The thermic effect of carbohydrate versus fat feeding in man.
Metabolic rate increases and heat is produced after eating a meal. This response has been termed the thermic effect of feeding. While some studies have found this response to be defective in obese subjects others have not. It is also unclear how dietary composition affects the thermic response to a meal. In this study, we evaluated the thermic response to both a high carbohydrate meal and a high fat meal in normal and obese subjects. Using the ventilated hood technique, metabolic rate was measured in seated subjects before and for 6 hours following a meal. Blood samples for insulin, glucose, and catecholamines were withdrawn each half hour to evaluate their possible role in regulating the thermic response. The overall response to the high carbohydrate meal was greater than to high fat (0.26 +/- .07 v 0.18 +/- 0.11 kcal/min; P less than .01). The thermic response to the high fat meal, however, was similar in the normal and obese groups. Although the 6-hour response to the high carbohydrate diet was not statistically different between the subject groups, there was a trend toward a diminished response in the obese relative to the normal group during the first 3 hours following the meal (0.30 +/- .06 v .22 +/- .09; P = .06). In our seated subjects, the thermic response to a meal accounted for 8%-13% of the total calories ingested, with the highest value found in the normal weight subjects after a high carbohydrate meal. No significant thermic response was noted when subjects were fed a noncaloric meal.(ABSTRACT TRUNCATED AT 250 WORDS)


Establishment of a PBMC-derived induced pluripotent stem cell (NJUCMi001-A) from a patient with LAMA2-related congenital muscular dystrophy (MDC1A) carrying frameshift deletion c.3367delA in LAMA2 gene.
LAMA2-related congenital muscular dystrophy (MDC1A), the most commonly recognized type of congenital muscular dystrophies, is a severe neonatal onset muscle disease caused by recessive mutations in the LAMA2 gene. Here, we established an induced pluripotent stem cell line from a MDC1A patient carrying a frameshift deletion c.3367delA in LAMA2 gene. The iPSC line expressed pluripotency markers, retained normal karyotype, showed capability of differentiating into three germ layers. The iPSC line will help to further elucidate the pathogenic mechanisms of LAMA2 mutation, and benefit treatment for congenital muscular dystrophies in the future.


Experimental deterministic correction of qubit loss.
The successful operation of quantum computers relies on protecting qubits from decoherence and noise, which-if uncorrected-will lead to erroneous results. Because these errors accumulate during an algorithm, correcting them is a key requirement for large-scale and fault-tolerant quantum information processors. Besides computational errors, which can be addressed by quantum error correction1-9, the carrier of the information can also be completely lost or the information can leak out of the computational space10-14. It is expected that such loss errors will occur at rates that are comparable to those of computational errors. Here we experimentally implement a full cycle of qubit loss detection and correction on a minimal instance of a topological surface code15,16 in a trapped-ion quantum processor. The key technique used for this correction is a quantum non-demolition measurement performed via an ancillary qubit, which acts as a minimally invasive probe that detects absent qubits while imparting the smallest quantum mechanically possible disturbance to the remaining qubits. Upon detecting qubit loss, a recovery procedure is triggered in real time that maps the logical information onto a new encoding on the remaining qubits. Although the current demonstration is performed in a trapped-ion quantum processor17, the protocol is applicable to other quantum computing architectures and error correcting codes, including leading two- and three-dimensional topological codes. These deterministic methods provide a complete toolbox for the correction of qubit loss that, together with techniques that mitigate computational errors, constitute the building blocks of complete and scalable quantum error correction.


Supplementation of vitamin D isolated or calcium-associated with bone remodeling and fracture risk in postmenopausal women without osteoporosis: A systematic review of randomized clinical trials.
Menopause and vitamin D deficiency increase bone reabsorption and bone fracture risk in women in postmenopause, and vitamin D supplementation may improve bone health and decrease bone fracture risk. This study aims to discuss the effect of vitamin D supplementation, isolated or calcium-associated, on remodeling and fracture risk bone in women in postmenopause without osteoporosis. This study was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO database registration: CRD42022359796). A search was conducted in four databases and gray literature using MeSH and similar terms related to supplements, vitamin D, calcium, remodeling, and fracture bone, without the restriction of language and year of publication. A total of 3460 studies were identified, and nine were selected. Vitamin D supplementation increased 25-hydroxyvitamin D levels ≥10 ng/mL and decreased parathyroid hormone secretion dependent on baseline levels. The doses of 400 IU of vitamin D improved the percentage of carboxylated osteocalcin, whereas 800 to 1000 IU combined with calcium resulted in reduced, improved, or maintained bone mineral density and reduced alkaline phosphatase levels. However, 4000 IU alone or combined with calcium for 6 mo did not improve C-telopeptide and procollagen type 1 peptide levels. Additionally, 15 000 IU/wk increased the cortical area of metacarpal bone, whereas 500 000 IU of vitamin D annually for 5 y did not contribute to reducing the fracture risk and falls. Only one study found a reduction in fracture risk (dose of 800 IU of vitamin D plus 1200 mg of calcium). Thus, the vitamin D supplementation, alone or calcium-associated, improved the status of 25-hydroxyvitamin D and bone remodeling, but it was not possible to assert that it reduced fracture bone risk in postmenopausal women.


Closing spontaneous portosystemic shunts in cirrhosis: Does it make sense? Does it work? What does it take?
Spontaneous portosystemic shunts (SPSS) are an often neglected cause of hepatic encephalopathy associated with cirrhosis. Nowadays, SPSS are considered as radiological biomarkers of clinically significant portal hypertension rather than the previous dogmatic perceived decompressive vessels. SPSS are not rare as they can be diagnosed in over 60% of the patients with cirrhosis by mere contrast-enhanced CT. Moreover, they are clinically relevant since they impact on all portal hypertensive related complications, in particular medically refractory HE, and represent an independent predictor of decompensation and mortality in cirrhosis, irrespective of the type of SPSS. Taken together, these elements warrant strategies to target these shunts directly which is currently is achieved via interventional radiology embolization. In this review, we discuss why it makes sense to tackle SPSS, how to do it and what it takes to do it right based on aggregated literature.


Sintilimab versus docetaxel as second-line treatment in advanced or metastatic squamous non-small-cell lung cancer: an open-label, randomized controlled phase 3 trial (ORIENT-3).
Treatment options for Chinese patients with locally advanced or metastatic squamous-cell non-small-cell lung cancer (sqNSCLC) after failure of first-line chemotherapy are limited. This study (ORIENT-3) aimed to evaluate the efficacy and safety of sintilimab versus docetaxel as second-line treatment in patients with locally advanced or metastatic sqNSCLC. ORIENT-3 was an open-label, multicenter, randomized controlled phase 3 trial that recruited patients with stage IIIB/IIIC/IV sqNSCLC after failure with first-line platinum-based chemotherapy. Patients were randomized in a 1:1 ratio to receive either 200 mg of sintilimab or 75 mg/m2 of docetaxel intravenously every 3 weeks, stratified by the Eastern Cooperative Oncology Group performance status. The primary endpoint was overall survival (OS) in the full analysis set (FAS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), duration of response (DoR) and safety. Between August 25, 2017, and November 7, 2018, 290 patients were randomized. For FAS, 10 patients from the docetaxel arm were excluded. The median OS was 11.79 (n = 145; 95% confidence interval [CI], 10.28-15.57) months with sintilimab versus 8.25 (n = 135; 95% CI, 6.47-9.82) months with docetaxel (hazard ratio [HR]: 0.74; 95% CI, 0.56-0.96; P = 0.025). Sintilimab treatment significantly prolonged PFS (median 4.30 vs. 2.79 months; HR: 0.52; 95% CI, 0.39-0.68; P < 0.001) and showed higher ORR (25.50% vs. 2.20%, P < 0.001) and DCR (65.50% vs. 37.80%, P < 0.001) than the docetaxel arm. The median DoR was 12.45 (95% CI, 4.86-25.33) months in the sintilimab arm and 4.14 (95% CI, 1.41-7.23) months in the docetaxel arm (P = 0.045). Treatment-related adverse events of grade ≥ 3 were reported in 26 (18.1%) patients in the sintilimab arm and 47 (36.2%) patients in the docetaxel arm. Exploratory biomarker analysis showed potential predictive values of expression levels of two transcription factors, including OVOL2 (HR: 0.35; P < 0.001) and CTCF (HR: 3.50; P < 0.001),for sintilimab treatment. Compared with docetaxel, sintilimab significantly improved the OS, PFS, and ORR of Chinese patients with previously treated locally advanced or metastatic sqNSCLC.


Impairments due to tooth loss and prosthetic expectations in patients from an urban area and a rural area in Sweden. A qualitative study.
To explore impairments due to tooth loss and expectations of prosthetic replacements in an urban group and a rural group of patients in Sweden. Semi-structured interviews were performed on 35 partially edentulous patients from prosthodontic specialist clinics located in an urban area and a rural area in Sweden. The interviews focused on impairments due to tooth loss and expectations of prosthetic restorations. Analysis was made using the grounded theory approach, allowing in-depth investigation of the phenomenon. Functional, aesthetic and social impairments were mentioned, and coping strategies (eg chewing differently and laughing less) and modifications (eg age, time and social setting) of the impairments were described. The rural patient group accepted impairments somewhat better than the urban one. Otherwise, there was only minor difference between the groups. Removable prosthodontic restorations were more acceptable among rural patients. Urban patients insisted more often on implant-based restorations and had higher expectations of longevity. Patients with minor impairments still wanted treatment, based on concerns about the future of their dentition. The interviews themselves generated new thoughts in the patients and were thus considered valuable by the patients. Impairments due to tooth loss and expectations of prosthetic replacements were expressed in the same way in the rural and urban patient groups. However, in the rural population, there was a higher acceptance of impairments and also of removable prosthetic restorations, whereas the urban population expressed a higher demand for implant-based restorations.


Feasibility and acceptability of a novel cervicovaginal lavage self-sampling device among women in Kigali, Rwanda.
The Delphi Screener is a novel cervicovaginal lavage self-sampling device. Sixty women in Kigali (Rwanda) assessed the Screener at 2 consecutive visits. Between the visits, ease of use improved, reported difficulties decreased, and the collected sample weight increased. Most women preferred self-collection over a speculum examination.


