2,5-Piperazinedione inhibits quorum sensing-dependent factor production in Pseudomonas aeruginosa PAO1.
The effects of 2,5-piperazinedione in reducing the production of quorum sensing (QS)-dependent factors in Pseudomonas aeruginosa PAO1 were assessed both in vitro and in vivo. 2,5-Piperazinedione exhibited a 69% reduction in the azocasein-degrading proteolytic activity and a 48% reduction in the elastolytic activity of PAO1. Further, it showed 85% and 96% reduction in the production of pyocyanin and extracellular polymeric substances (EPS) of PAO1, respectively. In the swimming inhibition assay, 2,5-piperazinedione-treated PAO1 cells exhibited poor swimming motility in swim agar medium. In the in vivo analysis, an enhanced survival of PAO1-preinfected Caenorhabditis elegans was observed after treatment with 2,5-piperazinedione. Regarding the mode of action, in the molecular docking analysis, 2,5-piperazinedione interacts with the amino acid residue of the LasR receptor protein required for binding the natural ligand N -3-oxododecanoyl-l-homoserine lactone (3-oxo-C12-HSL). This demonstrates the probability of 2,5-piperazinedione to interfere with the binding process of 3-oxo-C12-HSL to its receptor protein. Thus, the findings of the present study reveal the potential of 2,5-piperazinedione in reducing the QS-dependent phenotypic features of PAO1.


Quantitative susceptibility mapping of the midbrain in Parkinson's disease.
Parkinson's disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD. Quantitative susceptibility mapping and R2* maps were obtained from 47 PD patients and 47 healthy controls. Midbrain susceptibility and R2* values were analyzed by using both voxel-based and region-of-interest approaches in normalized space, and analyzed along with clinical data, including disease duration, Unified Parkinson's Disease Rating Scale (UPDRS) I, II, and III subscores, and levodopa-equivalent daily dosage. All studies were done while PD patients were "on drug." Compared with controls, PD patients showed significantly increased susceptibility values in both right (cluster size = 106 mm(3)) and left (164 mm(3)) midbrain, located ventrolateral to the red nucleus that corresponded to the substantia nigra pars compacta. Susceptibility values in this region were correlated significantly with disease duration, UPDRS II, and levodopa-equivalent daily dosage. Conversely, R2* was increased significantly only in a much smaller region (62 mm(3)) of the left lateral substantia nigra pars compacta and was not significantly correlated with clinical parameters. The use of quantitative susceptibility mapping demonstrated marked nigral changes that correlated with clinical PD status more sensitively than R2*. These data suggest that quantitative susceptibility mapping may be a superior imaging biomarker to R2* for estimating brain iron levels in PD.


Lower extremity compartment syndrome following a laparoscopic Roux-en-Y gastric bypass.
Bariatric surgery has the potential for serious complications. A case is presented of unilateral lower extremity compartment syndrome after a laparoscopic Roux-en-Y gastric bypass performed in the modified lithotomy position. A 38-year-old female (weight 134.5 kg, BMI 49.6) underwent a laparoscopic Roux-en-Y gastric bypass (operating time 375 min). Postoperatively, she complained of bilateral lower extremity pain that gradually subsided over the course of the day. However, on the 1st postoperative day she developed numbness on the dorsum of the foot and compartment syndrome was diagnosed (anterior compartment pressure 71 mmHg). She underwent emergency fasciotomy, which resulted in a reduction of the pain and numbness on the dorsum of the foot. The next day she ambulated without difficulty and was discharged home on the 5th postoperative day. 12 days after her operation, delayed primary closure of the fasciotomy wound was done with the assistance of a novel device (Proxiderm) that applies constant tension to the wound edges. Subsequent recovery was uneventful, and at 4-month follow-up the patient had a weight loss of 28 kg without any right leg motor or sensory deficits. Bariatric surgeons should be aware of compartment syndrome as a rare but serious complication. Prevention, early recognition, and prompt fasciotomy are crucial for a favorable outcome.


Control of gastrointestinal nematodes in first-season grazing calves by two strategic treatments with doramectin.
Twenty first-season Holstein crossbred calves were used in a study conducted to investigate the efficacy of two strategic treatments with doramectin (s.c. 200 micrograms kg-1 bodyweight). They were allocated in two equal groups: Group D was treated with doramectin at turn-out and 8 weeks later and Group C served as control group. Tracers were used at turn-out, in August and before housing. At monthly intervals all principal animals were weighed, and their faeces were sampled for faecal egg counts and cultured for larval identification. Serum samples were collected for determination of pepsinogen. Animals were slaughtered for worm counts 3 weeks after housing. Clinical signs of parasitic gastroenteritis (PGE) in Group C necessitated a salvage treatment with pyrantel citrate. No signs of PGE were seen in Group D. The faecal egg output remained very low (less than 50 eggs g-1) in Group D, whereas in Group C a mean geometric maximum of 352 eggs g-1 was observed. Pepsinogen levels were below 2000 mU tyrosine in Group D, compared with maximum levels of 4190 mU tyrosine in Group C. The worm counts of the tracers at housing showed an overall reduction of 94% in the total number of gastrointestinal nematodes present on the D pasture, compared with the C pasture. Worm counts of the principal animals showed an 87.8% reduction in the total worm burden. The present results show clearly that doramectin given at turn-out and at Week 8 controls PGE in calves during the first grazing season.


Factors in narratives to questions in the Short-Term Life Review interviews of terminally ill cancer patients and utility of the questions.
Although the Short-Term Life Review elevated the spiritual well-being of terminally ill cancer patients in our previous study, we have not examined what patients reviewed for each question item of it. We examined factors in narratives to questions in the Short-Term Life Review interviews of terminally ill cancer patients and utility of the questions. Thirty-four terminally ill cancer patients received the Short-Term Life Review interview in which there were two sessions. In the first session patients reviewed their lives, and an interviewer made a simple album of the patient based on patients' narrative. After 1 week, there was a second session. Qualitative analysis was conducted on patients' answers to each question using computational word mining, and factors were identified. Twenty patients' narratives were analyzed. "Human relationships" was identified under "important things in life." "Pleasant memories" were associated with "impressive memories." "Illness" and "marriage and divorce" were related to "turning points in the life." "Raising children and education" and "company or work" were identified as "roles in life." "Achievements at work" were identified with "pride." "Message to my children" was identified with "what I want to say to my family." "To live sincerely" and "consideration for others" were identified as "advice for the next generation." Patients reviewed few for topics such as "pride," "what I want to say to my family," "advice for the next generation," and "summing up my life." Factors such as human relationships, raising children, and education as a role and source of pride, and concerns about children's future, were associated with elevating spiritual well-being. Question to which that patients easily answered were selected.


Association study of miR-149, miR-196a2, and miR-499a polymorphisms with coronary artery aneurysm of Kawasaki disease in southern Chinese population.
Accumulating evidence suggests that several microRNA (miRNA) polymorphisms are closely associated with disease susceptibility or progression, such as in Kawasaki disease (KD). Our previous studies revealed the association of miR-149 rs2292832 T>C and miR-196a2 rs11614913 C>T polymorphisms with KD susceptibility. The present study further focused on the relationship between three miRNA polymorphisms (miR-149 rs2292832 T>C, miR-196a2 rs11614913 C>T and miR-499a rs3746444 A>G) and the risk of coronary artery aneurysm (CAA) in southern Chinese KD patients. We evaluated 318 KD patients with CAAs and 784 patients without CAAs. TaqMan assays were used to estimate genotyping and analyze the relationship between miRNA polymorphisms (miR-149 rs2292832 T>C, miR-196a2 rs11614913 C>T and miR-499a rs3746444 A>G) and risk associations of CAA by odds ratios (ORs) and 95% confidence intervals (CIs). We found that the miR-149 rs2292832 TC/CC genotype increased the CAA risk (adjusted OR = 1.53, 95% CI = 1.15-2.03, p = 0.003 for TC, adjusted OR = 1.63, 95% CI = 1.08-2.47, p = 0.021 for CC), whereas the miR-499a rs3746444 AG genotype decreased the CAA risk in KD patients (adjusted OR = 0.33, 95% CI = 0.25-0.45 p ≤ 0.001). Moreover, patients carrying two or three of these single nucleotide polymorphism (SNP) genotypes (rs2292832 TC/CC and rs11614913 TT and rs3746444 AA) had a higher risk for CAA than those who harbored only zero or one of these SNP genotypes. Our results demonstrated that the miR-149 rs2292832 T>C polymorphism increased the risk of CAA in KD patients and that the miR-499a rs3746444 A>G polymorphism decreased the risk of CAA in KD patients. Further studies with larger sample sizes and different centers are needed to confirm the findings of the present study.


Coaggregation of mineral filler particles and starch granules as a basis for improving filler-fiber interaction in paper production.
The sustainable, efficient use of renewable bio-based additives in the production of various materials fits well into the concept of sustainability. Here, the concept of coaggregation of mineral filler particles and starch granules for improving filler-fiber interaction in paper-based cellulosic networks is presented. Coaggregation of precipitated calcium carbonate filler particles and uncooked, unmodified corn starch granules by cationic polyacrylamide (a cationic high molecular weight polymer flocculant) in combination with bentonite (an anionic microparticle) prior to addition to cellulosic fiber slurry delivered enhanced filler bondability with cellulosic fibers. For instance, under the conditions studied, preaggregation resulted in an increase in filler bondability factor from 9.24 to 15.21 at starch dosage of 1% (on the basis of the dry weight of papermaking stock). The swelling and gelatinization of the starch granules in starch-filler preaggregates or hybrids enabled the "bridging" of the gaps in cellulosic networks, leading to structural consolidation and strength enhancement.


Manipulate the Electronic and Magnetic States in NiCo2 O4 Films through Electric-Field-Induced Protonation at Elevated Temperature.
Ionic-liquid-gating- (ILG-) induced proton evolution has emerged as a novel strategy to realize electron doping and manipulate the electronic and magnetic ground states in complex oxides. While the study of a wide range of systems (e.g., SrCoO2.5 , VO2 , WO3 , etc.) has demonstrated important opportunities to incorporate protons through ILG, protonation remains a big challenge for many others. Furthermore, the mechanism of proton intercalation from the ionic liquid/solid interface to whole film has not yet been revealed. Here, with a model system of inverse spinel NiCo2 O4 , an increase in system temperature during ILG forms a single but effective method to efficiently achieve protonation. Moreover, the ILG induces a novel phase transformation in NiCo2 O4 from ferrimagnetic metallic into antiferromagnetic insulating with protonation at elevated temperatures. This study shows that environmental temperature is an efficient tuning knob to manipulate ILG-induced ionic evolution.


