing with schizophrenia, and delusions with no deficitary evolution.


Bone formation controlled by biologically relevant inorganic ions: role and controlled delivery from phosphate-based glasses.
The role of metal ions in the body and particularly in the formation, regulation and maintenance of bone is only just starting to be unravelled. The role of some ions, such as zinc, is more clearly understood due to its central importance in proteins. However, a whole spectrum of other ions is known to affect bone formation but the exact mechanism is unclear as the effects can be complex, multifactorial and also subtle. Furthermore, a significant number of studies utilise single doses in cell culture medium, whereas the continual, sustained release of an ion may initiate and mediate a completely different response. We have reviewed the role of the most significant ions that are known to play a role in bone formation, namely calcium, zinc, strontium, magnesium, boron, titanium and also phosphate anions as well as copper and its role in angiogenesis, an important process interlinked with osteogenesis. This review will also examine how delivery systems may offer an alternative way of providing sustained release of these ions which may effect and potentiate a more appropriate and rapid tissue response.


Distractor cueing effects on choice reaction time and their relationship with schizotypal personality.
Although usually displaying increased distractibility, schizophrenic patients sometimes show a reduced influence of distractors during selective attention tasks. This study explored whether reduced distractor processing effects can also occur in healthy individuals with high levels of schizotypal personality traits. In all, 36 healthy volunteers completed schizotypal personality scales and a choice reaction time (RT) task in which they responded to the central letter of triads (XMX, YCY), ignoring the flanking distractors. RT increases on low-probability probe trials (YMY, XCX) measured distractor processing ('the distractor cueing effect'). Correlations between schizotypy scores and distractor cueing were evaluated. Healthy participants with high positive schizotypy scores (i.e. those reporting more hallucination-like experiences and delusion-like beliefs) showed smaller distractor cueing effects than those with lower scores. This association was independent of the influence of other schizotypal personality traits (disorganized, negative or asocial schizotypy) and was significant only for right-hand responses. These findings closely parallel the previously reported reduced distractor cueing effect, for right-hand responses, among acute-phase schizophrenic patients. Finding reduced distractor cueing effects in healthy participants with high levels of positive schizotypy increases confidence that reduced distractor cueing is a specific feature, rather than a non-specific consequence, of acute-phase schizophrenia.


Some properties of spectrin-like proteins from Pisum sativum.
Proteins cross-reacting with antibodies directed against alpha- and beta-spectrin were recently detected in plant cells. In this report we have studied the ability of these proteins to interact with other components of membrane skeleton such as ankyrin, f-actin and calmodulin. It was found that the polypeptide of high molecular weight reacting with anti-alpha-spectrin antibody binds calmodulin in Ca(2+)-dependent manner. Protein complexes containing polypeptides cross-reacting with anti-spectrin antibodies interact with muscle f-actin (in co-sedimentation assay) and with erythrocyte ankyrin (ELISA-type assay). These data further substantiate a possibility of occurrence of spectrin-based membrane skeleton in higher plant cells.


Scale-dependent complementarity of climatic velocity and environmental diversity for identifying priority areas for conservation under climate change.
As most regions of the earth transition to altered climatic conditions, new methods are needed to identify refugia and other areas whose conservation would facilitate persistence of biodiversity under climate change. We compared several common approaches to conservation planning focused on climate resilience over a broad range of ecological settings across North America and evaluated how commonalities in the priority areas identified by different methods varied with regional context and spatial scale. Our results indicate that priority areas based on different environmental diversity metrics differed substantially from each other and from priorities based on spatiotemporal metrics such as climatic velocity. Refugia identified by diversity or velocity metrics were not strongly associated with the current protected area system, suggesting the need for additional conservation measures including protection of refugia. Despite the inherent uncertainties in predicting future climate, we found that variation among climatic velocities derived from different general circulation models and emissions pathways was less than the variation among the suite of environmental diversity metrics. To address uncertainty created by this variation, planners can combine priorities identified by alternative metrics at a single resolution and downweight areas of high variation between metrics. Alternately, coarse-resolution velocity metrics can be combined with fine-resolution diversity metrics in order to leverage the respective strengths of the two groups of metrics as tools for identification of potential macro- and microrefugia that in combination maximize both transient and long-term resilience to climate change. Planners should compare and integrate approaches that span a range of model complexity and spatial scale to match the range of ecological and physical processes influencing persistence of biodiversity and identify a conservation network resilient to threats operating at multiple scales.