D-cycloserine enhances short-delay, but not long-delay, conditioned taste aversion learning in rats.
NMDA receptors have been implicated in conditioned taste aversion (CTA), a form of associative learning with the unique temporal characteristic of associating taste and toxic stimuli across very long delays. d-cycloserine (DCS), an NMDA receptor agonist, has been shown to enhance short-delay CTA learning. Here we examined the interaction of DCS with varying temporal parameters of CTA. DCS (15 mg/kg) administered prior to the pairing of 0.125% saccharin and LiCl (38 mM, 12 ml/kg) enhanced CTA when there was a short delay between the taste-toxin pairing (10 min), but not when there was a long delay (45 min). DCS activity remained at effective levels over the long delay, because DCS administered 60 min prior to a short-delay pairing enhanced CTA. The interaction of DCS with the delay between taste stimulus onset and LiCl injection was investigated by administering DCS and then 5 min access to saccharin 45 min prior to a short-delay pairing of saccharin and LiCl. DCS failed to enhance CTA in rats pre-exposed to saccharin, even with a short delay between the second saccharin exposure and LiCl injection. These results suggest that DCS enhancement of CTA is dependent on mechanisms underlying gustatory processing during long-delay taste-toxin associations.


Tracheostomy in children--the Red Cross War Memorial Children's Hospital experience 1980-1985.
During the 6 years (1980-1985) at The Red Cross Children's Hospital 293 children required a tracheostomy during treatment of a variety of disorders. Of these children 44% were under 1 year of age. Indications are discussed of which the commonest was LTB. Of the 3500 children seen with laryngotracheobronchitis (LTB) 4.6% had a tracheostomy--28% of those requiring airway intervention. Overall 67% of the children were decannulated within 10 weeks and 92% within a year. For 56% one or more further procedures prior to decannulation were required, including 34 children who required a laryngotracheoplasty. Obstructing stomal granulation tissue had to be removed from 51 children and suprastomal collapse was a cause of decannulation failure in 52 children. Use of an expiratory valve as an aid to decannulation is discussed. Five children died of tracheostomy airway complications and 25 children of a medical disorder. One complication, laryngeal incompetence, was particularly associated with herpetic laryngeal ulceration. Staphylococcus aureus and Hemophilus influenzae were the main organisms cultured in the early weeks, with Pseudomonas and Streptococcus species predominating later.


Catastrophic hypoadrenalism in a case of Sjögren's syndrome.
We describe a patient with Sjögren's syndrome who died from undiagnosed adrenocortical failure. A positive test for adrenocortical antibody, performed pre-terminally, suggested the underlying diagnosis, which was subsequently confirmed at post-mortem. This case highlights the rare association of Sjögren's syndrome with occult adrenocortical failure. Perhaps a greater awareness of this association and more frequent serological screening are necessary to prevent a fatal outcome.


Population genomics reveals that within-fungus polymorphism is common and maintained in populations of the mycorrhizal fungus Rhizophagus irregularis.
Arbuscular mycorrhizal (AM) fungi are symbionts of most plants, increasing plant growth and diversity. The model AM fungus Rhizophagus irregularis (isolate DAOM 197198) exhibits low within-fungus polymorphism. In contrast, another study reported high within-fungus variability. Experiments with other R. irregularis isolates suggest that within-fungus genetic variation can affect the fungal phenotype and plant growth, highlighting the biological importance of such variation. We investigated whether there is evidence of differing levels of within-fungus polymorphism in an R. irregularis population. We genotyped 20 isolates using restriction site-associated DNA sequencing and developed novel approaches for characterizing polymorphism among haploid nuclei. All isolates exhibited higher within-isolate poly-allelic single-nucleotide polymorphism (SNP) densities than DAOM 197198 in repeated and non-repeated sites mapped to the reference genome. Poly-allelic SNPs were independently confirmed. Allele frequencies within isolates deviated from diploids or tetraploids, or that expected for a strict dikaryote. Phylogeny based on poly-allelic sites was robust and mirrored the standard phylogeny. This indicates that within-fungus genetic variation is maintained in AM fungal populations. Our results predict a heterokaryotic state in the population, considerable differences in copy number variation among isolates and divergence among the copies, or aneuploidy in some isolates. The variation may be a combination of all of these hypotheses. Within-isolate genetic variation in R. irregularis leads to large differences in plant growth. Therefore, characterizing genomic variation within AM fungal populations is of major ecological importance.


Carotid Artery Entrapment by the Hyoid Bone-A Rare Cause of Recurrent Strokes in a Young Patient.
The search for etiology of stroke in a young patient may present a diagnostic challenge. In rare cases, chronic trauma to the carotid artery may be the cause of cerebral thromboembolic events. The hyoid bone lies in close proximity to the carotid artery bifurcation, and anatomic variants have been implicated in carotid compression, stenosis, dissection, and pseudoaneurysm. We report a case of recurrent strokes in a 32-year-old woman due to an elongated hyoid bone causing thrombus formation in her right internal carotid artery (ICA), resulting in recurrent embolic strokes confirmed on diffusion-weighted magnetic resonance imaging. Computed tomography angiography of the neck and head demonstrated the right hyoid bone was located between the ICA and external carotid artery (ECA), just above the carotid bifurcation, with residual nonocclusive thrombus in the right ICA. Carotid duplex ultrasonography confirmed that with the neck in neutral position, the hyoid was located between the ICA and ECA; however, with neck rotation, the hyoid slipped across the ICA and out of the bifurcation. There was no evidence of carotid stenosis. After an initial course of anticoagulation and antiplatelet therapy, resection of the greater cornu of the hyoid bone with release of the right ICA was performed. One year postoperatively, the patient had complete return of neurologic function and had no further neurologic events. Hyoid bone entrapment of the carotid artery is a rare etiology of thromboembolic stroke caused by repetitive local trauma. The diagnosis can be confirmed by carotid duplex with provocative maneuvers. Partial hyoid resection is a safe and effective treatment to relieve recurrent symptoms. Hyoid bone entrapment may be an important and under-recognized cause of stroke in young adults.


Corticosteroid-induced arrest of HELLP syndrome progression in a marginally-viable pregnancy.
Corticosteroid therapy in preterm pregnancy complicated by severe pre-eclampsia as HELLP syndrome temporarily stabilizes the HELLP syndrome. One such patient complicated by extreme prematurity was treated with long-term high-dose corticosteroid therapy. The HELLP syndrome was temporarily stabilized and additional in utero fetal maturation was gained.


PExFInS: An Integrative Post-GWAS Explorer for Functional Indels and SNPs.
Expression quantitative trait loci (eQTLs) mapping and linkage disequilibrium (LD) analysis have been widely employed to interpret findings of genome-wide association studies (GWAS). With the availability of deep sequencing data of 423 lymphoblastoid cell lines (LCLs) from six global populations and the microarray expression data, we performed eQTL analysis, identified more than 228 K SNP cis-eQTLs and 21 K indel cis-eQTLs and generated a LCL cis-eQTL database. We demonstrate that the percentages of population-shared and population-specific cis-eQTLs are comparable; while indel cis-eQTLs in the population-specific subsection make more contribution to gene expression variations than those in the population-shared subsection. We found cis-eQTLs, especially the population-shared cis-eQTLs are significantly enriched toward transcription start site. Moreover, the National Human Genome Research Institute cataloged GWAS SNPs are enriched for LCL cis-eQTLs. Specifically, 32.8% GWAS SNPs are LCL cis-eQTLs, among which 12.5% can be tagged by indel cis-eQTLs, suggesting the fundamental contribution of indel cis-eQTLs to GWAS association signals. To search for functional indels and SNPs tagging GWAS SNPs, a pipeline Post-GWAS Explorer for Functional Indels and SNPs (PExFInS) has been developed, integrating LD analysis, functional annotation from public databases, cis-eQTL mapping with our LCL cis-eQTL database and other published cis-eQTL datasets.


Effects of cisplatin on different haemopoietic progenitor cells in mice.
The effects of Cisplatin on marrow haemopoietic progenitor cells, WBC and RBC were measured and compared in F1 (CBA x C57BL) female mice. Dose/survival curves of Cisplatin for CFU-S, CFU-C and BFU-E were found to be simply exponential, indicating that the effect of the drug has no cell-cycle dependency. BFU-E also appeared significantly (P less than 0.001) more sensitive to Cisplatin than CFU-S and CFU-C. After a single dose of 12 mg/kg of Cisplatin, WBC, MNC and CFU-E were seen to be markedly less reduced and to recover much earlier than CFU-C, and particularly BFU-E and CFU-S. Results suggest that the drug is more toxic for earlier haemopoietic progenitor cells than for the more mature cells, and that the latter are not reliable parameters for complete haemopoietic recovery in mice after treatment with this agent. In the animals treated, there was also a subsequent significant decrease of the RBC count, accompanied by a marked increase of the marrow CFU-E concentration. Possible underlying mechanisms (e.g. alterations of RBC after exposure to Cisplatin) were discussed.


A family study of patients with temper outbursts.
To evaluate the heritability of a personality trait, "having temper outbursts," and of associated diagnoses, we obtained histories of first degree relatives on two groups: (1) patients with temper outbursts (N = 33), and (2) diverse psychiatric patients without temper outbursts (N = 12). Family interviews were conducted blind to patient (temper or not) status, using a modified version of the Family History RDC. Though Ns are relatively small, and results therefore require confirmation, the data indicate familial transmission of temper problems; an average of 18.2% of Group 1 relatives had temper problems, compared to 4.3% for Group 2. The trait of having temper outbursts was more strongly transmitted than were specific diagnoses (e.g. Intermittent Explosive Disorder, Antisocial Personality Disorder or Residual Attention Deficit Disorder) associated with temper outbursts. Patients with neurological conditions apparently related to their temper outbursts were less likely to have positive family histories.


A comparison of androgen production and clearance in hirsute and obese women.
Virilization in women is associated with increased production of testosterone as well as a variety of androgenic prehormones, including androstenedione, androstenediol, DHEA, DHEA-sulfate, dihydrotestosterone and androstanediol. Of these hormones, it is likely that testosterone is the androgen which initiates a series of androgen-receptor mediated events resulting in stimulation of 5 alpha reductase in the skin and hair follicles, producing dihydrotestosterone locally. The metabolism of testosterone to dihydrotestosterone within the hair follicle results in increased clearance of testosterone, however at the expense of hair follicle stimulation. Increased 5 alpha reductase of the skin and hair allows other prehormones to be metabolized to dihydrotestosterone and androstanediol, further stimulating the hair follicle (multiplier effect). In obese women, androgen production rates are elevated and SHBG levels are depressed, in many cases to the same magnitude as that observed in hirsute women. Increased androgen production rates in obesity, however, are associated with major increases in clearance rates of these androgens. Resultant androgen blood levels are even lower than observed in the non-obese population. It appears likely that adipose tissue is the site of the increased clearance rates and metabolism of prehormones to dihydrotestosterone and androstanediol. A delicate balance likely exists between production and clearance of these biologically active hormones. Minor aberrations in this balance may result in the increased incidence of hirsutism seen in the obese female population.