Composting of waste paint sludge containing melamine resin as affected by nutrients and gypsum addition and microbial inoculation.
Melamine formaldehyde resins have hard and durable properties and are found in many products, including automobile paints. These resins contain high concentrations of nitrogen and, if properly composted, can yield valuable products. We evaluated the effects of starter compost, nutrients, gypsum and microbial inoculation on composting of paint sludge containing melamine resin. A bench-scale composting experiment was conducted at 55 °C for 91 days and then at 30 °C for an additional 56 days. After 91 days, the composts were inoculated with a mixed population of melamine-degrading microorganisms. Melamine resin degradation after the entire 147 days of composting varied between 73 and 95% for the treatments with inoculation of microorganisms compared to 55-74% for the treatments without inoculation. Degradation was also enhanced by nutrients and gypsum additions. Our results infer that large scale composting of melamine resins in paint sludge is possible.


[Separation of enantiomers of amino acid derivatives by high performance liquid chromatography on teicoplanin chiral stationary phase].
Direct enantioseparations of seven N-fluorenylmethoxycarbonyl-amino acids (Fmoc-Val, Fmoc-Ser, Fmoc-Leu, Fmoc-Ile, Fmoc-Met, Fmoc-Ala, and Fmoc-Phe) were achieved by high performance liquid chromatography using a 250 mm x 4. 6 mm i.d. column bonded teicoplanin on silica gel as chiral stationary phase and methanol-acetic acid-triethylamine mixtures as mobile phase. The comparison of retention behavior and enantioseparation of N-Fmoc-Val and its non-blocked analogue on a Chirobiotic column with different mobile phase systems is presented. The effects of the content of acetic acid and triethylamine and the content ratio of acetic acid and triethylamine in the mobile phase on the enantioseparation of some N-Fmoc-amino acids were examined. The results showed that variations of column temperatureand flow rate of mobile phase also had effects on enantioseparation of N-Fmoc-amino acids. The method had been successfully applied to the determination of optical purity of some derivatized amino acids.


The visfatin (PBEF1) G-948T gene polymorphism is associated with increased high-density lipoprotein cholesterol in obese subjects.
The newly discovered adipokine visfatin has been hypothesized to be related to obesity and insulin resistance. In this study, we investigate if the 2 single nucleotide polymorphisms rs4730153 and G-948T are associated with obesity and/or related traits and whether they influence the messenger RNA (mRNA) levels of PBEF1 (originally the abbreviation for pre-B-cell colony-enhancing factor 1) in visceral and subcutaneous adipose tissue (VAT and SAT). We found that obese carriers of the PBEF1 G-948T variant allele had significantly higher levels of high-density lipoprotein cholesterol (GG, 1.1 [0.97-1.3] mmol/L; GT + TT, 1.3 [1.0-1.5] mmol/L; P = .02). Other than that, neither rs4730153 nor G-948T had any major impact on any of the obesity-related phenotypes. There was no difference in mRNA expression between VAT and SAT (2.08 +/- 0.17 and 2.09 +/- 0.14, respectively; P = .26), but there was a nonsignificant trend toward higher PBEF1 mRNA levels in the variant allele carriers concerning both VAT and SAT for both single nucleotide polymorphisms. A significant correlation was observed between body mass index and PBEF1 mRNA expression in SAT (R = 0.37, P = .03) but not in VAT (R = 0.26, P = .12). In conclusion, PBEF1 G-948T is associated with increased high-density lipoprotein cholesterol; but genetic variation in PBEF1 does not seem to have a major impact on the development of obesity or on the expression of the gene.


Analysis of the early clinical outcomes of arthroscopic debridement in the treatment of shoulder tuberculosis.
Due to atypical clinical symptoms, it is difficult to diagnose joint tuberculosis infection, which often results in misdiagnosis and missed diagnosis. It is easy to cause joint disability. And there are few reports of using arthroscopy to diagnose and treat shoulder tuberculosis. This case series aims to introduce the clinical outcomes of arthroscopic treatment of shoulder tuberculosis. Twenty-nine patients with shoulder tuberculosis from September 2013 to February 2019 were included (10 males, 19 females; age range from 22 to 69; the average age is 37.6 years). All patients underwent arthroscopic lesion debridement, with preoperative and postoperative regular use of isoniazid, rifampicin, pyrazinamide, and streptomycin quadruple anti-tuberculosis drugs. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were recorded before and at the last follow-up. The shoulder function was evaluated according to the visual analogue scoring method (visual analogue scale, VAS) pain score and Constant score. Twenty-nine patients were followed up from 12 months to 2 years, and the average follow-up time was 15.7 months. The pathological diagnosis of all patients after surgery was shoulder tuberculosis. No serious complications were found at the last follow-up, and the incision healed well. VAS pain score, Constant score, ESR, and CRP at the last follow-up were significantly improved compared with those before treatment (P < 0.05). On the basis of the standard use of anti-tuberculosis drugs before and after surgery, shoulder arthroscopy is used to treat early and mid-term shoulder tuberculosis, which can be diagnosed by direct observation under the arthroscope and postoperative pathological examination. It has the advantages of thorough lesion removal, minimal invasiveness, rapid recovery, and reliable clinical effect.


Na+/H+ antiporter gene expression increases during retinoic acid-induced granulocytic differentiation of HL60 cells.
During differentiation of human leukemic HL60 cells into granulocytes, sustained increases in intracellular pH and Na+/H+ antiporter activity have been observed. In the present study we report that retinoic acid (RA)-induced granulocytic differentiation of HL60 cells causes an approximately 18-fold increase in the steady-state mRNA levels for the Na+/H+ antiporter. This was due to an increase in the rate of Na+/H+ antiporter gene transcription as measured by nuclear run-on analysis. Antiporter protein synthesis increased by seven-fold during RA-induced granulocytic differentiation of HL60 cells as measured by immunoprecipitation of 35S-methionine-labeled proteins with the RP1-c28 Na+/H+ antiporter antibody. No increase in antiporter mRNA was observed in response to etretinate, an analogue of retinoic acid, which did not induce differentiation. Thus, Na+/H+ antiporter gene expression is associated with RA-induced granulocytic differentiation of HL60 cells. The present findings and our previous data (Rao et al., 1991) demonstrate that Na+/H+ antiporter gene expression is a generalized feature of HL60 cell differentiation.


Novel antifolate resistant mutations of Plasmodium falciparum dihydrofolate reductase selected in Escherichia coli.
A simple and effective system has been developed from which a number of Plasmodium falciparum dihydrofolate reductase (pfDHFR) mutants conferring resistance to antifolates were randomly generated and characterized. The system exploited error-prone PCR to generate random mutations in the pfDHFR. Using the synthetic gene encoding for wild-type and quadruple mutant (N51I+C59R+S108N+I164L) pfDHFRs as templates, mutants resistant to pyrimethamine (Pyr), m-Cl analogue of Pyr (SO3) and WR99210 were selected by bacterial complementation system in which the endogenous DHFR activity of bacterial host cells, but not of Plasmodium, is selectively inhibited by trimethoprim (Tmp). Mutants conferring resistance to antimalarial antifolates were selected under the condition that inhibited the growth of the wild-type pfDHFR. All obtained Pyr resistant mutants possessed S108 mutation, in combination with common mutations of N51I, C59R and I164L previously found in the field. New Pyr resistant mutants with novel mutations (K27T, N121D, N144K and V213E) not found in the field were also identified. Exposure of the randomly mutated pfDHFR libraries to WR99210 or SO3 resulted in selection of novel single and multiple mutants including D54N, F58L and a combination of C50R, K181R, T219P and K227E, which exhibited 2- to over 2000-fold increase in resistance against antifolates. Kinetic analysis of these mutants suggested that apart from the active site residues that are crucial for DHFR activity, residues remote from the binding pocket also play essential roles in substrate and inhibitor binding.


Knock down of heat shock protein 27 (HspB1) induces degradation of several putative client proteins.
Hsp27 belongs to the heat shock protein family and displays chaperone properties in stress conditions by holding unfolded polypeptides, hence avoiding their inclination to aggregate. Hsp27 is often referenced as an anti-cancer therapeutic target, but apart from its well-described ability to interfere with different stresses and apoptotic processes, its role in non-stressed conditions is still not well defined. In the present study we report that three polypeptides (histone deacetylase HDAC6, transcription factor STAT2 and procaspase-3) were degraded in human cancerous cells displaying genetically decreased levels of Hsp27. In addition, these proteins interacted with Hsp27 complexes of different native size. Altogether, these findings suggest that HDAC6, STAT2 and procaspase-3 are client proteins of Hsp27. Hence, in non stressed cancerous cells, the structural organization of Hsp27 appears to be a key parameter in the regulation by this chaperone of the level of specific polypeptides through client-chaperone type of interactions.


Pupil staging and EEG measurement of sleepiness.
The goal of this multi-method study was to examine the validity (accuracy) of the pupillometric Alertness Level Test (ALT) as a physiologic measure of sleepiness. The study used a pooled-time series-correlation design with 16 untreated narcolepsy (8 F, 8 M), 16 untreated obstructive sleep apnea (OSA) (7 F, 9 M) and 16 healthy control (8 F, 8 M) subjects. Participants underwent EEG/polysomnography testing using standard Multiple Sleep Latency Test electrode placement concurrent with the 15 min pupillometric ALT. EEG data were examined to determine if theta power (4-7 Hz) increased during 2-s periods of proportional pupil size decreases (pupil Stage 1, 95% or more of maximal pupil size to Stage 4, 65-74% of maximal size). Printed EEG records also were visually scored. Self-report sleepiness measures included the Pittsburgh Sleep Quality Index, the Profile of Mood States and the Epworth Sleepiness Scale. Within subject groups, theta power ratios significantly increased across pupil stages for the sleep disorder groups but not for controls (theta activity increased 42% for narcoleptic and 36% for OSA subjects). Between subject groups, the amount of theta activity was significantly greater for narcoleptic and OSA subjects than that for controls. Visual EEG scoring and self-report measures were usually consistent with objective findings. The ALT is convenient, easily repeatable and less technically demanding than EEG sleepiness measures, and it deserves more comprehensive testing as a valid measure of sleepiness.