Release of ANP and fat oxidation in overweight persons during aerobic exercise in water.
Exercise in water compared to land-based exercise (LE) results in a higher release of natriuretic peptides, which are involved in the regulation of exercise-induced adipose tissue lipolysis. The present study was performed to compare the release of atrial natriuretic peptide (ANP) and free fatty acids (FFA) during prolonged aerobic water-based exercise (WE) with the release after an identical LE. 14 untrained overweight subjects performed 2 steady state workload tests on the same ergometer in water and on land. Before and after exercise, venous blood samples were collected for measuring ANP, FFA, epinephrine, norepinephrine, insulin and glucose. The respiratory exchange ratio (RER) was determined for fat oxidation.The exercises resulted in a significant increase in ANP in LE (61%) and in WE (177%), and FFA increased about 3-fold in LE and WE with no significant difference between the groups. Epinephrine increased, while insulin decreased similarly in both groups. The RER values decreased during the exercises, but there was no significant difference between LE and WE. In conclusion, the higher ANP concentrations in WE had no additional effect on lipid mobilization, FFA release and fat oxidation. Moderate-intensity exercises in water offer no benefit regarding adipose tissue lipolysis in comparison to LE.


[Concentrations of serum iron and transferrin in children with nephrotic syndrome].
Nephrotic syndrome (NS) is characterized by marked urinary excretion of albumin and other intermediated-size plasma proteins such as transferrin. The aim of this study was to determine the changes of serum iron and transferrin and the relationship between the serum and urinary transferrin. The indexes related to iron metabolism, including serum iron, ferritin, transferrin, total iron-binding capacity, transferrin saturation and hematological parameters (Hb, MCV, MCH), and urinary transferrin were measured in 37 children with NS before treatment and at the remission stage. Thirty-five age-matched healthy children served as controls. Serum iron levels (18.8 +/- 3.8 micromol/L) in NS patients before treatment were significantly lower than in the healthy controls (22.2 +/-3.8 micromol/L) and those measured at the remission stage (21.0 +/- 3.5 micromol/L) (P < 0.01). Serum transferrin levels in NS patients before therapy (1.9 +/- 0.3 g/L) also decreased compared with those in the healthy controls (3.1 +/- 0.5 g/L) and those measured at the remission stage (2.9 +/- 0.6 g/L) (P < 0.01). In contrast, serum total iron-binding capacity and transferrin saturation were noticeably higher in NS patients before treatment than those in the healthy controls (total iron-binding capacity 56.4 +/- 9.2 micromol/L vs 50.7 +/- 6.8 micromol, P < 0.01; transferrin saturation 55.7 +/- 9.2 % vs 46.4 +/- 8.2%, P < 0.01) and were also higher than those measured at the remission stage (51.9 +/-7.7 micromol/L and 47.4 +/- 13.3%) (P < 0.01). Serum transferrin positively correlated to serum albumin (r = 0.609, P < 0.01) and negatively correlated to urinary transferrin (r = -0.550, P < 0.01) in NS patients before treatment. Serum iron and transferrin levels markedly decreased in NS patients, which may be partially related to the urinary loss of transferrin.