Hypoxia-inducible factor-1α and excision repair cross-complementing 1 in patients with small cell lung cancer who received front-line platinum-based chemotherapy: a retrospective study.
Hypoxia-inducible factor-1α (HIF-1α), which plays an essential role in the adaptive response of cells to hypoxia, is associated with aggressive tumor behavior. Furthermore, a relationship between excision repair cross-complementing 1 (ERCC1) expression and platinum resistance has been reported in patients with various malignancies. The aim of this study was to investigate the expression of HIF-1α and ERCC1 and to elucidate the clinical significance of their expression in patients with small cell lung cancer (SCLC) treated with front-line platinum-based chemotherapy. SCLC biopsy samples were obtained before front-line platinum-based chemotherapy from 111 patients with SCLC (limited disease, 29; extensive disease [ED], 82) between January 2002 and December 2009 at Gyeongsang National University Hospital. The expression levels of HIF-1α and ERCC1 were assessed by immunohistochemistry. High expression levels of ERCC1 and HIF-1α were observed in 49 (44.1%) and 71 (64.0%) of 111 patients, respectively. Expression of ERCC1 and HIF-1α was not significantly associated with age, sex, Eastern Cooperative Oncology Group performance status, weight loss, or response to treatment, regardless of stage. In ED-SCLC, low expression in the HIF-1α group showed statistically better survival compared with high expression in the HIF-1α group (p = 0.018). Multivariate analysis revealed that response to front-line platinum-based chemotherapy (p < 0.001), good Eastern Cooperative Oncology Group performance status (0-1) (p = 0.002), and low expression of HIF-1α (p = 0.004) were independent predictors of better overall survival in ED-SCLC. Low expression of HIF-1α may be a useful predictor of better overall survival in ED-SCLC patients treated with front-line platinum-based chemotherapy.


High-yield synthesis of CsPbBr3nanoparticles: diphenylphosphine as a reducing agent and its effect in Pb-seeding nucleation and growth.
Based on the reported nucleation mechanisms for CsPbX3and II-VI/IV-VI quantum dots, CsPbBr3nanoparticles with a higher reaction-yield (up to 393% mass-increment) were synthetized by the hot-injection method. The introduction of diphenylphosphine (DPP) as a reducing agent improved nanoparticle nucleation and growth, giving out evidence for Pb-seeding in CsPbBr3nanoparticles formation. Additionally, a clear influence of the DPP in a CsPbBr3-Cs4PbBr6incomplete phase transformation was observed, marked by the appearance of several PbBr2nanoparticles. This indicated the need for an improved ratio between the stabilizing agents and the precursors, due to the increased number of nucleation sites produced by DPP. The resulting CsPbBr3nanoparticles showed high quality, as they displayed 70%-90% photoluminescence quantum yield; narrow size distribution with an average nanoparticle size of∼10 nm; and the characteristic cubic morphology reported in previous works. This increment in CsPbBr3nanoparticles' reaction yield will contribute to making them a more attractive option for different optoelectronic applications.


Involvement of alternative oxidase (AOX) in adventitious rooting of Olea europaea L. microshoots is linked to adaptive phenylpropanoid and lignin metabolism.
Alternative oxidase (AOX) has been proposed as a functional marker candidate in a number of events involving cell differentiation, including rooting efficiency in semi-hardwood shoot cuttings of olive (Olea europaea L.). To ascertain the general importance of AOX in olive rooting, the auxin-induced rooting process was studied in an in vitro system for microshoot propagation. Inhibition of AOX by salicylhydroxamic acid (SHAM) significantly reduced rooting efficiency. However, the inhibitor failed to exhibit any effect on the preceding calli stage. This makes the system appropriate for distinguishing dedifferentiation and de novo differentiation during root induction. Metabolite analyses of microshoots showed that total phenolics, total flavonoids and lignin contents were significantly reduced upon SHAM treatment. It was concluded that the influence of alternative respiration on root formation was associated to adaptive phenylpropanoid and lignin metabolism. Transcript profiles of two olive AOX genes (OeAOX1a and OeAOX2) were examined during the process of auxin-induced root induction. Both genes displayed stable transcript accumulation in semi-quantitative RT-PCR analysis during all experimental stages. In contrary, when the reverse primer for OeAOX2 was designed from the 3'-UTR instead of the ORF, differential transcript accumulation was observed suggesting posttranscriptional regulation of OeAOX2 during metabolic acclimation. This result confirms former observations in olive semi-hardwood shoot cuttings on differential OeAOX2 expression during root induction. It further points to the importance of future studies on the functional role of sequence and length polymorphisms in the 3'-UTR of this gene. The manuscript reports the general importance of AOX in olive adventitious rooting and the association of alternative respiration to adaptive phenylpropanoid and lignin metabolism.


[Spectrophotometric determination of deoxyribonucleic acid by its quenching effect on acridine orange].
Based on the reaction of acridine orange with deoxyribonucleic acid (DNA), and under the optimized condition, a novel method to determine the DNA was developed with the spectrophotometry. The absorbance of acridine orange at the maximum absorption wavelength of 444 nm responded to the concentration of DNA negatively with excellent linearity. It has an upper linear limit concentration of 8.0 microg x mL(-1) and a detection limit of 0.12 microg x mL(-1) with the correlation coefficient of 0.999 8. The method is simple, rapid and sensitive, and could be applied to sample assay satisfactorily. Finally, the reaction mechanism is discussed.


Expression of arachidonic acid-metabolizing cytochrome P450s in human megakaryocytic Dami cells.
Cytochrome P450s (P450s) are involved in the metabolism of arachidonic acid (ARA), and ARA metabolites are associated with various cellular signaling pathways, such as blood hemostasis and inflammation. The present study demonstrates the expression of ARA-metabolizing P450s in the human megakaryocytic Dami cells using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunublotting analysis followed by activity assays using ARA as a substrate. In addition to the previously identified CYP5A1, both protein and mRNAs of CYP1A1, 2U1, and 2J2 bands were detected. Ethoxyresorufin-O-deethylase (EROD) activity was observed in Dami cells, and its activity was significantly decreased after treatment with the P450 inhibitor SKF-525A when compared to the control groups (60% reduction, P < 0.001). CYP1A1 protein expression in Dami cells was induced by 3-methylenecholantheren. This increase in CYP1A1 protein level was correlated with enhanced EROD activity (fourfold increase vs. the control), as well as with increased metabolites, such as 20-hydroxyeicosatrienoic acid (20-HETE), 14, 15-EET (14-,15-epoxyeicosatrienoic acid), and 14, 15-dihydroxyeicosatrienoic acid (14, 15-DHET). The expression of soluble epoxide hydrolase, an enzyme responsible for the synthesis of DHETs from EETs, was confirmed by RT-PCR. Furthermore, 15 ARA metabolites, including 8,9-EET, 14,15-EET, and 20-HETE, were detected by LC-MS/MS in ARA-treated Dami cells, and their levels were decreased with the treatment of the SKF-525A. The present data suggest the possibility that the P450s play a role in the metabolism of ARA and other CYP-related substrates in human megakaryocytes and that P450 expression in megakaryocytic cell lines may predict their existences in platelets with functional activities.


The anti-oestrogen tamoxifen is a calcium antagonist in perfused rat mesentery.
The anti-oestrogen tamoxifen in the range 10(-7)-10(-5) M induced concentration-related inhibition of potassium-stimulated vasospasm in the isolated perfused rat mesentery vascular bed. In contrast, responses to noradrenaline did not fall below control levels until the tamoxifen concentration exceeded 4 X 10(-6) M. Recovery of the potassium-stimulated responses was also concentration-related. The most likely explanation is that while tamoxifen can obstruct the entry of extracellular calcium, it is unable to prevent the intracellular release of the ion by noradrenaline.


Platinum-folate compounds: synthesis, properties and biological activity.
Cis-diamminediaquaplatinum(II)-ion, the biologically active form of the anticancer agent Cisplatin, reacted readily with tetrahydrofolate at pH 7 and 37 degrees C to produce a stable complex. The reaction was monitored spectrophotometrically by the change in absorbance maximum from 298 nm (tetrahydrofolate) to 275 nm (complex); occurrence of isobestic points at 282 and 327 nm indicated that a single product was formed. Purity of platinum-tetrahydrofolate, after isolation in ca. 70% yield, was established by TLC and HPLC. Elemental analysis, absorbance spectra at various pH values and nmr spectra provided evidence that the diammine platinum moiety was bridged across the N-5 and N-10 positions of tetrahydrofolate. Complexation also occurred with 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, Methotrexate and aminopterin, but not with folate or 7,8-dihydrofolate. Biological implications of these observations have been investigated. Intracellular folates in L1210 cells have been identified and quantitated via reverse phase HPLC (C18 column; tetrabutylammonium phosphate as the pairing ion) and changes in the levels of these compounds, after exposure of cells to Cisplatin, have been measured. Platinum derivatives of tetrahydrofolate or other reduced folates were not found, but there was a decrease in the level of 5,10-methenyltetrahydrofolate, accompanied by an increase in 5-formyl and 10-formyltetrahydrofolate (and perhaps tetrahydrofolate). The chemical interaction of the diaqua form of Cisplatin with Methotrexate resulted in decreased uptake of the latter by L1210 cells. The platinum complex of tetrahydrofolate was a reasonably good inhibitor (Ki = 4 microM) of L1210 dihydrofolate reductase and of the folate transport system (50% inhibition at ca. 200 microM) of L1210 cells.


The Soft X-ray Research instrument at the Linac Coherent Light Source.
The Soft X-ray Research instrument provides intense ultrashort X-ray pulses in the energy range 280-2000 eV. A diverse set of experimental stations may be installed to investigate a broad range of scientific topics such as ultrafast chemistry, highly correlated materials, magnetism, surface science, and matter under extreme conditions. A brief description of the main instrument components will be given, followed by some selected scientific highlights.