BCG in the treatment of superficial cancer of the bladder: a review.
Superficial Bladder Cancer can be treated in several ways. During the last decades, intravesical instillation of Bacillus Calmette Guerin (BCG) has emerged as an effective therapy. The history of how BCG became an antitumoral treatment is long and intriguing, and the theoretical background is fragile. In numerous studies, involving over 3,000 patients, intravesical instillation of BCG has been shown to be an effective treatment for superficial cancer of the urinary bladder in humans. Temporarily, BCG can eradicate residual disease after surgery, it can prevent local recurrence, and it can halt deterioration of malignancy in recurrences. However, its effect on survival is uncertain. For patients, treatment with BCG is prolonged, expensive, associated with side-effects, and may even be harmful. The mode of action is obscure. The theoretical framework on which this therapy is based is purely speculative, if existing at all. Although BCG has been classified as a biological response modifier, and the treatment is termed immunotherapy, proof is still lacking that the mechanism is immunological.


Clinical Benefit of Everolimus as Second-Line Therapy in Metastatic Renal Cell Carcinoma: The French Retrospective SECTOR Study.
Real-world data of everolimus after vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitor (TKI) therapy in metastatic renal cell carcinoma (mRCC) are limited. The retrospective, noninterventional SECTOR (SECond line with afiniTOR) study (N = 165) assessed outcomes of second-line everolimus after initial VEGFR-TKI (TKI-everolimus, n = 144) and of third-line VEGFR-TKI after everolimus (TKI-everolimus-TKI, n = 59) in patients with mRCC. The primary end point was duration of everolimus therapy for both populations. Median duration was 4.0 months (range, 0.0-33.0 months) for second-line everolimus and 18.0 months (range, 2-78 months) for sequential VEGFR-TKI and everolimus. Median overall survival (OS) for this sequence was 36.0 months (95% confidence interval [CI], 27.0-56.0 months) and was longer for patients who received a first-line TKI for ≥ 9 months (not reached) than for < 9 months (28.0 months; P < .001). During second-line everolimus treatment, commonly reported adverse events (all grades) were fatigue (n = 66, 40.7%), anemia (n = 58, 35.8%), and stomatitis (n = 41, 25.3%). Median duration from initiation of first-line TKI to the end of the third-line TKI was 24.0 months (95% CI, 19.0-29.0 months). Median OS for this sequence was 41.0 months (95% CI, 25.0-57.0 months) and was significantly longer for patients who received the first-line TKI for ≥ 9 months (37.5 months) than for < 9 months (19.0 months; P < .0001). These results reflect clinical use of sequential TKI-everolimus and TKI-everolimus-TKI and provide additional evidence that everolimus could be an option in second-line therapy in mRCC. Results of the CheckMate-025 (Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma) and METEOR (Metastatic RCC Phase 3 Study Evaluating Cabozantinib versus Everolimus) studies might change the treatment landscape.


Plasma ascorbic acid: measurement, stability and clinical utility revisited.
To compare plasma ascorbic acid results by the colorimetric FRASC (Ferric Reducing/Antioxidant and Ascorbic Acid) assay and a reference HPLC method; to re-examine plasma ascorbic acid stability, and anticoagulant effect. For method comparison, 31 plasma samples were tested by both methods. For stability, matching EDTA, heparin, citrate and fluoride/oxalate plasma, stored under different conditions of time and temperature, was measured. FRASC is an acceptable alternative to HPLC for plasma ascorbic acid: precision, limit of detection and recovery were similar, and results by the two methods were indistinguishable: mean (95% CI) difference:1.8 (-1.1-4.6; n = 31) micromol/L. Ascorbic acid was most stable in heparinized plasma. Marked loss (p < 0.05) in EDTA plasma occurred within 30 min of blood collection. FRASC offers a speedy and reliable alternative to HPLC for plasma ascorbic acid. Heparin is proposed as the anticoagulant of choice; loss of ascorbic acid is rapid in EDTA plasma ex vivo.


Trabecular metal spacers as standalone or with pedicle screw augmentation, in posterior lumbar interbody fusion: a prospective, randomized controlled trial.
This prospective randomized comparative trial compared radiological and clinical outcome of Trabecular Metal™ (TM) spacers in PLIF, used as standalone (SA) devices, to TM spacers in PLIF with pedicle screw fixation (PF), in patients with single-level degenerative disc disease (DDD). Patients (n = 80) with chronic low back pain and single-level degenerative disc were randomly assigned to the SA PLIF (n = 40) or PLIF with PF (n = 40). The primary radiological outcome was the evaluation of a long-term (±6 years; range 6.0-7.7 years) stable construct measured by dynamic X-rays. CT scan does not allow judging the bony bridging between vertebrae, because of Tantalum artefacts. The clinical evaluation (6 weeks, 6, 12 and 24 months) consisted of the Oswestry Disability Index (ODI) score, intensity of low back pain (Visual Analogue Scale) and quality of life (Short Form-36). At 6-year follow-up, X-rays showed a stable construct in 94 % of patients treated by SA TM-500 spacers and in 97 % of those with additional PF. Neither subsidence nor migration was observed in either the SA or the PF group. The average improvement in ODI scores at 24-month clinical follow-up was 14.4 and 13.8 for the SA and PF group, respectively. The VAS score showed an average improvement of 6.4 (SA) and 6.7 (PF), 2 years after implantation. No significant difference between groups was observed at all the evaluation points. In this study, TM spacers were found to provide a solid construct at more than 6-year follow-up after PLIF for DDD both with and without additional pedicle fixation. The clinical, but also radiological results were not significantly different between both cohorts. Future studies focusing on the differences of SA and PF at L4/5 level should be powered to study differences in post-surgery stability at the long term.


3D left ventricular extracellular volume fraction by low-radiation dose cardiac CT: assessment of interstitial myocardial fibrosis.
Myocardial fibrosis leads to impaired cardiac function and events. Extracellular volume fraction (ECV) assessed with an iodinated contrast agent and measured by cardiac CT may be a useful noninvasive marker of fibrosis. The purpose of this study was to develop and evaluate a 3-dimensional (3D) ECV calculation toolkit (ECVTK) for ECV determination by cardiac CT. Twenty-four subjects (10 systolic heart failure, age, 60 ± 17 years; 5 diastolic failure, age 56 ± 20 years; 9 matched healthy subjects, age 59 ± 7 years) were evaluated. Cardiac CT examinations were done on a 320-multidetector CT scanner before and after 130 mL of iopamidol (Isovue-370; Bracco Diagnostics, Plainsboro, NJ, USA) was administered. A calcium score type sequence was performed before and 7 minutes after contrast with single gantry rotation during 1 breath hold and single cardiac phase acquisition. ECV was calculated as (ΔHUmyocardium/ΔHUblood) × (1 - Hct) where Hct is the hematocrit, and ΔHU is the change in Hounsfield unit attenuation = HUafter iodine - HUbefore iodine. Cardiac magnetic resonance imaging was performed to assess myocardial structure and function. Mean 3D ECV values were significantly higher in the subjects with systolic heart failure than in healthy subjects and subjects with diastolic heart failure (mean, 41% ± 6%, 33% ± 2%, and 35% ± 5%, respectively; P = 0.02). Interobserver and intraobserver agreements were excellent for myocardial, blood pool, and ECV (intraclass correlation coefficient, >0.90 for all). Higher 3D ECV by cardiac CT was associated with reduced systolic circumferential strain, greater end-diastolic and -systolic volumes, and lower ejection fraction (r = 0.70, r = 0.60, r = 0.73, and r = -0.68, respectively; all P < 0.001). 3D ECV by cardiac CT can be performed with ECVTK. We demonstrated increased ECV in subjects with systolic heart failure compared with healthy subjects. Cardiac CT results also showed good correlation with important functional heart biomarkers, suggesting the potential for myocardial tissue characterization with the use of 3D ECV by cardiac CT. This trial is registered at www.ClinicalTrials.gov as NCT01160471.


COVID-19 and Vaccination Status in Lysosomal Storage Diseases: A Single-Center Experience.
Coronavirus disease 2019 (COVID-19) causes significant morbidity and mortality in individuals with chronic disease. There is not enough information about the course of coronavirus disease in lysosomal storage diseases. This study aimed to evaluate coronavirus disease vaccination status and the impact of coronavirus disease on lysosomal storage disease. The study included 87 lysosomal storage disease patients. The patients' diagnoses were Gaucher, mucopolysaccharidosis I, II, IVA, VI, VII, Fabry, and Pompe. A questionnaire assessing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, coronavirus disease symptoms, and vaccine status was administered in person or by phone calls. The number of coronavirus disease positive patients was 8 (9.1%). Only 2 patients were treated in the intensive care unit. Other coronavirus disease patients had mild symptoms and stayed in-home quarantine. Patients over 12 years of age could receive a COVID-19 vaccine. 63.5% of those aged ≥12 years were vaccinated. Lysosomal storage disease patients did not have an increased risk of COVID-19 compared to the healthy population, despite the chronic inflammatory disease. Vaccination of lysosomal storage disease patients will be protective against severe coronavirus disease.


Fragment hopping-based discovery of novel sulfinylacetamide-diarylpyrimidines (DAPYs) as HIV-1 nonnucleoside reverse transcriptase inhibitors.
The fragment hopping approach is widely applied in drug development. A series of diarylpyrimidines (DAPYs) were obtained by hopping the thioacetamide scaffold to novel human immunodeficiency virus type 1 (HIV-1) nonnucleoside reverse transcriptase inhibitors (NNRTIs) to address the cytotoxicity issue of Etravirine and Rilpivirine. Although the new compounds (11a-l) in the first-round optimization possessed less potent anti-viral activity, they showed much lower cytotoxicity. Further optimization on the sulfur led to the sulfinylacetamide-DAPYs exhibiting improved anti-viral activity and a higher selectivity index especially toward the K103N mutant strain. The most potent compound 12a displayed EC50 values of 0.0249 μM against WT and 0.0104 μM against the K103N mutant strain, low cytotoxicity (CC50 > 221 μM) and a high selectivity index (SI WT > 8873, SI K103N > 21186). In addition, this compound showed a favorable in vitro microsomal stability across species. Computational study predicted the binding models of these potent compounds with HIV-1 reverse transcriptase thus providing further insights for new developments.