KBi(2-x)Pbx (0 < x <or= 1): a Zintl phase evolving from a distortion of the cubic Laves-phase structure.
The quasibinary system KBi(2-x)Pbx has been investigated, both experimentally and theoretically. Phases with compositions 0 < or = x < or = 1.2 were synthesized and structurally characterized by X-ray diffraction experiments. For low values of x (0 < or = x < 0.6), KBi(2-x)Pbx adopts the cubic Laves-phase structure MgCu2 (space group Fdm), which contains a rigid framework of corner-condensed symmetry-equivalent tetrahedra formed by randomly distributed Bi and Pb atoms. For compositions x > or = 0.6, these tetrahedra become alternately elongated and contracted. The distortion of the framework lowers the space-group symmetry to F43m (KBi(1.2)Pb(0.8), F43m, Z = 8, a = 9.572(1) A). Magnetometer measurements show that KBi2 (x = 0) is metallic and goes through a superconducting transition below 3.5 K. First principles calculations reveal that the Fd3m --> F43m distortion is largest for KBiPb (x = 1.0), which at the same time turns into a semiconductor. Thus, F43m KBiPb corresponds to a proper charge-balanced Zintl phase, K+[BiPb]-, with separated polyanionic tetrahedra, (Bi2Pb2)2-. However, it was not possible to prepare F43m KBiPb. Syntheses attempting to increase the Pb content in KBi(2-x)Pbx above x = 0.8 yielded additional, not yet characterized, ternary phases.


Bilateral superior concha bullosa: a rare case overlooked.
Concha bullosa is generally defined as the pneumatization of the middle turbinate and, rarely, of the superior or the inferior turbinates. A symptomatic pneumatization of the superior turbinate is extremely rare. When symptomatic, concha bullosa may cause various problems. Concha bullosa can be easily recognized in paranasal sinus computed tomography. In this article we present a very rare case with bilateral pneumatization of the superior turbinates in a patient with relevant symptomatology.


Dual Alignment for Partial Domain Adaptation.
Partial domain adaptation (PDA) aims to transfer knowledge from a label-rich source domain to a label-scarce target domain based on an assumption that the source label space subsumes the target label space. The major challenge is to promote positive transfer in the shared label space and circumvent negative transfer caused by the large mismatch across different label spaces. In this article, we propose a dual alignment approach for PDA (DAPDA), including three components: 1) a feature extractor extracts source and target features by the Siamese network; 2) a reweighting network produces "hard" labels, class-level weights for source features and "soft" labels, instance-level weights for target features; 3) a dual alignment network aligns intra domain and interdomain distributions. Specifically, the intra domain alignment aims to minimize the intraclass variances to enhance the intraclass compactness in both domains, and interdomain alignment attempts to reduce the discrepancies across domains by domain-wise and class-wise adaptations. The negative transfer can be alleviated by down-weighting source features with nonshared labels. The positive transfer can be enhanced by upweighting source features with shared labels. The adaptation can be achieved by minimizing the discrepancies based on class-weighted source data with hard labels and instance-weighed target data with soft labels. The effectiveness of our method has been demonstrated by outperforming state-of-the-art PDA methods on several benchmark datasets.


Calcium requirements: new estimations for men and women by cross-sectional statistical analyses of calcium balance data from metabolic studies.
Low intakes of calcium are associated with an increased risk of both osteoporosis and cardiovascular disease. To provide new estimates of the average calcium requirement for men and women, we determined the dietary calcium intake required to maintain neutral calcium balance. Calcium balance data [calcium intake -(fecal calcium + urinary calcium)] were collected from 155 subjects [women: n = 73; weight: 77.1 +/- 18.5 kg; age: 47.0 +/- 18.5 y (range: 20-75 y); men: n = 82; weight: 76.6 +/- 12.5 kg; age: 28.2 +/- 7.7 y (range: 19-64 y)] who participated in 19 feeding studies conducted in a metabolic unit. Balance data from the final 6-12 d of each dietary period (minimum length:18 d) of each study (1-9 observations per subject) were analyzed. Data were excluded if individual intakes of magnesium, copper, iron, phosphorus, or zinc fell below the estimated average requirements or exceeded the 99 th percentile of usual intakes from the 1994 Continuing Survey of Food Intakes by Individuals (for iron, above the upper limit). Daily intakes of calcium ranged between 415 and 1740 mg. The relation between intake and output was examined by fitting random coefficient models. Coefficients were included to test for sex and age differences. The models predicted a neutral calcium balance [defined as calcium output (Y) equal to calcium intake (C)] at intakes of 741 mg/d [95% prediction interval (PI): 507, 1035; Y = 148.29 + 0.80C], 9.4 mg kg body wt(-1) d(-1) [95% PI: 6.4, 12.9; Y = 1.44 + 0.85C], or 0.28 mg kcal(-1) d(-1) [95% PI: 0.19, 0.38; Y = 0.051 + 0.816C]. Neither age nor sex affected the estimates when calcium intakes were expressed as mg/d or as mg kg body wt(-1) d(-1). The findings suggest that the calcium requirement for men and women is lower than previously estimated.