Gibberellin production and phosphate solubilization by newly isolated strain of Acinetobacter calcoaceticus and its effect on plant growth.
Plant growth-promoting rhizobacteria with gibberellins (GA)-producing potential were isolated from soil and screened for plant growth promotion. A new strain, Acinetobacter calcoaceticus SE370, produced extracellular GA and also had phosphate solubilising potential. It produced 10 different gibberellins, including the bioactive GA(1), GA(3) and GA(4) which were at, respectively, 0.45, 6.2 and 2.8 ng/100 ml. The isolate solubilised tricalcium phosphate and lowered pH of the medium during the process. Culture filtrates of the organism after growth on broth promoted growth of cucumber, Chinese cabbage and crown daisy.


Improving the reproducibility of the NAP1/B1/027 epidemic strain R20291 in the hamster model of infection.
Comparative analysis of the Clostridium difficile BI/NAP1/027 strain R20291 and ClosTron-derived ermB mutants in the hamster infection model are compromised by the clindamycin susceptibility of the parent. Mutants can appear more virulent. We have rectified this anomaly by genome engineering. The variant created (CRG20291) represents an ideal control strain for virulence assays of ClosTron mutants.


The role of the macrophage in immune regulation.
The macrophage plays an important role in both the innate and acquired (humoral and cellular) immune responses. Their specialized derivatives, the dendritic cells (DCs), are uniquely potent in induction of naive T and B lymphocytes, whereas macrophages influence a range of immune responses by antigen recognition, capture, clearance and transport. They recruit haemopoietic cells to local sites of inflammation and immunity and regulate their activities. We have used various myeloid-restricted membrane antigens and receptors as markers and functional contributors to these activities, and briefly review their role in immune regulation in vivo and in vitro.


Dose- and Time-Dependent Effect of Dietary Blueberries on Diabetic Vasculature Is Correlated with Gut Microbial Signature.
Evidence from our lab and others indicates the vascular effects of dietary blueberries. In the present study, we determined dietary blueberries' dose- and time-dependent effects on diabetic vasculature and their association with gut microbes. Seven-week-old db/db diabetic male mice were fed a diet supplemented with ± freeze-dried wild blueberry powder (FD-BB) for 4, 8, or 12 weeks (three cohorts). Diets contained 0%, 1.23%, 2.46%, and 3.7% of FD-BB, equivalent to 0, ½, 1, and 1.5 human servings of wild blueberries, respectively. The non-diabetic db/+ mice fed a standard diet served as controls. Metabolic parameters, vascular inflammation, and gut microbiome were assessed. Dietary supplementation of 3.7% FD-BB improved vascular inflammation in diabetic mice without improving systemic milieu in all three cohorts. Blueberries improved diabetes-induced gut dysbiosis depending on blueberry dosage and treatment duration. Spearman's correlation indicated that the opportunistic microbes and commensal microbes were positively and negatively associated with indices of vascular inflammation, respectively. Dietary blueberries reduced the opportunistic microbe that was positively associated with vascular inflammation (Desulfovibrio), and increased the commensal microbe that was negatively associated with vascular inflammation (Akkermansia). Dietary blueberries could be a potential adjunct strategy to beneficially modulate gut microbes and improve vascular complications in diabetes.


Measurement of the uniaxial mechanical properties of healthy and atherosclerotic human coronary arteries.
Atherosclerosis is a common arterial disease which alters the stiffness of arterial wall. Arterial stiffness is related to many cardiovascular diseases. In this investigation, maximum stress and strain as well as physiological and maximum elastic modulus of 22 human coronary arteries are measured. In addition, the force-displacement diagram of human coronary artery is obtained to discern the alterations between the healthy and atherosclerotic arterial wall stiffness. The age of each specimen and its effect on the elastic modulus of human coronary arteries is also considered. Twenty-two human coronary arteries, including eight atherosclerotic and fourteen healthy arteries are excised within 5 hours post-mortem. Samples are mounted on a tensile-testing machine and force is applied until breakage occurs. Elastic modulus coefficient of each specimen is calculated to compare the stiffness of healthy and atherosclerotic coronary arteries. The results show that the atherosclerotic arteries bear 44.55% more stress and 34.61% less strain compared to the healthy ones. The physiological and maximum elastic moduli of healthy arteries are 2.53 and 2.91 times higher than that of atherosclerotic arteries, respectively. The age of specimens show no correlation with the arterial wall stiffness. A combination of biomechanics and mathematics is used to characterize the mechanical properties of human coronary arteries. These results could be utilized to understand the extension and rupture mechanism of coronary arteries and has implications for interventions and surgeries, including balloon-angioplasty, bypass, and stenting.


Association between behavioral phenotypes and sustained use of smartphones and wearable devices to remotely monitor physical activity.
Smartphones and wearable devices can be used to remotely monitor health behaviors, but little is known about how individual characteristics influence sustained use of these devices. Leveraging data on baseline activity levels and demographic, behavioral, and psychosocial traits, we used latent class analysis to identify behavioral phenotypes among participants randomized to track physical activity using a smartphone or wearable device for 6 months following hospital discharge. Four phenotypes were identified: (1) more agreeable and conscientious; (2) more active, social, and motivated; (3) more risk-taking and less supported; and (4) less active, social, and risk-taking. We found that duration and consistency of device use differed by phenotype for wearables, but not smartphones. Additionally, "at-risk" phenotypes 3 and 4 were more likely to discontinue use of a wearable device than a smartphone, while activity monitoring in phenotypes 1 and 2 did not differ by device type. These findings could help to better target remote-monitoring interventions for hospitalized patients.


Management of spontaneous enophthalmos due to silent sinus syndrome: a case report.
Silent sinus syndrome (SSS) is a rare disease exhibiting unilateral enophthalmos and hypoglobus. A 26-year-old white female presented with right side enophthalmos and hypoglobus. There was no history of previous trauma or maxillary sinus diseases. A CT scan showed an opacified right maxillary antrum with decreased volume and downward bowing of the right orbital floor. From clinical and radiological findings the diagnosis SSS was made. Biopsies were collected from the maxillary sinus for the exclusion of malignancy. Two months later orbital floor reconstruction was carried out. Before antrostomy of the affected maxillary sinus, a relative enophthalmos of 4mm was determined. Five days after antrostomy the value reduced to 2.3mm. During the following 2 months the enophthalmos remained constant. At the end of the operation for orbital floor reconstruction it was 0.1mm. Five days after surgery the relative enophthalmos increased to 0.8mm. The value remained constant during the following 3 months. Initial antrostomy of the affected maxillary sinus may lead to a relevant, spontaneous reduction of enophthalmos. After a minimum period of 2 months a re-evaluation should be made, if a reconstruction of the orbital floor is still necessary for the correction of the globe position.


Serum albumin enhances polyethylenimine-mediated gene delivery to human respiratory epithelial cells.
The interaction of polyethylenimine (PEI) polyplexes with proteins in cystic fibrosis (CF) airway secretions poses a significant hurdle to this nonviral delivery system. The aim of this study was to evaluate whether albumin may increase the efficiency of PEI complexes in mediating gene transfer into respiratory epithelial cells in the presence of CF mucus. PEI (25 kDa) was complexed to DNA in the presence of human serum albumin (HSA) and used to transfect confluent A549 and 9HTEo- cells. Alternatively, albumin was added to preformed PEI-DNA complexes. The cytotoxicity of complexes was analysed by the LDH (lactate dehydrogenase) assay. CF CFT1-C2 cells were allowed to polarise and were transfected either with luciferase- or CFTR-expressing plasmids. To evaluate the effect of CF respiratory secretions on transfection efficiency, confluent cells were transfected in the presence of sputum obtained from two CF patients. The ternary PEI-HSA complexes increased luciferase expression in confluent cultures in a dose-dependent fashion up to 100 times as compared to PEI-DNA. The number of GFP-expressing cells, as evaluated by epifluorescence, was augmented several-fold. When HSA was added to preformed PEI-DNA complexes, a further 5-10-fold increase in gene expression was observed. No significant cytotoxicity was observed with either PEI or PEI-HSA polyplexes. The ternary complexes determined detectable CFTR gene transfer and expression at the apical membrane in polarised CFT1-C2 cells, as evaluated by confocal microscopy. CF sputum inhibited PEI-mediated gene transfer by 7-186-fold. Although luciferase expression mediated by PEI-HSA was still inhibited by CF sputum, these levels were 18-83.8-fold higher than with PEI. Our results demonstrate that albumin increases PEI gene transfer efficiency in confluent and polarised respiratory epithelial cells and can allow CFTR gene expression in the appropriate cellular compartment. PEI-HSA complexes display a higher efficiency than PEI also in the presence of CF sputum, indicating that albumin-containing polyplexes may help overcome barriers imposed by CF airway secretions.


Extended reconstruction rate for limb salvage with intraoperative prereconstruction angiography.
A prospective study was performed between May 1982 and March 1987 to assess the value of intraoperative prereconstruction angiography (IPA) in limb salvage. Eligibility was limited to patients with rest pain, ischemic ulcers, or gangrene limited to the toes: only candidates for infrapopliteal bypass were included. Seventy-eight such patients were examined with preoperative angiography. Delayed films, selective catheterization, reactive hyperemia, or vasodilators were used routinely. In only 11 of 78 patients (14%) was the runoff adequately visualized, demonstrating the tibial vessels and the pedal arch. The remaining 67 patients (86%) (with nonreconstructable disease by currently accepted outflow criteria) had surgical exposure of a tibial or pedal artery for IPA. In 56 of these patients (84%) good runoff was demonstrated and bypass was performed. The reconstruction rate was 86% (67 of 78 patients), significantly higher than the 33% rate reported by others. The operative mortality rate was 2.8% (2 of 78 patients). We concluded that in severe ischemia preoperative angiography is often inadequate in demonstrating runoff, even with adjunctive measures to dilate the outflow vessels. IPA through the tibial and pedal vessels eliminates all of the proximal vascular resistance, thereby providing a "completion angiogram" before reconstruction. This in turn extends reconstructability to many patients who would otherwise undergo primary amputation.


Enterococci in post-cesarean endometritis.
Three hundred eleven patients with post-cesarean endometritis were treated with clindamycin and gentamicin. Isolation of enterococci in the endometrium was associated with use of cephalosporin prophylaxis (P less than .001). Other risk factors for enterococcus-associated endometritis included increased numbers of vaginal examinations (P = .018) and increased length of internal monitoring (P = .006). Patients with enterococcus-associated endometritis were less likely to respond to therapy with clindamycin and gentamicin than were patients without enterococci (82.4 versus 92.7%, respectively; P = .015). Patients with enterococcus-associated endometritis also were significantly more likely to have wound infection (15.7 versus 3.2%, respectively; P = .001). In a retrospective survey of 14 patients with postpartum enterococcal bacteremias, four (29%) had a poor response to initial therapy.