"Technical" Contributors and Authorship Distribution in Health Science.
In health sciences, technical contributions may be undervalued and excluded in the author byline. In this paper, I demonstrate how authorship is a historical construct which perpetuates systemic injustices including technical undervaluation. I make use of Pierre Bourdieu's conceptual work to demonstrate how the power dynamics at play in academia make it very challenging to change the habitual state or "habitus". To counter this, I argue that we must reconceive technical contributions to not be a priori less important based on its nature when assigning roles and opportunities leading to authorship. I make this argument based on two premises. First, science has evolved due to major information and biotechnological innovation; this requires 'technicians' to acquire and exercise a commensurate high degree of both technical and intellectual expertise which in turn increases the value of their contribution. I will illustrate this by providing a brief historical view of work statisticians, computer programmers/data scientists and laboratory technicians. Second, excluding or undervaluing this type of work is contrary to norms of responsibility, fairness and trustworthiness of the individual researchers and of teams in science. Although such norms are continuously tested because of power dynamics, their importance is central to ethical authorship practice and research integrity. While it may be argued that detailed disclosure of contributions (known as contributorship) increases accountability by clearly identifying who did what in the publication, I contend that this may unintentionally legitimize undervaluation of technical roles and may decrease integrity of science. Finally, this paper offers recommendations to promote ethical inclusion of technical contributors.


The predictive role of the neutrophil-lymphocyte ratio in the prognosis of adult patients with stroke.
Our study aimed to determine the effect of the neutrophil-lymphocyte ratio on the prognosis of adult patients with acute stroke. We searched the Web of Science, PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure databases and selected all of the potentially eligible studies. From the included studies, we extracted characteristics such as the stroke type and acquisition time until routine blood collection and the odds ratios across studies. The 95% confidence intervals and odds ratios were pooled to calculate the effect size for the neutrophil-lymphocyte ratio in acute stroke patients. We defined poor function outcomes according to the modified Rankin Scale ≥ 3 or Glasgow Outcome Scale< 3.Thirteen studies with 4443 patients were included in our analysis, including 7 ischemic and 6 hemorrhagic stroke studies. The pooled odds ratios for poor functional outcome at 3 months with a higher neutrophil-lymphocyte ratio in acute ischemic and hemorrhagic patients were 1.689 (95% CI = 1.184-2.409, p < 0.001) and 1.125 (95% CI = 1.022-1.239, p < 0.001), respectively, and the overall pooled odds ratio for poor functional outcome following stroke was 1.257 (95% CI = 1.146-1.379, p < 0.001). At the same time, the overall combined odds ratio for death at 3 months was 1.632 (95% CI = 1.155-2.306, p < 0.001).The neutrophil-lymphocyte ratio, an easily calculated marker, plays a predictive role in the short-term outcomes of adult patients (mean age ≥ 50 years) following acute ischemic and hemorrhagic stroke.


Mutations in the S gene and in the overlapping reverse transcriptase region in chronic hepatitis B Chinese patients with coexistence of HBsAg and anti-HBs.
The mechanism underlying the coexistence of hepatitis B surface antigen and antibodies to HBsAg in chronic hepatitis B patients remains unknown. This research aimed to determine the clinical and virological features of the rare pattern. A total of 32 chronic hepatitis B patients infected by HBV genotype C were included: 15 carrying both HBsAg and anti-HBs (group I) and 17 solely positive for HBsAg (group II). S gene and reverse transcriptase region sequences were amplified, sequenced and compared with the reference sequences. The amino acid variability within major hydrophilic region, especially the "a" determinant region, and within reverse transcriptase for regions overlapping the major hydrophilic region in group I is significantly higher than those in group II. Mutation sI126S/T within the "a" determinant was the most frequent change, and only patients from group I had the sQ129R, sG130N, sF134I, sG145R amino acid changes, which are known to alter immunogenicity. In chronic patients, the concurrent HBsAg/anti-HBs serological profile is associated with an increased aa variability in several key areas of HBV genome. Additional research on these genetic mutants are needed to clarify their biological significance for viral persistence.


Characteristics of the activation by dithiothreitol and Fe(2+) of tryptophan hydroxylase from the rat brain.
The preincubation of tryptophan hydroxylase extracted from various areas of the central nervous system of the rat with 30 mM dithiothreitol and 50 muM ferrous ammonium sulfate under nitrogen atmosphere resulted in a persistent increase of its activity. Studies on the enzyme characteristics indicated that this activation was associated with a doubling in its Vmax and a shift (from 7.6 to 7.2) of the optimal pH for its activity. In contrast, the molecular weight and the apparent affinities of tryptophan hydroxylase for its pterin cofactor and for tryptophan were not significantly altered by the preincubation with dithiothreitol and ferrous ammonium sulfate. Since this treatment did not prevent the stimulatory effects of various compounds (phosphatidylserine, ATP and MG(2+), Ca(2+)) on tryptophan hydroxylase activity, this might be a good procedure to activate this enzyme with only minor changes in its regulatory properties.


Analysis of genetic relationships and antimicrobial susceptibility of verotoxin-producing Escherichia coli strains isolated in Nagasaki Prefecture, Japan in 1996.
A total of 19 Escherichia coli O157 isolates were obtained in Nagasaki Prefecture, in the south-western part of Japan, between 1990 and 1996. Pulsed-field gel electrophoresis (PFGE) and computer-assisted analysis were applied to determine genetic relationships among these strains. Fragment patterns of the isolates in Nagasaki, as determined by PFGE, were compared with those of isolates in other areas where large outbreaks and sporadic cases of E. coli O157 infection occurred. Similarity values of all the strains isolated in Nagasaki Prefecture were over 0.65 except for E. coli O26. Some strains were identical to the strains isolated from the areas where large outbreaks occurred. All strains were susceptible to ampicillin, fosfomycin, minocycline, amikacin, ofloxacin and sulfamethoxazole-trimethoprim.


Screening for dilated cardiomyopathy in dogs.
Dilated cardiomyopathy (DCM) is the most common cardiac disease in large breed dogs. The disease can start with arrhythmias or with systolic dysfunction of the myocardium. To describe screening methods for DCM in various breeds and provide a new, modified staging system. Screening for occult DCM should start at three years of age and use Holter monitoring in Boxers and Dobermans and might be useful also in other breeds. Single ventricular premature complexes (VPCs) can be detected in many healthy dogs, but healthy animals typically have <50 VPCs in 24 h and demonstrate minimal complexity most often occurring only as single ectopic beats. In general, >100 VPCs in 24 h was recommended as the cut-off value for establishing a diagnosis of DCM. However, there are breed-specific recommendations related to Holter recording diagnosis of DCM in Dobermans and Boxers. Yearly screening over the life of a dog is recommended, as a one-time screening is not sufficient to rule out the future development of DCM. Several echocardiographic methods such as M-mode derived measurements, the measurement of the left ventricular (LV) volume by Simpson's method of discs (SMOD), and E-point to septal separation (EPSS) are recommended for screening purposes. The value of additional tests such as cardiac biomarkers (troponin I and N-terminal pro-B-type natriuretic peptide) as well as a 5-min resting electrocardiogram (ECG) or newer echocardiographic methods such as strain measurements is discussed. This review suggests some guidelines for screening for DCM in various breeds.


Network approach in liquidomics landscape.
Tissue-based biopsy is the present main tool to explore the molecular landscape of cancer, but it also has many limits to be frequently executed, being too invasive with the risk of side effects. These limits and the ability of cancer to constantly evolve its genomic profile, have recently led to the need of a less invasive and more accurate alternative, such as liquid biopsy. By searching Circulating Tumor Cells and residues of their nucleic acids or other tumor products in body fluids, especially in blood, but also in urine, stools and saliva, liquid biopsy is becoming the future of clinical oncology. Despite the current lack of a standardization for its workflows, that makes it hard to be reproduced, liquid biopsy has already obtained promising results for cancer screening, diagnosis, prognosis, and risk of recurrence.Through a more accessible molecular profiling of tumors, it could become easier to identify biomarkers predictive of response to treatment, such as EGFR mutations in non-small cell lung cancer and KRAS mutations in colorectal cancer, or Microsatellite Instability and Mismatch Repair as predictive markers of pembrolizumab response.By monitoring circulating tumor DNA in longitudinal repeated sampling of blood we could also predict Minimal Residual Disease and the risk of recurrence in already radically resected patients.In this review we will discuss about the current knowledge of limitations and strengths of the different forms of liquid biopsies for its inclusion in normal cancer management, with a brief nod to their newest biomarkers and its future implications.


A 61-Year-Old Man With Shortness of Breath and Eye Swelling.
A 61-year-old man presented to the pulmonary clinic with symptoms of dyspnea and productive cough for the last 6 months. Within the last 2 months, he started noticing bulging of his eyes associated with blurry vision. He denied hemoptysis, fever, night sweats, weight loss, skin rash, and dry eyes or mouth. He is a former smoker, and he denied any recent travel history. The patient has a history of microscopic polyangiitis, which was treated with cyclophosphamide and mycophenolate maintenance therapy and has been in remission for the last 7 years.