Beyond Physical Well-being: Exploring Demographic Variances in Psychosocial Well-being before Breast Reconstruction.
A patient's preoperative satisfaction with their breasts and baseline psychosocial, sexual, and physical well-being are important considerations when planning breast reconstruction. We sought to elucidate variances in preoperative responses among patients undergoing postmastectomy breast reconstruction. Preoperative BREAST-Q responses and demographic data, including race, generation, median household incomeinstitutional review board and body mass index (BMI) were collected from breast cancer patients scheduled for mastectomy. Associations between demographic group and survey response were analyzed by chi-square or independent t-tests. In total, 646 of 826 patients identified had complete data and were included in the final analysis. Patients in BMI group 1 (16-24.9) were more likely to report feeling "very satisfied" with how they looked unclothed compared with patients in other BMI groups (P = 0.031). Conversely, patients in groups 3 and 4 (35+), reported lower satisfaction (P = 0.037) and felt less attractive without clothes (P = 0.034). Asian women were less likely to feel attractive (P = 0.007), and Black patients were less likely to feel of equal worth to other women (P < 0.001). Finally, patients were less likely to report confidence in social settings if they were Black (P < 0.001), Asian (P < 0.001), from the millennial generation (P = 0.017), or living in zip codes with median household income less than $55,000 (P = 0.042). Breast cancer patients' feelings toward their natural breasts vary widely between demographic groups. Understanding baseline psychosocial factors in this population is key to informing preoperative discussions and interpreting postoperative satisfaction.


Continuous high-dose estrogen controls serum FSH and LH levels: new treatment strategy for extremely low ovarian reserve patients, two case reports.
At present, there are no proven therapies to improve ovarian function in women with premature ovarian insufficiency (POI) or in those with extremely low ovarian reserve (LOR). We report successful IVF outcomes achieved with continuous high-dose estrogen supplementation in patients with LOR. Patients were 33- and 42-year-old nulligravidae with high-serum FSH (over 30 IU/L) and undetectable serum AMH (under 0.1 ng/mL) levels; however, neither patient fulfilled the diagnostic criteria for POI. After cycle cancellation and unsuccessful IVF treatment, both patients received conjugated estrogen (CE) supplementation (2.5-3.75 mg/day) from day 2 of their menstrual cycle to the day of HCG administration in their IVF treatment cycles. Following continuous high-dose estrogen supplementation, oocytes were successfully retrieved from both patients and fertilized. Both patients also achieved ongoing pregnancy through frozen-thawed embryo transfer cycles. In conclusion, high-dose estrogen supplementation down-regulated serum FSH and LH within their physiological ranges, which led to functional follicle growth and prevented early luteinization. Further studies will be needed to confirm the effect of this treatment on POI patients and to establish a new and individualized protocol for LOR patients.


Development of the oxygenator: past, present, and future.
From the 1950s to the 1980s, the most widely used oxygenator in the clinical field was the disposable bubble oxygenator. However, membrane oxygenators have become the preferred clinical choice over the years. In the United States, membrane oxygenators used in cardiopulmonary bypass operations account for the majority of clinical oxygenator use. Membrane oxygenators have an equal capability for oxygenating venous blood compared with other type of oxygenators such as the bubble type and film type; however, the membrane oxygenator requires a smaller volume for priming to achieve a sufficient gas transfer rate and results in less blood trauma such as hemolysis because it uses a similar mechanism to the natural lung. In the 1980s, the first capillary-type oxygenator adopted the system of intracapillary blood perfusion. However, this induced high pressure resistance in the module and caused hemolysis. Thus, at present, capillary oxygenators commonly adopt the system of extracapillary blood perfusion. Microporous hollow-fiber membranes are primarily used for short-term cardiopulmonary bypass application, whereas nonmicroporous hollow-fiber membranes are primarily used for long-term extracorporeal membrane oxgenation application.