Computer-assisted paranasal sinus operation induces diving bradycardia.
Unintentional mechanical manipulation anywhere in the distribution of the trigeminal nerve might activate a reflexive bradycardia. Neurosurgeons need to bear in mind detrimental consequences on cardiac function. A female patient (53 years) underwent a computer-assisted (CAS), paranasal sinus operation performed under general anesthesia. During left sided CAS and preparation of the sinus ethmoidalis, heart rate significantly fell from 68 to 32 /min, while systolic arterial blood pressure decreased from 105 to 75 mmHg. Continuation of the preparation again decreased heart rate progressing to transient asystole lasting for 15 s. After removal of the instruments, asystole terminated without medical support. As heart rate decreased after renewed insertion of the CAS probe, sinus ethmoidalis surgery was completed after atropine administration. During neurosurgical procedures, the incidence of the reflex varies between 10 and 18%. To the best of our knowledge, we report for the first time on a direct stimulation of the ethmoidal nerve with instruments (CAS probe) during paranasal surgery. Although normally cardioprotective, exaggeration of the diving reflex can be detrimental and has been implicated in cardiorespiratory disorders, including sudden death and the sudden infant death syndrome.


Transvaginal and transobturator autologous vaginal tape cystocele treatment: About an uncommon case.
Pelvic organ prolapse (POP) significantly impairs women's quality of life. The literature reports that nearly one in five women will require surgery in their lifetime, and nearly 40.6% involve anterior wall repair, specifically cystocele. Several techniques and surgical approaches have been used for cystocele management. These were performed by transvaginal and/or transabdominal approach and involved the use of native tissue or prosthesis. Nevertheless, since the transvaginal mesh ban recommended by the FDA and learned societies, autologous tissue repair has become the cornerstone of all vaginal prolapse surgery. We hereby present the case of a 71-year-old widow who had undergone three vaginal deliveries. The patient reported that she no longer had sexual intercourse. The preoperative functional signs observed included: stress urinary incontinence, urinary urgency, dysuria and disabling vaginal ball feeling. The management strategy chosen in consultation with the patient was a repair using autologous material via the vaginal route. The vaginal strips were passed through trans-obturator and retro pubic route allowed support of the bladder. This technique using autologous material was easy, fast and inexpensive. It was developed on the basis of the TVT and TOT techniques and stood out for its tolerance and long-lasting functional effectiveness. It avoids all the complications due to polypropylene trans-vaginal prostheses that led to the banning of trans-vaginal mesh.


Propionigenium and Vibrio species identified as possible component causes of shrimp white feces syndrome (WFS) associated with the microsporidian Enterocytozoon hepatopenaei.
White feces syndrome (WFS) in cultivated shrimp is characterized by white shrimp midguts (intestines) and white fecal strings that float as mats on pond surfaces. The etiology of WFS is complex, but one type called EHP-WFS is associated with the microsporidian Enterocytozoon hepatopenaei (EHP). The hepatopancreas (HP), midgut and fecal strings of EHP-WFS shrimp exhibit massive quantities of EHP spores together with mixed, unidentified bacteria. In EHP-WFS ponds, some EHP-infected shrimp show white midguts (WG) and produce white feces while other EHP-infected shrimp in the same pond show grossly normal midguts (NG) and produce no white feces. We hypothesized that comparison of the microbial flora between WG and NG shrimp would reveal probable combinations of microbes significantly associated with EHP-WFS. To test this, we selected a Penaeus vannamei cultivation pond exhibiting severe WFS and used microscopic and microbial profiling analyses to compare WG and NG samples. Histologically, EHP was confirmed in the HP and midgut of both WG and NG shrimp, but EHP burdens were higher and EHP tissue damage was more severe in WG shrimp. Further, intestinal microbiomes in WG shrimp were less diverse and had higher abundance of bacteria from the genera Vibrio and Propionigenium. Propionigenium burden in the HP of WG shrimp (9364 copies/100 ng DNA) was significantly higher (P = 1.1 × 10-5) than in NG shrimp (12 copies/100 ng DNA). These findings supported our hypothesis by revealing two candidate bacterial genera that should be tested in combination with EHP as potential component causes of EHP-WFS in P. vannamei.


Review: indications for interventional radiology in the management of patients with spinal cord injuries.
To outline a range of minimally invasive image-guided procedures that benefit spinal cord-injured patients and may expedite clinical care. Pictorial review. Image-guided procedures have made a significant impact in medical management in many specialties. These techniques continue to evolve rapidly and afford opportunities to reduce patient morbidity and in-patient length of stay.


Bilateral temporal lobe agenesis with bilateral arachnoid cysts - a rare congenital anomaly.
Bilateral temporal lobe agenesis/hypogenesis along with middle cranial fossa arachnoid cysts (ACs) is extremely rare, and very few cases have been reported in the literature. We present the case of 2-year-old female presenting with chief complaints of headache, vomiting, and fever. There was a history of premature delivery in the seventh month and up-rolling of eyes since birth. Magnetic resonance imaging findings revealed bilateral temporal lobe agenesis with bilateral ACs, along with encephalomalacia in both parietal lobes. Ultrasound abdomen findings and biochemical tests revealed renal parenchymal disease. The lipid profile analysis revealed highly elevated triglyceride levels to 457.4 mg% and also enhanced very-low-density lipoprotein levels to 91.5 mg%. Presently, the patient is being treated on conservative lines. To our knowledge, this is the first report of an unusual association between bilateral temporal lobe agenesis associated with renal parenchymal disease and dyslipidaemia.


Spatial dynamics of long-term urban retail decline in three transatlantic cities.
This paper studies the effects of the centrality, connectivity and agglomeration of retail establishments on their long-term viability in three cities in the United States, United Kingdom and The Netherlands. As retail is declining in all three markets, there is a dearth of knowledge on the spatial patterns of this decline. This obstructs the substantiation of development decisions and public policy on urban retail retention and growth. Without knowing where stores are most at risk of closing, where can we decide to invest or divest? This paper uses a self-built dataset of store locations and store closures over the span of more than a century in the urban cores of Detroit, Michigan; Birmingham, England; and The Hague, The Netherlands. While taking different paths, all three cities have experienced significant retail decline over the past century. The probability of store closure over time is compared to the metric distance of stores to the retail center of gravity (centrality), store location along well-used streets as measured by their Choice value (connectivity), and the number of surrounding stores (agglomeration). These three comparisons are statistically analyzed using simple line regression, panel regression, and spatial autoregressive probit models. Across these models, store closure is most significantly affected by agglomeration, then by centrality, followed by connectivity. The significance of all three measures is strongest in The Hague, followed by Birmingham and Detroit - two cities that experienced large-scale urban renewal and socio-economic decline.


Status of basal-supported oral therapy in Chinese type 2 diabetic patients with inadequate glycemic control on oral anti-diabetic drugs.
Timely initiation and titration of basal insulin added on to oral anti-diabetic drugs contribute to better glycemic control. However, implementation of basal-supported oral therapy in China is not yet clear. This nationwide, prospective, 12-week observational study was designed to explore the current status of basal-supported oral therapy in patients with type 2 diabetes in China. Type 2 diabetic patients with inadequate glycemic control on anti-diabetic drugs who were to start basal-supported oral therapy with insulin glargine at outpatient clinics were enrolled from 134 hospitals in China. Both the decision to initiate basal insulin and insulin dose adjustment were at the physician's discretion. Fasting plasma glucose (FPG) and haemoglobin A1c were measured, and the starting dose of insulin were recorded at baseline. Self-monitored fasting capillary blood glucose and the adjusting dose of insulin were collected during the study. A total of 11,192 out of 13,259 enrolled patients finished the 12-week study. FPG and haemoglobin A1c at basal-supported oral therapy initiation were 11.2 mmol/L and 9.4%, respectively, with insulin glargine started at 0.190 IU/kg/day. Insulin dose was increased 1.8 IU in average within 12 weeks. Fifty-nine percent of the patients achieved fasting capillary blood glucose ≤ 7.0 mmol/L. More patients achieved the glucose target in the group with lower baseline FPG level. Notable geographical differences of physicians' treatment habits in the current management of basal-supported oral therapy were also observed. A great gap between everyday clinical practice and guidelines exists in China, reflected by the delayed initiation, slow dose titration and geographical differences of basal-supported oral therapy management. A concrete guideline of basal-supported oral therapy management is needed in the clinical application.


[Transthoracic defibrillation. Physiologic and pathophysiologic principles and their role in the outcome of resuscitation].
As one major link in the chain of survival, early transthoracic (external) cardiac defibrillation is aimed at the termination of ventricular flutter and ventricular fibrillation. Most important to the success of defibrillation is the passage of a defined amount of current through a critical mass of heart muscle. Different transthoracic resistances reduce the effective density of the current within the heart. As for other therapeutic intervention procedures, recommendations for the optimal strength of current to be applied to the fibrillating heart need to be evaluated and defined for therapeutical defibrillation too. Unnecessarily high current density causes damage to the heart and should be prevented. By using biphasic waveforms in contrast to monophasic impulses, the amount of current can be reduced but the same or even higher efficacy is attained. Therefore possible myocardial damage might be clearly reduced. Even with individually altered thoracic impedance effective conversion of cardiac rhythm can be achieved by device-controlled compensation and biphasic waveforms. According to their different mechanisms or origin (electrically induced or spontaneously caused by organic heart disease) the probability of successful conversion of the cardiac rhythm by one single electrical impulse varies. The optimum point in time for defibrillation during resuscitation needs to be redefined. In order to improve comparability, further studies should use standardized definitions for successful defibrillation relating to the resulting cardiac rhythm.


Fetal isoform of human retinoic acid receptor beta expressed in small cell lung cancer lines.
The retinoic acid receptor type beta (RAR beta) complementary DNA from a small cell tumor line was amplified, sequenced, and found to be homologous to the murine RAR beta 1. Seventeen lung tumor lines were analyzed. Five of seven small cell lung carcinoma lines expressed RAR beta 1, but only one other line (epidermoid) expressed the isoform, and this was at trace levels. Two other epidermoid lines, as well as three adenocarcinoma, two adenosquamous, and two large cell-derived lines did not express RAR beta 1. Nine adult human tissues, including lung, were analyzed, and in contrast to what has been reported for the mouse, undetectable or barely detectable levels were observed. On the other hand, a total of 13 different fetal tissues, at three different developmental stages, all expressed RAR beta 1. RAR beta 1 may be a master developmental gene in humans, and the remarkably specific association with small cell lung carcinoma suggests a molecular link between this type of cancer and development.