The effect of aging on the mechanical properties of 3-dimensional printed biocompatible resin materials used in dental applications: An in vitro study.
The mechanical properties of biocompatible printable resin materials in an intraoral environment is still being investigated. This study aimed to assess the effect of the aging process on the mechanical properties of resin samples produced by stereolithography appearance (SLA) and digital light processing (DLP) 3-dimensional printer systems. The cylindrical sample (4.00 × 20.00 mm) was designed by software, and the data were transformed into digital format. A DLP printer (n = 40) and an SLA printer (n = 40) carried out the printing process. The aging procedure was applied to 20 samples from each group using a thermocycling device. After the aging procedure, the samples were placed in the universal testing device for the 3-point bending test. This study showed that the aging procedure decreased maximum load, bending stress, and Young's modulus values and increased maximum deflection values of the DLP group (P <0.01). However, no statistical difference was detected in the parameters compared with the SLA group except for the maximum deflection values. Furthermore, statistically significant differences were found between maximum deflection and Young's module values of SLA and DLP control and study groups (P <0.05). This in vitro study revealed that the biocompatible printable resin materials produced by DLP and SLA printers had the mechanical strength to resist the values resembling the physiological occlusal forces even after the aging procedure and could produce intraoral appliances.


Evaluating the Performance of High-Dimensional Propensity Scores Compared with Standard Propensity Scores for Comparing Antihypertensive Therapies in the CPRD GOLD Database.
Propensity score (PS) matching is widely used in medical record studies to create balanced treatment groups, but relies on prior knowledge of confounding factors. High-dimensional PS (hdPS) is a semi-automated algorithm that selects variables with the highest potential for confounding from medical databases. The objective of this study was to evaluate performance of hdPS and PS when used to compare antihypertensive therapies in the UK clinical practice research datalink (CPRD) GOLD database. Patients initiating antihypertensive treatment with either monotherapy or bitherapy were extracted from the CPRD GOLD database. Simulated datasets were generated using plasmode simulations with a marginal hazard ratio (HRm) of 1.29 for bitherapy versus monotherapy for reaching blood pressure control at 3 months. Either 16 or 36 known covariates were forced into the PS and hdPS models, and 200 additional variables were automatically selected for hdPS. Sensitivity analyses were conducted to assess the impact of removing known confounders from the database on hdPS performance. With 36 known covariates, the estimated HRm (RMSE) was 1.31 (0.05) for hdPS and 1.30 (0.04) for PS matching; the crude HR was 0.68 (0.61). Using 16 known covariates, the estimated HRm (RMSE) was 1.23 (0.10) and 1.09 (0.20) for hdPS and PS, respectively. Performance of hdPS was not compromised when known confounders were removed from the database. With 49 investigator-selected covariates, the HR was 1.18 (95% CI 1.10; 1.26) for PS and 1.33 (95% CI 1.22; 1.46) for hdPS. Both methods yielded the same conclusion, suggesting superiority of bitherapy over monotherapy for time to blood pressure control. HdPS can identify proxies for missing confounders, thereby having an advantage over PS in case of unobserved covariates. Both PS and hdPS showed superiority of bitherapy over monotherapy for reaching blood pressure control.


Maternal periodontitis and preterm birth: Systematic review and meta-analysis.
To assess the association between periodontitis and preterm birth in women of childbearing age. This review included analytical case-control studies and prospective cohort studies evaluating the association between maternal periodontitis and preterm birth. Of the 3104 screened articles, 31 met the inclusion criteria for the review, and 20 met the quality criteria. The selected studies included a total of 10 215 women. Twenty articles contributed to the meta-analysis; 16 used a case-control design, and 4 were prospective cohort studies. The study heterogeneity was low (Q = 24.2464; P = 0.1869; I2 = 21.63%). A positive association between maternal periodontitis and preterm birth was found in 60% of the studies. Under the random-effects model, meta-analysis gave an odds ratio (OR) of 2.01 (95% CI 1.71, 2.36), representing a significant positive association between the explanatory and outcome variables. Pregnant mothers with periodontitis double the risk of preterm birth. There is a lack of international consensus for diagnosing maternal periodontitis.


C1q production and C1q-mediated immune complex retention in lymphoid follicles of rat spleen.
Involvement of C1q in retaining immune complexes in germinal centers in rat spleen was studied in vivo and in vitro. C1q production was found in fibroblastic reticulum cells in the peripheral mantle zone, in follicular dendritic cells in germinal centers, and in transitional forms between these two cells in the inner mantle zone. In passively immunized animals, immune complexes were found transiently on fibroblastic reticulum cells, then on the transitional forms and follicular dendritic cells. Extracellular C1q was detected by the presence of immune complexes on both the transitional forms and follicular dendritic cells, but not on fibroblastic reticulum cells. Thus, the fibroblastic reticulum cell appeared to trap immune complexes but not to retain either immune complexes or C1q. The morphology and function of the fibroblastic reticulum cell and the follicular dendritic cell suggest that they belong to the same lineage. Immune complexes were bound in vitro to germinal centers in cryostat spleen sections in the same manner as those retained in vivo. The binding required no complement in the incubation medium and was inhibited by C1q-suppressing factors. The extracellular C1q originating from the follicular cells may therefore play a role in retaining immune complexes in the germinal center.


The effect of endothelin receptor A antagonism on basilar artery endothelium-dependent relaxation after ischemic stroke.
Endothelin (ET) receptor A antagonism decreases neuronal damage in experimental models of stroke. Since large arteries like basilar artery contribute significantly to total cerebrovascular resistance and are major determinants of microvascular pressure, dysregulation of basilar artery function may worsen stroke injury. ET-1 is involved in the regulation of basilar constriction. However, whether stroke influences vasoreactivity of basilar artery and to what extent ET-1 contributes to basilar vascular dysfunction after stroke remained unknown. The goal of this study was to test the hypothesis that ET-1 impairs basilar artery vasorelaxation after ischemia/reperfusion (I/R) injury via activation of ET(A) receptor. Male Wistar rats were subjected to 3h middle cerebral artery occlusion (MCAO) and 21 h reperfusion. One group received ET(A) receptor antagonist atrasentan (5 mg/kg, i.p.) at reperfusion. At 24h, basilar arteries were isolated from control non-stroked, stroked and stroked+atrasentan-treated animals for vascular reactivity measurements using pressurized arteriograph. Acetylcholine (Ach)-induced maximum relaxation (R(max)) was decreased in stroked animals as compared to non-stroked group and ET(A) antagonism partially restored it. There was also a trend for decreased EC(50) value for the antagonist treatment group indicating improved Ach sensitivity. These findings suggest that I/R not only affects vessels distal to the occlusion but also impairs relaxation of proximal large vessels. ET-1-mediated basilar artery dysfunction may contribute to neurovascular damage after stroke and early restoration of vascular function by ET receptor antagonism after I/R injury may offer a therapeutic strategy.


Calcium current in single human cardiac myocytes.
Significant species-, tissue-, and age-dependent differences have been described for the L-type calcium current (ICa). Therefore, extrapolation of data obtained from the many animal models to human cardiac physiology is difficult. In this study, we have characterized the voltage-dependent properties of ICa from pediatric and adult, atrial and ventricular human heart tissue. ICa was measured in single human heart muscle cells using the "whole cell," voltage clamp method. Single myocytes were isolated from myocardial specimens obtained intraoperatively from both pediatric and adult patients (ages 3 months to 75 years) undergoing cardiac surgery. Cells obtained for these experiments appeared to be healthy; the resting potential was between -80 and -85 mV. The action potential shape and duration and current-voltage relationship for ICa were similar to that reported by others for human heart cells. The steady-state activation variable, d infinity, was found to be similar in both pediatric atrial and ventricular cells but shifted approximately 5 mV negative in the adult atrial and ventricular cells. ICa of all cells displayed biexponential inactivation and steady-state inactivation was incomplete at positive potentials (steady-state inactivation curves turned up at positive potentials) consistent with inactivation arising from voltage-dependent and calcium-dependent processes as reported in heart cells from many species. The potential of maximal inactivation was more negative for adult cells (around -10 mV) than pediatric cells (around 0 mV). Estimates of the calcium "window" current, using a modified Hodgkin-Huxley model, could explain measured differences in action potential shape and duration. Human cardiac ICa can be investigated using whole cell, voltage clamp methods and a modified Hodgkin-Huxley model. Quantitative characterization of many of the properties of ICa in human heart tissue suggests that important species differences do exist and that further investigations are required to characterize the dependence of inactivation on [Ca2+]i in human heart cells. Since the array of characteristics of ICa in different species varies, the study of human myocardial cells per se continues to be important when examining human cardiac physiology.


Perioperative bowel habits of women undergoing gynecologic surgery: a pilot study.
To describe perioperative bowel habits of women undergoing gynecologic surgery. This prospective cohort study included women undergoing gynecologic surgery. Before surgery, participants completed the Bristol Stool Form Scale (BSFS), a validated instrument describing stool characteristics consistent with transit categories: slow (BSFS 1-2), normal (BSFS 3-5), and fast (BSFS 6-7). For 2 weeks after surgery, the participants recorded daily medications and bowel movements (BM), and completed BSFS. The χ(2) test, the Fisher exact test, analysis of variance, t tests, and ordinal regression were used. Preoperatively, most (70%) of 340 women had normal stool transit, with 15% having slow transit and 7% having fast transit. Complete postoperative data were available for 170 (50%). Mean ± SD time to first postoperative BM was 2.8 ± 1.4 days with transit classification: 48% normal, 32% slow, and 20% fast. Most women had normal stool transit both preoperatively and postoperatively. Time to first BM was longer after open surgery by approximately 3 days.