Multi-regional COVID-19 epidemic forecast in Sweden.
The novel coronavirus disease 2019 (COVID-19) is a contagious disease with high transmissibility to spread worldwide, reported to present a certain burden on worldwide public health. This study aimed to determine epidemic occurrence probability at any reasonable time horizon in any region of interest by applying modern novel statistical methods directly to raw clinical data. This paper describes a novel bio-system reliability approach, particularly suitable for multi-regional health and stationary environmental systems, observed over a sufficient period of time, resulting in a reliable long-term forecast of the highly pathogenic virus outbreak probability. For this study, COVID-19 daily recorded patient numbers in most affected Sweden regions were chosen. This work aims to benchmark state-of-the-art methods, making it possible to extract necessary information from dynamically observed patient numbers while considering relevant territorial mapping. The method proposed in this paper opens up the possibility of accurately predicting epidemic outbreak probability for multi-regional biological systems. Based on their clinical survey data, the suggested methodology can be used in various public health applications. Key findings are: A novel spatiotemporal health system reliability method has been developed and applied to COVID-19 epidemic data.Accurate multi-regional epidemic occurrence prediction is made.Epidemic threshold confidence bands given.


Critical pore radius and transport properties of disordered hard- and overlapping-sphere models.
Transport properties of porous media are intimately linked to their pore-space microstructures. We quantify geometrical and topological descriptors of the pore space of certain disordered and ordered distributions of spheres, including pore-size functions and the critical pore radius δ_{c}. We focus on models of porous media derived from maximally random jammed sphere packings, overlapping spheres, equilibrium hard spheres, quantizer sphere packings, and crystalline sphere packings. For precise estimates of the percolation thresholds, we use a strict relation of the void percolation around sphere configurations to weighted bond percolation on the corresponding Voronoi networks. We use the Newman-Ziff algorithm to determine the percolation threshold using universal properties of the cluster size distribution. The critical pore radius δ_{c} is often used as the key characteristic length scale that determines the fluid permeability k. A recent study [Torquato, Adv. Wat. Resour. 140, 103565 (2020)10.1016/j.advwatres.2020.103565] suggested for porous media with a well-connected pore space an alternative estimate of k based on the second moment of the pore size 〈δ^{2}〉, which is easier to determine than δ_{c}. Here, we compare δ_{c} to the second moment of the pore size 〈δ^{2}〉, and indeed confirm that, for all porosities and all models considered, δ_{c}^{2} is to a good approximation proportional to 〈δ^{2}〉. However, unlike 〈δ^{2}〉, the permeability estimate based on δ_{c}^{2} does not predict the correct ranking of k for our models. Thus, we confirm 〈δ^{2}〉 to be a promising candidate for convenient and reliable estimates of the fluid permeability for porous media with a well-connected pore space. Moreover, we compare the fluid permeability of our models with varying degrees of order, as measured by the τ order metric. We find that (effectively) hyperuniform models tend to have lower values of k than their nonhyperuniform counterparts. Our findings could facilitate the design of porous media with desirable transport properties via targeted pore statistics.


Obsessive-compulsive symptom exacerbation following cortisone treatment.
We here report a case of obsessive-compulsive symptom exacerbation during cortisone therapy in an adult patient without organic brain disorder. Possible clinical and pathophysiological considerations are discussed.