Conventional histological and cytological staining with simultaneous immunohistochemistry enabled by invisible chromogens.
Conventional histological stains, such as hematoxylin plus eosin (H&E), and immunohistochemistry (IHC) are mainstays of histology that provide complementary diagnostic information. H&E and IHC currently require separate slides, because the stains would otherwise obscure one another. This consumes small specimen, limiting the total amount of testing. Additionally, performing H&E and IHC on different slides does not permit comparison of staining at the single cell level, since the same cells are not present on each slide, and alignment of tissue features can be problematic due to changes in tissue landscape with sectioning. We have solved these problems by performing conventional staining and IHC on the same slide using invisible IHC chromogens, such that the chromogens are not visible when viewing the conventional stain and the conventional stain is excluded from images of the IHC. Covalently deposited chromogens provided a convenient route to invisible chromogen design and are stable to reagents used in conventional staining. A dual-camera brightfield microscope system was developed that permits simultaneous viewing of both visible conventional stains and invisible IHC chromogens. Simultaneous staining was demonstrated on several formalin-fixed paraffin-embedded tissue specimens using single and duplex IHC, with chromogens that absorb ultraviolet and near infrared light, followed by H&E staining. The concept was extended to other conventional stains, including mucicarmine special stain and Papanicoulou stain, and further extended to cytology specimens. In addition to interactive video review, images were recorded using multispectral imaging and image processing to provide flexible production of color composite images and enable quantitative analysis.


The philosopher's swoon--the concussion of Michel de Montaigne: a historical vignette.
The French philosopher Michel Eyquem de Montaigne (1533-1592) sustained a transient loss of consciousness due to a head injury. Montaigne described his concussion as a "swoon," with astutely illustrative details of the symptoms he experienced, including brief loss of consciousness, with apparent (temporary) confusion, and post-traumatic amnesia. His vivid portrayal of the recovery period lends understanding of the process of conscious awakening after his near-death experience. Thanks to his power of introspection and literary talent we may gain insight into the feelings and perceptions of some patients during their recovery from concussion.


Relationship between self-report and clinician-rated impairment in depressed outpatients.
This study examined the potential of using the Global Assessment of Functioning (GAF) scale as a valid measure of patient-reported status and predictor of three-month outcomes for 59 patients seeking outpatient treatment for depression. A moderate relationship between the GAF and patient report at baseline and follow-up suggests it may be clinically useful for routine monitoring of depressed patients.


Variation in Small Bowel Length and Its Influence on the Outcomes of Sleeve Gastrectomy.
Small bowel length is drawing attention in the development of gastrointestinal bariatric/metabolic surgery, but the importance of the length of the small bowel in bariatric/metabolic is not clear. The present study was conducted to investigate variations in small bowel length and their clinical significance in patients undergoing laparoscopic sleeve gastrectomy (LSG). Small bowel length was measured in 620 patients diagnosed with obesity who underwent LSG between March 2014 and August 2018. Prospectively obtained demographic and clinical data were investigated, focusing on the association between small bowel length and weight loss. Small bowel length varied widely among patients (mean 739.8 + 115.7 cm, range 380-1050 cm). Linear regression analysis revealed a significant association between small bowel length and body height, body weight, waist circumference, and serum levels of low-density lipoprotein cholesterol, hemoglobin, C-peptide, glycated hemoglobin (A1C), and gamma-glutamyl transferase (r-GT). Multivariate analysis confirmed that body height and serum A1C% levels independently predicted small bowel length in bariatric patients, strongly with body height (p < 0.001) but weakly with A1C%(p = 0.021). One-year follow-up rate was 75.3% (467/620), and small bowel length did not influence weight loss or the reduction of obesity related cardiovascular risk factors after LSG. In this study, small bowel length varied widely among bariatric patients and was strongly associated with body height and weakly with serum A1C levels. Small bowel length has no significant role in weight loss or the resolution of cardiovascular risk factors after LSG.


Exploration of the counseling needs of infertile couples: A qualitative study.
Identification of the main needs of infertile patients is essential to provision of appropriate supportive services and care based on their needs. Thus, the present study aims to explore infertile couples' counseling needs. This study was carried out with an inductive qualitative content analysis approach during 2012-2013. The participants of this study included 26 Iranian infertile couples and 7 medical personnel (3 gynecologists and 4 midwives). The infertile couples were selected through purposive sampling and considering maximal variation from patients attending state-run and private infertility treatment centers as well as infertility specialists, offices in Isfahan and Rasht, Iran. Unstructured in-depth interviews and field notes were utilized for data gathering and replying to this research main question, "What are the counseling needs of infertile couples?" The data from medical personnel was collected through semi-structured interviews. Data analysis was carried out through conventional content analysis. Data analysis revealed two main themes. The first theme was "a need for psychological counseling," which included four subthemes: Emotional distress management, sexual counseling, marital counseling, and family counseling. The second theme was "a need for guidance and information throughout treatment process," which included three subthemes: Treatment counseling, financial counseling, and legal counseling. The counseling needs of infertile couples are varied, and they require various psychosocial support and counseling interventions. The participants of this study identified clearly the significance of psychological counseling and information throughout the long and onerous journey of infertility and its treatment.


Immune-modulation via IgD B-cell receptor suppresses allergic skin inflammation in experimental contact hypersensitivity models despite of a Th2-favoured humoral response.
Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are common skin inflammatory conditions. B and T cells are strongly implicated in allergic contact hypersensitivity (CHS) conditions. Activation of IgD B-cell receptor (BCR) by anti-IgD stimulation depletes mature B cells and modulates T-helper cell type 1/2 (Th1/2) responses in vivo. It is not known whether these effects by anti-IgD exacerbates or ameliorates chronic skin inflammations. This study investigated the effects of anti-IgD and B-cell depleting anti-CD20 antibody on skin inflammation in CHS murine models. Chronic CHS were induced by challenges with allergens trimellitic anhydride (TMA) or 2,4 dinitrochlorobenzene (DNCB). Mice were treated with an anti-IgD or anti-CD20 at various time-points following allergen challenges. This study revealed that early therapeutic treatments with anti-IgD at 4 h after allergen challenge significantly reduced skin inflammation in both TMA- and DNCB-induced CHS models (P < 0.05). In contrast, anti-CD20 treatment exacerbated skin inflammation in DNCB-induced CHS despite of an extensive B cell depletion (P < 0.05). Anti-IgD treatment depleted mature CD19+IgD+ B cells but enhanced allergen-specific IgM and total IgE productions, suggesting a Th2-favoured humoral response. Anti-IgD reduced neutrophilic infiltrations but increases accumulation of mast cells in dermal tissues. The anti-inflammatory effects of anti-IgD were supported by evidence of an increase in the percentage of regulatory B cells and T cells. Collectively, this study demonstrates that immune-modulation by anti-IgD treatment suppresses Th2-mediated allergic skin inflammation in murine models despite a skew toward a Th2-favvoured humoral response and therefore may present a novel treatment for chronic human AD and ACD.


An input-output model for resources planning in a medical care system.
As medical care delivery systems grow in complexity, the understanding of interaction between entities within the system becomes a key aspect in resource planning. The model presented in this paper is geared to aiding resource planning both at the community or regional level and at the medical facility level. At the regional level the problem is related to the elimination of duplication and the sharing of services. At the medical facility level the concern is the balancing of the supply and demand of services among the departments. The framework of the model is a directed graph with nodes representing the service entities and branches representing the interrelationships. At the regional level, entities are hospitals, clinics, and centralized supportive units, such as the data center or the central laboratory. At the medical center level, entities are generally departments within the facility. An iterative procedure is used to simulate the propagation effect of a change on all entities. The model at the medical center level, as implemented in a minicomputer system was applied to a real problem. The results strongly correlated with another, independent study.


Vitreous and aqueous penetration of orally administered moxifloxacin in humans.
To investigate the intraocular penetration of moxifloxacin into the aqueous and vitreous after oral administration in humans. A prospective, nonrandomized study of 27 consecutive patients scheduled for elective parsplana vitrectomy surgery between 1 October and 31 December 2004 was carried out. Aqueous, vitreous, and serum samples were obtained and analysed after oral administration of a single 400 mg tablet of moxifloxacin a few hours before surgery. Assays were performed using high-performance liquid chromatography. Mean+/-SD moxifloxacin concentrations in the serum (n=27), aqueous (n=25), and vitreous (n=27) were 1.34+/-0.98, 0.21+/-0.21, and 0.09+/-0.09 microg/ml, respectively. The mean+/-SD sampling times after oral administration of the moxifloxacin tablet for serum, aqueous, and vitreous were 2.02+/-0.51, 1.53+/-0.45, and 1.55+/-0.46 h, respectively. The minimum inhibitory concentration for 90% of isolates (MIC90) was far exceeded in the aqueous for a wide spectrum of key pathogens, whereas it was not exceeded in the vitreous for several organisms. Of note, the MIC90 for Staphylococcus epidermidis was not exceeded in any of the samples. Orally administered moxifloxacin achieves measurable levels in the noninflammed human eye, with the aqueous levels effective against a variety of pathogens. However, the spectrum of coverage does not appropriately encompass the most common causative organisms in endophthalmitis, especially Staphylococcus epidermidis. Further studies are needed to precisely define the role of oral moxifloxacin in the treatment of or prophylaxis against intraocular infections.


Trends in childhood mortality from 1969 to 2004 in Finland.
The aim was to evaluate the trends in childhood mortality in Finland from 1969 to 2004. We especially wanted to find out whether the decline in mortality is continuous and whether there are still deaths that could be prevented. We analyzed mortality data obtained from the official cause of death statistics in Finland from 1969 to 2004. Annual mortality rates were calculated in proportion to those at risk of dying. Comparison of cause specific mortality rates was conducted for neonatal group and children aged 1 month to 15 years. Annual neonatal mortality declined from 11.13 per thousand in 1969 to 2.46 per thousand in 2004. The leading causes of death were perinatal disorders and congenital malformations. Mortality among children aged 1 month to 15 years declined from 0.67 per thousand in 1969 to 0.23 per thousand in 2004, with accidents the leading cause of death, although congenital malformations, tumours and haematological diseases, and infectious diseases were significant causes as well. There was a notable peak in total mortality in 2004, as 44 Finnish children died in the Asian tsunami in December of that year. Childhood mortality in Finland has decreased significantly during recent decades. Prevention programmes should be directed towards reducing mortality from accidents by promoting traffic safety and ensuring a safer environment. Even though child mortality is very low in Finland at present, continued reductions can still be achieved.