Influences of disc degeneration and bone mineral density on the structural properties of lumbar end plates.
Implants subsidence is a frequent complication of interbody fusion, which can result in pain, deformity, nerve damage, and even failure of surgery. The end plates as the interface between implants and the vertebral bodies play a very important role in sharing the compression on the vertebral bodies. The information on the structural property distribution of the end plate and its relationship with bone mineral density (BMD) and disc degeneration will be of great significance for the reduction in implants subsidence and improvement in related operative procedures to increase the success rate of interbody fusion. To investigate the structural property distribution of the lumbar end plate; the effects of disc degeneration on the biomechanical properties of the lumbar end plate; and the relationship between the biomechanical properties of the lumbar end plate and BMD. A biomechanical study was conducted in human cadaveric lumbar spine models. Indentation tests were performed at 24 standardized test sites in 120 bony end plates of intact human vertebrae (L1-L5) using a 1.5-mm-diameter, hemispherical indenter at a speed of 0.2mm/s. The failure load at each test site was determined using the load-displacement curve. Disc condition was evaluated using a four-point grading scale and bone density was measured using the lateral dual-energy radiograph absorptiometry scans. All end plates were divided into different disc degeneration groups based on the states of the adjacent degenerative discs and BMD groups according to BMD values of the corresponding vertebral bodies. The experimental results were statistically analyzed using the SPSS 15.0 with the disc degeneration and BMD being considered as independent factor, and the failure loads of the superior and inferior end plates were also compared. The peripheral regions of lumbar end plates were stronger than the central regions (p<.05), with the posterolateral sites in front of vertebral pedicles being the strongest regions. The inferior lumbar end plates were found to be stronger than the superior lumbar end plates (p<.05). The disc degeneration was negatively correlated with the failure loads of the lumbar end plates (r(s)=-0.563; p<.01). With increasing disc degeneration, the decreases of failure loads were nonuniform across the lumbar end plate, and the central region became weak with little strength change on the end plate periphery. The BMD was positively correlated with the failure loads of the lumbar end plates (r(s)=0.812; p<.01). The failure loads decreased uniformly across the end plate surfaces as the BMD dropped, and the BMD decrease did not change the structural property distributions of lumbar end plates. Preoperative evaluation of the states of intervertebral discs and BMD of patients is necessary for predicting risks of implants subsidence after interbody fusion. For patients with or without disc degeneration or osteoporosis, the implants should be placed at the peripheral regions, especially the posterolateral sites, to acquire higher mechanical strength to reduce subsidence as much as possible.


Chiral phosphoric acid catalyzed asymmetric addition of naphthols to para-quinone methides.
An asymmetric addition of naphthols to in situ generated para-quinone methides catalyzed by a chiral phosphoric acid is described. A range of useful triarylmethanes can be generated from stable general para-hydroxybenzyl alcohols with good efficiency and enantioselectivity.


Immobilization of lead by phosphate amended Polonite.
Polonite is an alkaline material that is used to remove nutrients from domestic wastewater and it has been evaluated as a fertilizer. Stabilization of Pb by Polonite and Polonite amended with orthophosphate, PO4, (Polonite-P) was studied. Octacalcium phosphate (Ca8H2(PO4)6·5H2O) was a primary species of PO4 formed on the surface of Polonite-P. Lead was found to be associated with pozzolanic reaction products in Pb treated Polonite and Pb treated Polonite-P samples. Formation of Pb oxides, as precipitates or surface complexes, were substantial constituents of Pb treated Polonite. Dissolution of Ca8H2(PO4)6·5H2O followed by formation of Pb4O(PO4)2 was a probable mechanism of Pb removal by Polonite-P. Polonite-P could be a suitable replacement for current PO4 sources as a Pb stabilization agent. Finally, LDI-TOF was an effective technique for evaluating forms of Pb on Polonite and Polonite-P.


Pulmonary involvement in systemic sclerosis: the detection of early changes by thin section CT scan, bronchoalveolar lavage and 99mTc-DTPA clearance.
Systemic sclerosis is frequently complicated by fibrosing alveolitis although clinical and radiological abnormalities are not usually apparent until the lung disease is well established. The aim of this study was to investigate pulmonary involvement in systemic sclerosis by thin section CT scan, bronchoalveolar lavage (BAL) and 99mTc-DTPA clearance studies, and assess the value of these tests in defining pulmonary abnormalities in patients with a normal chest radiograph. Patients were divided into those with an abnormal chest radiograph (Group I, n = 14) and those with a normal chest radiograph (Group II, n = 16). CT scans were abnormal in all patients in Group I and 7 of 16 (44%) in Group II. BAL inflammatory cell counts were raised in all 12 (100%) patients studied in Group I and 11 of 15 (73%) in Group II. There was no difference in the type of inflammatory cells observed between the two groups. 99mTc-DTPA clearance was faster than normal controls in ten of 14 patients (71%) in Group I and seven of 15 (47%) in Group II and correlated with carbon monoxide transfer factor (P less than 0.05). Lung biopsies were performed on nine patients in Group I and three in Group II all of whom had abnormal CT scans. Fibrosing alveolitis was confirmed in every case. Group II biopsies could not be distinguished from Group I biopsies; both showed fibrosis as well as inflammation suggesting that pulmonary fibrosis is an early abnormality in systemic sclerosis. Our results indicate that CT scans, BAL and 99mTc-DTPA are frequently abnormal in asymptomatic patients with systemic sclerosis who have normal chest radiographs. When the CT scan is normal abnormalities of BAL and/or 99mTc-DTPA (99mTechnetium diethylenetriamine pentacetate) clearance may indicate lung disease at a still earlier stage. This observation requires further investigation.


A hybrid fuzzy-neural system for computer-aided diagnosis of ultrasound kidney images using prominent features.
The objective of this work is to develop and implement a computer-aided decision support system for an automated diagnosis and classification of ultrasound kidney images. The proposed method distinguishes three kidney categories namely normal, medical renal diseases and cortical cyst. For the each pre-processed ultrasound kidney image, 36 features are extracted. Two types of decision support systems, optimized multi-layer back propagation network and hybrid fuzzy-neural system have been developed with these features for classifying the kidney categories. The performance of the hybrid fuzzy-neural system is compared with the optimized multi-layer back propagation network in terms of classification efficiency, training and testing time. The results obtained show that fuzzy-neural system provides higher classification efficiency with minimum training and testing time. It has also been found that instead of using all 36 features, ranking the features enhance classification efficiency. The outputs of the decision support systems are validated with medical expert to measure the actual efficiency. The overall discriminating capability of the systems is accessed with performance evaluation measure, f-score. It has been observed that the performance of fuzzy-neural system is superior compared to optimized multi-layer back propagation network. Such hybrid fuzzy-neural system with feature extraction algorithms and pre-processing scheme helps in developing computer-aided diagnosis system for ultrasound kidney images and can be used as a secondary observer in clinical decision making.


Leaching and bioavailability of dissolved organic matter from petrol-based and biodegradable plastics.
Petrol-based plastic debris reaching the ocean releases dissolved organic carbon (DOC) and it can also leach fluorescent dissolved organic matter (FDOM). DOC is available to microbial uptake but the FDOM bioavailability has been scarcely studied. Although the most common plastic found in the ocean is petrol-based, the use of biodegradable plastic has increased substantially over the last years. Here we analysed the DOC and FDOM released by three petrol-based (LDPE, PS and EPS) and one biodegradable plastic (PLA) in seawater and examined their bioavailability. We found that the three petro-based plastics released FDOM in the protein-like region while the biodegradable PLA did not. FDOM released by EPS was available to microbial uptake while in the LDPE and PS treatments an increase of FDOM was observed, likely because the FDOM production by bacteria was higher than the consumption in those treatments. Biodegradable PLA leached similar amounts of DOC with comparable microbial bioavailability than petrol-based plastics indicating that, in seawater, it was not degraded faster than petro-based plastics. Especial care should be taken with biodegradable plastic since not all the types degrade in the ocean.


Biliary lesions during radiofrequency ablation in liver. Study on the pig.
Radiofrequency (RF) is a method of in situ destruction of liver tumor. Biliary complications are bile ducts stenosis or biliary abcess. The aim of this work was to study consequences of liver RF on bile ducts. A porcine model of biliary lesions was created using radiofrequency ablation liver. Twenty-two pigs were used for the study. The RF RITA 1500 generator (RITA Medical Systems, Mountain View, Calif., USA) was used for all experiments. The needle was positioned under sonographic control in liver parenchyma beside bile ducts. Two lesions were performed in left liver. Four groups of 5 pigs were treated. The pigs were sacrificed 1 or 3 weeks after the procedure. Pringle maneuver was utilized in half of the RF procedures. An ex vivo cholangiogram was obtained by direct injection into the main bile duct. Samples of RF lesions of liver parenchyma near and at a distance from the RF lesions were taken for pathological studies. Radiological lesions were biliary stenosis, with or without upstream bile duct dilatation, or complete interruption of the bile duct, or extravasation of the radiological contrast agent. Histological lesions of bile ducts were observed near RF lesions and at distance of the RF lesions when a Pringle maneuver was used or when the liver was removed after 3 weeks. RF ablation in contact of the intrahepatic bile duct induced biliary lesions. Therefore, it is required to stay away from the bile duct or to protect it when performing RF ablation.


Manipulation of prenylation reactions by structure-based engineering of bacterial indolactam prenyltransferases.
Prenylation reactions play crucial roles in controlling the activities of biomolecules. Bacterial prenyltransferases, TleC from Streptomyces blastmyceticus and MpnD from Marinactinospora thermotolerans, catalyse the 'reverse' prenylation of (-)-indolactam V at the C-7 position of the indole ring with geranyl pyrophosphate or dimethylallyl pyrophosphate, to produce lyngbyatoxin or pendolmycin, respectively. Using in vitro analyses, here we show that both TleC and MpnD exhibit relaxed substrate specificities and accept various chain lengths (C5-C25) of the prenyl donors. Comparisons of the crystal structures and their ternary complexes with (-)-indolactam V and dimethylallyl S-thiophosphate revealed the intimate structural details of the enzyme-catalysed 'reverse' prenylation reactions and identified the active-site residues governing the selection of the substrates. Furthermore, structure-based enzyme engineering successfully altered the preference for the prenyl chain length of the substrates, as well as the regio- and stereo-selectivities of the prenylation reactions, to produce a series of unnatural novel indolactams.