Anthropometry, dietary patterns and nutrient intakes of Malaysian estate workers.
Studies were carried out in two estates in Kedah and Johor to characterize the anthropometry and dietary patterns of 334 (169 females, 165 males) Malaysian estate workers. Subjects were Malay and Indian adults (aged 18 to 60 years) engaged in various work activities including rubber tappers, palm fruit harvesters, field supervisors and workers in the estate factories. Anthropometric results showed that the prevalence of overweight (26% in men, 25% in women) and obesity (5% in men, 11% in women) were higher compared to prevalence of underweight (11% in men, 9% in women) in these workers despite being engaged in moderate to heavy activities. The dietary intake pattern revealed that the main sources of calories in the diet were rice, cooking oil and sugar. Major sources of protein in the Malay diet were anchovies and fish whilst in the Indian diet protein was provided by salted fish, anchovies, eggs, fish, and pulses. The consumption of poultry, meat and dairy products were low for both ethnic groups. The dietary intakes of a subsampel of 108 normal weight subjects (56 females, 52 males) were recorded for 3 days. The results showed that the mean energy intake was 8.44 ± 2.12 MJ in males and 6.48 ± 1.29 MJ in females. The contribution of calories from protein, fat and carbohydrate were 13%, 22% and 60% in males and 12%, 23% and 65% in females, respectively. Alcohol intake was found to contribute five percent of energy in the diet of the Indian male subjects. Calcium, iron, vitamin A, thiamin, riboflavin and niacin intake were below 66% of the Malaysian RDA, particularly amongst the women. Income appeared to have a significant correlation with energy and iron intakes of the female workers as well as thiamin, niacin and riboflavin intakes of the male workers. There is a need for improving the quality of the dietary intakes of these workers as well as nutrition education on the prevention of obesity and its consequences.


Noninvasive visualization of acute myocardial infarction in man with thallium-201.
Myocardial imaging using 201Tl was performed in 10 patients with supposedly normal myocardial perfusion and in 11 patients with acute myocardial infarction. In all patients with acute myocardial infarction the scintiscan showed an area with diminished radioactivity at the site corresponding the electrocardiographic localization of the infarction. 210Tl seems to be of diagnostic value for recognizing acute myocardial infarction in the very first hours after its onset and for visualizing infarction in patients in whom pre-existing electrocardiographic abnormalities prevent its diagnosis and/or localization.


Assessment of Phasic Changes of Vascular Size by Automated Edge Tracking-State of the Art and Clinical Perspectives.
Assessment of vascular size and of its phasic changes by ultrasound is important for the management of many clinical conditions. For example, a dilated and stiff inferior vena cava reflects increased intravascular volume and identifies patients with heart failure at greater risk of an early death. However, lack of standardization and sub-optimal intra- and inter- operator reproducibility limit the use of these techniques. To overcome these limitations, we developed two image-processing algorithms that quantify phasic vascular deformation by tracking wall movements, either in long or in short axis. Prospective studies will verify the clinical applicability and utility of these methods in different settings, vessels and medical conditions.


Diagnosis and treatment of Rasmussen's encephalitis pose a big challenge: Two case reports and literature review.
Rasmussen encephalitis (RE) is a rare disease of unknown etiology that causes severe chronic unihemispheric inflammatory disease of the central nervous system mainly in children. It leads to intractable seizures, cognitive decline and progressive neurological deficits in the affected hemisphere. We report two cases of RE, as defined by fulfillment of the 2005 Bien criteria. The diagnostic challenge of characterizing this rare disease will be highlighted by the extensive serum, CSF, MR imaging and EEG data in the two patients. In addition, we will review the various forms of therapy attempted in these two patients, namely anti-epileptic drug therapy and immunomodulatory therapy. Hemispherectomy was done for the second patient with favorable outcomes of controlling seizures, but unfortunately, he died because of meningitis. Until the causes of Rasmussen's encephalitis are known, it is difficult to anticipate how treatments will improve. Such a situation creates a therapeutic dilemma; hemispherectomy is not favored because of the inevitable postoperative functional deficits, but a real risk exists that treatments used to delay progression of the disease will defer definitive surgical treatment beyond the time when an optimum post-hemispherectomy outcome could be expected.