Corrigendum: GABA tonic currents and glial cells are altered during epileptogenesis in a mouse model of Dravet syndrome.
[This corrects the article DOI: 10.3389/fncel.2022.919493.].


Immobilization of laccase via cross-linked enzyme aggregates prepared using genipin as a natural cross-linker.
Genipin is a nontoxic natural cross-linker that was successfully used to prepare cross-linked enzyme aggregates (CLEAs) of Trametes versicolor laccase. The recovered activity of CLEAs was influenced by the co-solvent type, genipin concentration, cross-linking time, preparation pH, and bovine serum albumin (BSA; amino group feeder) concentration. The characteristics of CLEAs prepared using genipin under optimal conditions (genipin-BSA-CLEAs) were compared with those of typical CLEAs prepared using glutaraldehyde or dextran polyaldehyde. Genipin-BSA-CLEAs were nano-sized (average diameter, approximately 700 nm), had a ball-like shape, showed a narrow size distribution, and exhibited the highest substrate affinity among the prepared CLEAs. The thermal stability of genipin-BSA-CLEAs was 6.8-fold higher than that of free laccase, and their pH stability was also much higher than that of free laccase in the tested range. Additionally, genipin-BSA-CLEAs retained 85% of their initial activity after 10 cycles of reuse. Particularly, genipin-BSA-CLEAs showed higher thermal and pH stability than CLEAs that were cross-linked using glutaraldehyde. Therefore, genipin represents an alternative to toxic compounds such as glutaraldehyde during cross-linking to prepare CLEAs.


IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcusaureus.
Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.


Linguists and their work: Epistemic and ethical challenges.
This paper aims to show how the specific ethics of scientific undertaking tightly underlies epistemic reflection upon the nature of linguistic work and its outcome. The relationship between linguistics and ethics seems evident at the level of the narrative, i.e. the language in which the basic linguistic findings are established. The article is intended as an introduction to an interplay of linguistics, epistemology and the ethics of linguistic work. The departure point for the argument is the CONTAINER perception of language by linguists, which produces the well-established distinction between internalist and externalist positions. The paper, however, invites the reader to reconsider the tension between internalists and externalists and instead argues for a more general opposition, i.e. between the non-transcendental naturalists (naturalists) and transcendental naturalists (extra-naturalists). The polarity is seen as underpinning the present-day debates, while concurrently transversing the traditionally recognised dichotomies. The distinction promises to be productive both at the level of substantive assessment of linguistic research and at the level of epistemic qualification of the outcome of a linguistic study. Sharp and uncompromising as the naturalist vs extra-naturalist dichotomy seems to hold, the paper offers ways to bridge the gap between the apparently exclusive philosophies. The proposed solution, while seemingly only aesthetic, ultimately touches an ethical dimension as it centres on the appropriate construction of the narrative of linguistic fact-finding, which promotes approximative rather than definitive statements in the scholarly discourse. The desired effect is an ethical consensus underlying the work of a linguist.


Cyclic AMP increases thrombomodulin expression on membrane surface of cultured human umbilical vein endothelial cells.
Dibutyryl-cyclic AMP (Bt2cAMP; final concentration 1-5 mM) or beraprost sodium (synthetic prostacyclin, 100 nM) enhanced the expression of thrombomodulin (TM; an anticoagulant factor of endothelial cells) on the membrane surface of cultured human umbilical vein endothelial cells up to 1.4 times over the control within 9 hrs after the treatment, while the expression fell below the control level at 12 hrs and thereafter. 8-Bromo-cAMP (final concentration 1-5 mM) or 3-isobutyl-1-methylxanthine (IBMX; an inhibitor of phosphodiesterase; final concentration 10-1000 microM) enhanced the expression of TM on the cell surface at 12 hrs after the treatment. The enhancement of TM expression caused by Bt2cAMP was inhibited by incubation with phorbol 12-myristate 13-acetate. These results suggest that cAMP stimulates expression of TM in the endothelial cells.


Analysis of a calcium-binding EF-hand protein family in Fasciola gigantica.
Transcriptome data supports the notion of a Platyhelminthes-specific protein family that is characterized by combination of two N-terminal EF-hands and a C-terminal dynein light chain-like domain. Family members in schistosomes induce an IgE response that has been connected with resistance to reinfection in schistosomiasis and is considered as a marker of protection. In the present study, we have compared three homologs of the liver fluke Fasciola gigantica for their immunological properties in mouse. Antisera raised against the recombinant proteins detected the native proteins in tegumental type tissues and epithelial linings of excretory system and intestinal tract. The recombinant EF-hand domains induced strong IgG and IgE responses in immunised mice while only weak to moderate responses were observed against the complete recombinant proteins and their DLC-like domains. Parasite crude worm and tegumental extract antisera reacted predominantly with one isoform and its EF-hand domain. Sera of F. gigantica infected mice did not react with the recombinant proteins. The RNA products of the three genes were detected from the metacercarial up to the adult stage. These observations indicate that the investigated EF-hand proteins are not at the frontier of humoral host/parasite interaction in acute fascioliasis gigantica in mouse but are acting as intracellular proteins in tissues that interface with the parasite's environment or tubular tracts.


Ecotoxicity of nickel to Eisenia fetida, Enchytraeus albidus and Folsomia candida.
Despite growing concern about the potential adverse effects of elevated nickel concentrations in the environment, only a few toxicity data are available for terrestrial invertebrates. Therefore, chronic toxicity of nickel was assessed for Eisenia fetida, Enchytraeus albidus and Folsomia candida, the three invertebrates for which standard test protocols are available. The 21 d EC50 for the cocoon production of E. fetida was 362 (241-508) mg Ni/kg dry wt. For the reproduction of E. albidus, a 42 d EC50 of 275 (217-346) mg Ni/kg dry wt was observed. The 28 d EC50 for the reproduction of F. candida was 476 (347-671) mg Ni/kg dry wt. The obtained toxicity data were very similar to those of related species reported in literature. Although the presented data can be considered as a step forward in the assessment of the potential risks of nickel in terrestrial environments, further research is needed to evaluate the influence of soil parameters on the toxicity of nickel and to quantify the effect of ageing on bioavailability.


SEC-seq: association of molecular signatures with antibody secretion in thousands of single human plasma cells.
The secreted products of cells drive many functions in vivo; however, methods to link this functional information to surface markers and transcriptomes have been lacking. By accumulating secretions close to secreting cells held within cavity-containing hydrogel nanovials, we demonstrate workflows to analyze the amount of IgG secreted from single human B cells and link this information to surface markers and transcriptomes from the same cells. Measurements using flow cytometry and imaging flow cytometry corroborate the association between IgG secretion and CD38/CD138. By using oligonucleotide-labeled antibodies we find that upregulation of pathways for protein localization to the endoplasmic reticulum and mitochondrial oxidative phosphorylation are most associated with high IgG secretion, and uncover surrogate plasma cell surface markers (e.g., CD59) defined by the ability to secrete IgG. Altogether, this method links quantity of secretion with single-cell sequencing (SEC-seq) and enables researchers to fully explore the links between genome and function, laying the foundation for discoveries in immunology, stem cell biology, and beyond.


The activity of 2,4,5-triamino-6-hydroxypyrimidine in the phenylalanine hydroxylase system.
The pyrimidine moiety of a pterin, 2,4,5-triamino-6-hydroxypyrimidine, has been found to be active in the phenylalanine-hydroxylating system. The phenylalanine-dependent, phenylalanine hydroxylase-catalyzed reaction in the presence of the pyrimidine is largely, but not completely, uncoupled; the ratio of DPNH oxidized to tyrosine formed is about 20 to 1. In addition to the pyrimidine having activity with phenylalanine hydroxylase, a product of the pyrimidine is also a substrate for dihydropteridine reductase. The activity of the pyrimidine with the hydroxylase indicates that neither carbon atoms 6 or 7 of the pterin ring is involved in activation of oxygen during the hydroxylase-catalyzed reaction.


Linking herbivory and ecosystem services in urban forests.
Urban forests provide important benefits for humans. Species interactions, in particular herbivory, can alter their function and ultimately threaten their ecosystem service provisioning. We call for research that identifies herbivory drivers in urban forests and tests for links between herbivory and forest services. Knowledge gained can inform management of urban ecosystems.


Enhanced sputtering yields from single-ion impacts on gold nanorods.
Sputtering yields, enhanced by more than an order of magnitude, have been observed for 80 keV Xe ion irradiation of monocrystalline Au nanorods. Yields are in the range 100-1900 atoms/ion compared with values for a flat surface of ≈50. This enhancement results in part from the proximity of collision cascades and ensuing thermal spikes to the nanorod surfaces. Molecular dynamic modeling reveals that the range of incident angles occurring for irradiation of nanorods and the larger number of atoms in "explosively ejected" atomic clusters make a significant contribution to the enhanced yield.


Effect of garlic oil in experimental cholesterol atherosclerosis.
Addition of cholesterol in the diet of male albino rabbits produced hypercholesterolaemia, increased tissue cholesterol, and atheromatous changes in the aorta. Supplementation of garlic oil along with cholesterol significantly inhibited the hypercholesterolaemia, decreased tissue cholesterol and minimised the atheromatous changes in the aorta. These results show that the active constituent(s) in garlic responsible for its anti-atherogenic action is present in the oily fraction of garlic.


Impact of potent nucleos(t)ide therapy on hepatitis B hospitalisations in Spain.
Chronic hepatitis B virus (HBV) infection is a major cause of decompensated cirrhosis and liver cancer worldwide. Newborn HBV vaccination was implemented in Spain two decades ago, and potent oral antivirals entecavir and tenofovir were introduced around 2007. To assess the clinical benefits of these interventions nationwide. Including HBV as a diagnosis, we performed a retrospective study of all hospitalisations in Spain the Spanish National Registry of Hospital Discharges. Information was retrieved from 1997 to 2017. From 73,939,642 nationwide hospital admissions during the study period, 129,634 (0.17%) included HBV as diagnosis. Their number doubled from 2007 to 2017 and the median age increased from 44 to 58 years. Most HBV admissions recorded chronic hepatitis B. In-hospital death occurred in 6.4%. Co-infection with HIV or hepatitis C virus occurred in 11.9% and 23.3%, respectively. Patients with HIV-HBV co-infection had significantly greater mortality than individuals with HBV mono-infection. The rate of HBV hospitalisations significantly increased over time with a transient drop around 2007, coincident with the arrival of new potent oral antivirals. Although the proportion of HBV hepatic decompensation events has declined, the rate of liver cancer continues to rise. The small subset of patients with hepatitis delta superinfection increasingly and disproportionately accounts for hepatic decompensation events and liver cancer. Hospital admissions of individuals with HBV infection are increasing in Spain. While hepatic decompensation events declined following the introduction of potent oral nucleos(t)ide therapy, HBV-related liver cancer is rising. No benefit of oral antiviral therapies is seen on hepatitis delta.