Similar bacterial signatures in the gut microbiota of type 1 and type 2 diabetes patients and its association with G protein-coupled receptor 41 and 43 gene expression.
There are conflicting reports regarding the abundance of short-chain fatty acids producing bacteria in the gut microbiota in patients with type 1 and type 2 diabetes. We aimed to determine the amount of Akkermansia muciniphila, Anaerobutyricum hallii, Bifidobacterium adolescentis, Bifidobacterium longum, Collinsella aerofaciens, Faecalibacterium prausnitzii, Lacticaseibacillus rhamnosus, and Parabacteroides distasonis in the gut microbiota in patients with type1 and type2 diabetes, compared with the healthy controls and analyze the correlation between the gene expression levels of two short-chain fatty acids receptors GPR41 and GPR43. Forty type 1, 40 type 2 stool and blood samples of diabetes patients, and 40 healthy control samples were studied. DNA and RNA were extracted, and bacteria were detected using a Microbial DNA qPCR Assay kit. Gene expressions were detected with GPR41 and GPR43 primers via in-house qPCR. Compared with healthy controls, B.longum and F.prausnitzii abundance were significantly decreased in patients with type1 and type2 diabetes, A.hallii abundance was increased in patients with type1 and decreased in type2 diabetes contrarily A.muciniphila abundance was decreased in patients with type1 and increased in type2 diabetes. GPR43 gene expression was upregulated in both patients group, however GPR41 was upregulated only in patients with type2 diabetes. Elevated B. longum and F. prausnitzii abundances were detected in the gut microbiota of patients with type1 and type2 diabetes and compared with healthy controls. B. longum and F.prausnitzii abundances were also correlated with the GPR43 gene expression level in type1 diabetes patients. Extensive studies determining bacteria producing short-chain fatty acids in gut microbiota, and their contribution in the pathogenesis of diabetes, are needed to understand better the mechanism of these diseases.


Responses of macrozoobenthos communities to changes in submerged macrophyte biomass in 19 temperate lakes in China.
Macrozoobenthos and submerged macrophytes interact closely. However, studies in China have focused on the middle and lower reaches of the Yangtze River, where shallow lakes are concentrated, rather than on temperate lakes. To clarify the responses of taxonomic and functional groups of macrozoobenthos in temperate lakes to changes in submerged macrophyte biomass (BMac) on a large scale, 19 temperate lakes within Baiyangdian Lake were investigated in this study. The BMac differed greatly across the 19 lakes, and Potamogeton crispus was the dominant species. According to the BMac, the 19 lakes were divided into 4 groups. One-way analysis of variance and Pearson correlation analysis showed that the water environmental parameters were different among the 4 groups, and the BMac was significant correlated with all the physical and chemical parameters of water bodies (except for water depth). Forty-one taxa of macrozoobenthos were identified in the 19 lakes, with oligochaetes, Hirudinea, gastropods, crustaceans, chironomid larvae, and aquatic insects (excluding chironomid larvae) represented by 9, 1, 4, 2, 19, and 6 species, respectively. Chironomid larvae and oligochaetes dominated by density, and gastropods and chironomid larvae dominated by biomass. Canonical correspondence analysis showed that the BMac was the most important factor affecting the macrozoobenthos community structure in group 1 to group 4. Macrozoobenthos with low pollution tolerance values were mainly found in areas with high BMac, while species with high pollution tolerance values were mainly distributed in areas with low BMac and high nutrient contents. Different taxonomic and functional groups of macrozoobenthos responded differently to changes in BMac. As BMac increased, density and biomass of oligochaetes and chironomid larvae tended to decrease, while those of gastropods and aquatic insects tended to first decrease and then increase. Collectors had more species than any other functional group in group 1 to group 4. As BMac increased, density and biomass of collectors gradually decreased, while density of predators, shredders, and scrapers tended to first decrease and then increase.


Increased Mammalian Target of Rapamycin Signaling Contributes to the Accumulation of Protein Oxidative Damage in a Mouse Model of Down's Syndrome.
Neurodegenerative diseases are characterized by increased levels of oxidative stress and an altered mammalian target of rapamycin (mTOR)/autophagy axis; however, the mutual relationship between these two events is controversial. Previous studies in Down's syndrome (DS) and Alzheimer's disease (AD) suggested that the accumulation of protein oxidative damage results from the increased free radical production, mainly related to metabolic alterations, mitochondrial degeneration and amyloid-β deposition, and aberrant activity of protein degradative systems. This study analyzed mTOR signaling in Ts65Dn mice, a model of DS, at 6 and 12 months of age compared with euploid mice showing the early aberrant hyperphosphorylation of mTOR coupled with the reduction of autophagosome formation. Moreover, the evaluation of protein oxidation shows an increase in protein nitration and protein-bound 4-hydroxynonenal in 12-month-old Ts65Dn mice suggesting the potential involvement of altered autophagy in the buildup of protein oxidative damage. In addition, data obtained on cell culture support the protective role of autophagy in reducing protein oxidation. Overall, this study provides further evidence for the role of mTOR hyperactivation and reduced autophagy in the accumulation of protein oxidative damage during DS and AD pathologies.


Targeted drug delivery with polydisperse particle transport and deposition in patient-specific upper airway during inhalation and exhalation.
Identifying the deposition pattern of inhaled pharmaceutical aerosols in the human respiratory system and understanding the effective parameters in this process is vital for more efficient drug delivery to this region. This study investigated aerosol deposition in a patient-specific upper respiratory airway and determined the deposition fraction (DF) and pressure drop across the airway. An experimental setup was developed to measure the pressure drop in the same realistic geometry printed from the patient-specific geometry. The unsteady simulations were performed with a flow rate of 15 L/min and different particle diameters ranging from 2 to 30 µm. The results revealed significant flow circulation after the nasal valve in the upper and oropharynx regions, and a maximum local velocity observed in the nasopharynx. Transient cumulative deposition fraction showed that after 2 s of the simulation, all particles deposit or escape the computational domain. About 30 % of the injected large particles (dp ≥ 20 µm) deposited in the first 1 cm away from the nostril and more than 95 % deposited in the nasal airway before entering the oropharynx region. While almost 94 % deposition in trachea was composed of particles smaller than 5 µm. Approximately 20 % of inhaled fine particles (2-5 µm) deposited in the upper airway and the rest deposited in oropharynx, larynx and trachea.


Changes in diurnal salivary cortisol levels in response to an acute stressor in healthy young adults.
Knowledge of the diurnal cortisol response to acute stress in healthy individuals can help us better understand the physiological and health effects of chronic stress. To compare the diurnal patterns of cortisol secretion of 15 medical students 2 weeks before a major written examination (control phase) and 2 weeks later at the time of the examination (acute stress phase). Interrupted time series within-subjects. During the acute stress phase, less cortisol was secreted over the course of the day, as demonstrated by a more prolonged and steeper decline in cortisol levels. In addition, higher cortisol levels were present in the evening. Despite these changes in the usual diurnal pattern, overall exposure to cortisol remained the same for both phases. The results of this study suggest that specific adaptations to the diurnal pattern of cortisol are made in the face of acute stress, important information for understanding cortisol regulation in health and illness.


PRNP genetic variability and molecular typing of natural goat scrapie isolates in a high number of infected flocks.
One hundred and four scrapie positive and 77 negative goats from 34 Greek mixed flocks were analysed by prion protein gene sequencing and 17 caprine scrapie isolates from 11 flocks were submitted to molecular isolate typing. For the first time, the protective S146 variant was reported in Greece, while the protective K222 variant was detected in negative but also in five scrapie positive goats from heavily infected flocks. By immunoblotting six isolates, including two goat flockmates carrying the K222 variant, showed molecular features slightly different from all other Greek and Italian isolates co-analysed, possibly suggesting the presence of different scrapie strains in Greece.


Flexible and transparent composite nanofibre membrane that was fabricated via a "green" electrospinning method for efficient particulate matter 2.5 capture.
Air particulate pollution from ever-increasing industrialization poses an enormous threat to public health. Thus, the development of a green air filter with high efficiency and performance is of urgent necessity. In this study, we introduce a new effective air filtration membrane that can be used for outdoor protection. The air filter's composite nanofibre materials were prepared from polyvinyl alcohol (PVA)-sodium lignosulfonate (LS) via a "green" electrospinning method and thermal crosslinking. The addition of LS helped increase the PM2.5 removal efficiency compared to that of a pure PVA nanofibre membrane. The pressure drops of the electrospun PVA-LS membranes exceeded those of the pristine PVA air filter. The remarkable air filtration performance was maintained even after 10 cycles of circulation filtration. In addition, the PVA-LS composite nanofibre membrane exhibited excellent mechanical properties and transparency due to the introduction of LS. This study provides new insight into the design and development of high-performance and high-visibility green filter media, which include personal protection and building screens.


Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells.
High mobility group protein A2 (HMGA2) is an architectural transcription factor that plays an important role in development and progression of malignant neoplasias. Recently, some studies reported that HMGA2 is also implicated in epithelial-mesenchymal transitions (EMT) and cancer stem cells. But the underlying mechanisms of these conditions are poorly understood. Therefore, we established an EMT model of gastric carcinoma cells by overexpressing HMGA2 in vitro, then global mapping of HMGA2 potential transcription factor binding sites was identified by promoter microarray in these cells, and the date obtained from the microarrays were validated via chromatin immunoprecipitation-PCR (ChIP-PCR) and real-time PCR. HMGA2 potential target genes were classified in KEGG database and Gene Ontology (GO) analyses. To our knowledge, this is the first report on the genome-wide analysis of HMGA2 downstream direct targets, and these findings will be valuable in understanding the roles of HMGA2 in EMT.


Clinical efficacy and safety of bone cement combined with radiofrequency ablation in the treatment of spinal metastases.
To investigate the clinical efficacy and safety of bone cement combined with radiofrequency ablation (RFA) in the treatment of spinal metastases. The medical records of patients with spinal metastatic tumor admitted to our hospital from January 2016 to December 2018 were retrospectively analyzed. Based on different surgical methods, the patients were divided into groups A (treated with RFA combined with bone cement) and B (treated with bone cement only). Group A included 35 patients with 47 segments of diseased vertebral bodies. Group B consisted of 52 patients with 78 vertebral segments. Pain, quality of life score, vertebra height, bone cement leakage, postoperative tumor recurrence, and complications were assessed 3 days and 1 and 6 months after surgery. All the patients had smooth operation without paraplegia, spinal cord injury, and perioperative death. Visual analogue scales (VAS) and Oswestry Disability Index (ODI) scores of the two groups significantly improved 3 days and 1 month after surgery compared with those before surgery (P < 0.05), but no significant difference was observed between the two groups (P > 0.05). Six months after surgery, the VAS and ODI scores of patients in group A were lower than those in group B, with statistically significant differences (P < 0.05). The postoperative vertebral body height of the two groups significantly increased compared with that before surgery, and the difference was statistically significant (P < 0.05). Meanwhile, no significant difference was observed between the two groups (P > 0.05). Postoperative bone cement permeability in group A was 6.4%, and postoperative tumor recurrence rate was 11.4%. The permeability of bone cement in group B was 20.5%, and the tumor recurrence rate was 30.8%. The bone cement permeability and tumor recurrence rate in group A were lower than those in group B, with statistically significant differences (P < 0.05). Bone cement combined with RFA for the treatment of spinal metastases can achieve good efficacy, desirable analgesic effect, low incidence of complications, small surgical trauma, and high safety. The proposed method has the value of clinical popularization and application.