Replication stress caused by low MCM expression limits fetal erythropoiesis and hematopoietic stem cell functionality.
Replicative stress during embryonic development influences ageing and predisposition to disease in adults. A protective mechanism against replicative stress is provided by the licensing of thousands of origins in G1 that are not necessarily activated in the subsequent S-phase. These 'dormant' origins provide a backup in the presence of stalled forks and may confer flexibility to the replication program in specific cell types during differentiation, a role that has remained unexplored. Here we show, using a mouse strain with hypomorphic expression of the origin licensing factor mini-chromosome maintenance (MCM)3 that limiting origin licensing in vivo affects the functionality of hematopoietic stem cells and the differentiation of rapidly-dividing erythrocyte precursors. Mcm3-deficient erythroblasts display aberrant DNA replication patterns and fail to complete maturation, causing lethal anemia. Our results indicate that hematopoietic progenitors are particularly sensitive to replication stress, and full origin licensing ensures their correct differentiation and functionality.


One-pot three-component synthesis of novel pyrazolo[3,4-b]pyridines as potent antileukemic agents.
In the current study, we report on the development of novel series of pyrazolo[3,4-b]pyridine derivatives (8a-u, 11a-n, and 14a,b) as potential anticancer agents. The prepared pyrazolo[3,4-b]pyridines have been screened for their antitumor activity in vitro at NCI-DTP. Thereafter, compound 8a was qualified by NCI for full panel five-dose assay to assess its GI50, TGI and LC50 values. Compound 8a showed broad-spectrum anti-proliferative activities over the whole NCI panel, with outstanding growth inhibition full panel GI50 (MG-MID) value equals 2.16 μM and subpanel GI50 (MG-MID) range: 1.92-2.86 μM. Furthermore, pyrazolo[3,4-b]pyridines 8a, 8e-h, 8o, 8u, 11a, 11e, 11h, 11l and 14a-b were assayed for their antiproliferative effect against a panel of leukemia cell lines (K562, MV4-11, CEM, RS4;11, ML-2 and KOPN-8) where they possessed moderate to excellent anti-leukemic activity. Moreover, pyrazolo[3,4-b]pyridines 8o, 8u, 14a and 14b were further explored for their effect on cell cycle on RS4;11 cells, in which they dose-dependently increased populations of cells in G2/M phases. Finally we analyzed the changes of selected proteins (HOXA9, MEIS1, PARP, BcL-2 and McL-1) related to cell death and viability in RS4;11 cells via Western blotting. Collectively, the obtained results suggested pyrazolo[3,4-b]pyridines 8o, 8u, 14a and 14b as promising lead molecules for further optimization to develop more potent and efficient anticancer candidates.


Safety and advantage of perioperative autologous blood transfusion in hepatic resection for hepatocellular carcinoma.
The safety and advantages of perioperative autologous blood transfusion (ABT) were evaluated on hepatectomy for hepatocellular carcinoma (HCC). Blood samples were obtained and stored from 30 patients with HCC. HCC cells were investigated by the presence of AFPmRNA using RT-PCR after storage. We also reviewed postoperative liver function and the long-term outcomes of 138 patients who underwent hepatectomy receiving ABT compared with patients receiving homologous blood transfusion (HBT) and patients without blood transfusion. AFPmRNA was not detected in all samples stored for more than 14 days. Postoperative ALT, AST and total bilirubin in the HBT group were significantly higher than those of other groups. Patients in the HBT group had significantly lower survival rates than patients in the ABT group. ABT was safe after storage and it had advantages compared with HBT with regard to postoperative liver function and survival rate after the hepatectomy for HCC.


[Knee arthroplasty in patients with posttraumatic arthritis].
Arthroplasty in patients with posttraumatic arthritis can be challenging due to joint instability, malalignment, osseous defects, non-union, contracture, scarring, low-grade infections and pathologies of the patellofemoral joint. Detailed preoperative planning is recommended concerning incisions, soft tissue management, osseous reconstruction, hardware removal, potential infections and type of prosthesis (e.g. type of constraint, stems and augments). Severe difficulties can occur with exposure of the knee with respect to the extensor mechanism so that quadriceps snip or osteotomy of the tibial tuberosity may be necessary. Postoperative functional results are inferior to arthroplasty for atraumatic gonarthritis. Patients are at increased risk for intraoperative and postoperative complications (e.g. infections, instability, loosening and patellofemoral problems). Reconstructive alternatives (e.g. osteotomy, ligament reconstruction and cartilage repair) should always be considered especially in younger patients; however, most patients show a significant improvement in function and relief of pain after arthroplasty for posttraumatic gonarthritis.


Prognostic utility of T-wave alternans in a real-world population of patients with left ventricular dysfunction: the PREVENT-SCD study.
The predictive value of T-wave alternans (TWA) for lethal ventricular tachyarrhythmia in patients with left ventricular (LV) dysfunction is controversial. Also, long-term arrhythmia risk of patients ineligible for the TWA test is unknown. This was a multicenter, prospective observational study of patients with LV ejection fraction ≤40% due to ischemic or non-ischemic cardiomyopathies, designed to evaluate the prognostic value of TWA for lethal ventricular tachyarrhythmia. The primary end point was a composite of sudden cardiac death, sustained rapid ventricular tachycardia (VT) or ventricular fibrillation (VF), and appropriate defibrillator therapy for rapid VT or VF. Among 453 patients enrolled in the study, 280 (62%) were eligible for the TWA test. TWA was negative in 82 patients (29%), who accounted for 18% of the total population. The median of follow-up was 36 months. The 3-year event-free rate for the primary end point was significantly higher in TWA-negative patients (97.0%) than in TWA non-negative patients (89.5%, P = 0.037) and those ineligible for the TWA test (84.4%, P = 0.003). Multivariable analysis identified both non-negative TWA [hazard ratio (HR) 4.43; 95% confidence interval (CI) 1.02-19.2; P = 0.047) and ineligibility for the TWA test (HR 6.89; 95% CI 1.59-29.9; P = 0.010) to be independent predictors of the primary end point. TWA showed high negative predictive ability for lethal ventricular tachyarrhythmia in patients with LV dysfunction, although the TWA-negative patients accounted for only 18% of the entire population. Those ineligible for the TWA test had the highest risk for lethal ventricular tachyarrhythmia.


Once-monthly administration of darbepoetin alfa for the treatment of patients with chronic heart failure and anemia: a pharmacokinetic and pharmacodynamic investigation.
In patients with chronic heart failure (CHF), anemia is associated with more severe symptoms and worse prognosis. Erythropoiesis-stimulating proteins (ESPs) increase hemoglobin and may be of therapeutic benefit. We investigated the pharmacokinetics and pharmacodynamics of the long-acting ESP, darbepoetin alfa, administered on 2 occasions 1 month apart to 30 healthy subjects and 33 patients with symptomatic CHF and anemia (hemoglobin<or=12.5 g/dL) in 2 randomized, double-blind, placebo-controlled studies. Subcutaneous (SC) and intravenous administration of 0.75 microg/kg of darbepoetin alfa were compared in a crossover study. The second study compared 2.0, 3.0, and 5.0 microg/kg SC doses with placebo. Darbepoetin alfa (0.75 microg/kg SC) pharmacokinetics were similar in CHF patients and healthy subjects, with a mean (+/-SD) bioavailability of 29 (+/-11)% and 37 (+/-8)%, respectively. In anemic CHF patients, mean (+/-SD) increases in hemoglobin at 4 weeks after the second monthly dose of 2.0, 3.0, and 5.0 microg/kg (SC) of darbepoetin alfa were 2.3 (+/-0.6), 1.4 (+/-1.0), and 2.4 (+/-1.9) g/dL, respectively. Darbepoetin alfa 0.75 microg/kg (SC) given twice, 1 month apart, was insufficient to increase hemoglobin in this study. No severe, drug-related adverse events occurred. Darbepoetin alfa administered once monthly elevates and maintains the hemoglobin concentration in patients with CHF and anemia.


Synthesis and structure-activity relationship study of lamellarin derivatives.
Ten derivatives (3-12) of marine alkaloid lamellarin D (1) were synthesized and evaluated for cytotoxicity against a HeLa cell line in an effort to examine their structure-activity relationships. It appeared that the hydroxyl groups at positions C-8 and C-20 of 1 were important structural requirements for cytotoxic activity, while the hydroxyl group at C-14 and the two methoxy groups at C-13 and C-21 were not necessary for the activity.


Low doses of 2,4,5-trichlorophenoxyacetic acid are behaviorally teratogenic to rats.
Pre-natal exposure of rats to 2,4,5-T has long-term effects on behavior. A test for novelty responding detects abnormalities after exposure to a single dose as low as 6 mg/kg on day 8 of gestation. This is well below doses reported to be morphologically teratogenic, and raises concern for human exposure.


Hydrothermal Synthesize of HF-Free MIL-100(Fe) for Isoniazid-Drug Delivery.
Sustainable development of drug delivery materials with good biocompatibility and controlled-release is a popular topic among researchers. In this research study, we demonstrated the potential of the metal-organic framework, that is MIL-100(Fe), as a drug delivery platform for isoniazid (INH). The MIL-100(Fe) was prepared by using the hydrofluoric acid-free hydrothermal method. Several physical measurements were conducted to characterize the MIL-100(Fe), including x-ray diffraction (XRD), scanning electron microscopy (SEM), nitrogen sorption, and thermal-gravimetric (TG). The synthesized MIL-100(Fe) has octahedron-shaped particles with superior properties, that is large surface area (1456.10 m2/g) and pore volume (1.25 cm3/g). The drug loading rate and capacity were determined by means of adsorption kinetic and isotherm. The studied INH@MIL-100(Fe) adsorption system kinetics follow the pseudo-first-order model, while the isotherm system follows the Langmuir model with the maximum adsorption capacity of 128.5 mg/g at 30 °C. MIL-100(Fe) shows adequate biocompatibility, also exhibits a reasonable and controlled drug release kinetics. The results obtained show that MIL-100 (Fe) can be a good choice of drug delivery platform among other available platforms.