MRI-based Radiomics Model for Preoperative Prediction of Lateral Pelvic Lymph Node Metastasis in Locally Advanced Rectal Cancer.
To develop a magnetic resonance imaging (MRI)-based radiomics model for preoperative prediction of lateral pelvic lymph node (LPLN) metastasis (LPLNM) in patients with locally advanced rectal cancer MATERIALS AND METHODS: We retrospectively enrolled 263 patients with rectal cancer who underwent total mesorectal excision and LPLN dissection. Radiomics features from the primary lesion and LPLNs on baseline MRI images were utilized to construct a radiomics model, and their radiomics scores were combined to develop a radiomics scoring system. A clinical prediction model was developed using logistic regression. A hybrid predicting model was created through multivariable logistic regression analysis, integrating the radiomics score with significant clinical risk factors (baseline Carcinoembryonic Antigen (CEA), clinical circumferential resection margin status, and the short axis diameter of LPLN). This hybrid model was presented with a hybrid clinical-radiomics nomogram, and its calibration, discrimination, and clinical usefulness were assessed. A total of 148 patients were included in the analysis and randomly divided into a training cohort (n = 104) and an independent internal testing cohort (n = 44). The hybrid clinical-radiomics model exhibited the highest discrimination, with an area under the receiver operating characteristic (AUC) of 0.843 [95% confidence interval (CI), 0.706-0.968] in the testing cohort compared to the clinical model [AUC (95% CI) = 0.772 (0.589-0.856)] and radiomics model [AUC (95% CI) = 0.731 (0.613-0.849)]. The hybrid prediction model also demonstrated good calibration, and decision curve analysis confirmed its clinical usefulness. This study developed a hybrid MRI-based radiomics model that incorporates a combination of radiomics score and significant clinical risk factors. The proposed model holds promise for individualized preoperative prediction of LPLNM in patients with locally advanced rectal cancer. The data presented in this study are available on request from the corresponding author.


Nasopharyngeal angiofibroma. surgical approach using a transoral Le Fort I osteotomy following embolization: a case report.
Nasopharyngeal angiofibroma (NA) is a rare vascular benign nonencapsulated neoplasm, characterized by local aggressiveness and destructive potential, typically diagnosed in adolescent males. We report a case of NA affecting a 15-year-old male that presented with a persistent nasal obstruction and epistaxis with 1 year of evolution. Clinical and radiological patterns pointed out a differential diagnosis of NA. Arteriography demonstrates the vascular support of the tumor and evinces the embolization of the internal maxillary artery. The surgical approach was procedure by Le Fort I osteotomy exposing the tumor and promoting easy access for posterior removal. The surgery was carried out without hemorrhagic problems. The maxilla was fixed in the original position with 4 L-shape plaques. Histopathological findings supported the diagnosis of NA. The patient presented after 8 months of postoperative follow-up, without clinical signs of recurrence or residual tumor and without palatal or maxillary teeth paresthesia.


Intraoral Hodgkin's disease.
An 85-year-old woman presented with an intraoral lesion involving the edentulous soft tissue of the mandibular alveolar crest between the first premolar and first molar teeth. Diagnosis was made with the aid of a biopsy. The gallium scan and CT scan were used successfully for noninvasive staging. However, initial treatment was delayed due to the patient's wishes, overall poor health, and decreased tolerance to both radiation and chemotherapy. This resulted in spread of the disease leading to her death.


The androgen receptor is a therapeutic target in desmoplastic small round cell sarcoma.
Desmoplastic small round cell tumor (DSRCT) is an aggressive, usually incurable sarcoma subtype that predominantly occurs in post-pubertal young males. Recent evidence suggests that the androgen receptor (AR) can promote tumor progression in DSRCTs. However, the mechanism of AR-induced oncogenic stimulation remains undetermined. Herein, we demonstrate that enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) block 5α-dihydrotestosterone (DHT)-induced DSRCT cell proliferation and reduce xenograft tumor burden. Gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to elucidate how AR signaling regulates cellular epigenetic programs. Remarkably, ChIP-seq revealed novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators, including WT1 (the C-terminal partner of the pathognomonic fusion protein) and FOXF1. Additionally, AR occupied enhancer sites that regulate the Wnt pathway, neural differentiation, and embryonic organ development, implicating AR in dysfunctional cell lineage commitment. Our findings have direct clinical implications given the widespread availability of FDA-approved androgen-targeted agents used for prostate cancer.


Randomized, double-blind trial of CO2 versus air insufflation in children undergoing colonoscopy.
Studies in adults have shown that postprocedural abdominal pain is reduced with the use of carbon dioxide (CO(2)) instead of air for insufflation during colonoscopy. The aim of our study was to compare postprocedural abdominal pain and girth in children undergoing colonoscopy using CO(2) or air for insufflation. This was a prospective, randomized, double-blind study that included 76 consecutive pediatric patients undergoing colonoscopy for various indications. Patients were randomly assigned to either CO(2) or air insufflation. At 2, 4, and 24 hours after the examination, the patients' pain was assessed by using the 11-point numerical rating scale. The waist circumference was measured 10 minutes and 2 and 4 hours after colonoscopy. A significantly higher proportion of patients had no pain after colonoscopy in the CO(2) group compared with the air group (82 vs 37% at 2 hours and 95% vs. 63% at 4 hours, P < .001). Mean abdominal pain scores 2 and 4 hours after the procedure were statistically significantly lower in the CO(2) group compared with the control air group (0.5 vs 2.6 at 2 hours and 0.1 vs 1.2 at 4 hours, P < .001). There was no difference in waist circumference between the 2 groups at all time intervals. The results of this randomized trial show clear benefits of CO(2) insufflation for colonoscopy in reducing postprocedural discomfort. ( NCT02407639.).


Expression of human interferon alpha-1 with enhanced stability via the tagging system of a stabilizing peptide.
Human interferon alpha-1 (hIFNA1) is one of several interferon alpha subtypes that have been studied and commercialized to treat various viral diseases including hepatitis B and C as well as malignant melanoma. Protein aggregation has been problematic for every step in commercial production, from purification to the packaging and delivery of pharmaceutical proteins. In a previous study, we demonstrated that a stabilizing peptide from the C-terminal acidic tail of alpha-synuclein (ATS) could be used as an effective fusion tag to increase the stability of target proteins such as human growth hormone (hGH) and granulocyte colony-stimulating factor (G-CSF). In this study, we applied this ATS fusion system to hIFNA1 in order to protect against the aggregation of hIFNA1 by environmental stresses, since hIFNA1 aggregates elicit an undesirable immune response in humans. As expected, ATS-fused hIFNA1 (hIFNA1-ATS) protein showed enhanced stability against thermal stress, agitation stress, and repetitive freeze/thawing stress in comparison with native hIFNA1. More importantly, hIFNA1-ATS fusion protein appeared to be 1.6 times more active than hIFNA1 in a cell anti-proliferation assay. Furthermore, the solubility of hIFNA1-ATS appeared to be 1.7 times higher than that of native protein. Our results suggest that the ATS-tag system could be a useful means for protecting hIFNA1 protein from aggregation by various external stresses and could be used to increase the solubility of protein.


Back-priming of the RCM1 leucocyte-reduction filter: consequences for filtration efficacy.
The RCM1 leucocyte-reduction filter has been incorporated into two types of blood-donation sets of which one uses back-priming of the leucocyte filter with SAG-M solution. In this study we have compared the leucocyte-reduction efficacy of the RCM1 filter with or without back priming with SAG-M solution. This study was a retrospective analysis of quality control data of 3529 leucocyte-filtered red cell units. Of these, 1002 whole-blood units were collected in a donation set that was back-primed by letting the SAG-M solution in the final storage bag run backwards through the filter into the bag of concentrated red cells. The remaining 2527 units were collected in a donation set that required no back-priming. Postfiltration leucocyte concentration was assessed using flow cytometry. There was a significant trend towards lower leucocyte concentration in the units in which back-priming of the filter preceded filtration, as compared to units filtered without back-priming [chi2trend= 18.8, degrees of freedom (d.f.) = 1, P < 0.0005]. Back-priming of the RCM1 filter for red cells with SAG-M solution is superior to no back-priming with regard to leucocyte-reduction efficacy.


StemTextSearch: Stem cell gene database with evidence from abstracts.
Previous studies have used many methods to find biomarkers in stem cells, including text mining, experimental data and image storage. However, no text-mining methods have yet been developed which can identify whether a gene plays a positive or negative role in stem cells. StemTextSearch identifies the role of a gene in stem cells by using a text-mining method to find combinations of gene regulation, stem-cell regulation and cell processes in the same sentences of biomedical abstracts. The dataset includes 5797 genes, with 1534 genes having positive roles in stem cells, 1335 genes having negative roles, 1654 genes with both positive and negative roles, and 1274 with an uncertain role. The precision of gene role in StemTextSearch is 0.66, and the recall is 0.78. StemTextSearch is a web-based engine with queries that specify (i) gene, (ii) category of stem cell, (iii) gene role, (iv) gene regulation, (v) cell process, (vi) stem-cell regulation, and (vii) species. StemTextSearch is available through http://bio.yungyun.com.tw/StemTextSearch.aspx.


Home parenteral nutrition in children: bioavailability of vitamins in binary mixtures stored for 8 days.
Vitamin supply in children on long-term parenteral nutrition depends on the specific age-related needs and on the bioavailability of vitamins when introduced into nutritional bags. The present study aimed to investigate the vitamin status in children on home TPN receiving nutritional bags which had been stored during a prolonged period of 8 instead of 4 days and where the new vitamin preparation Cernevit has been introduced. 19 children aged from 5 months to 11 years receiving home parenteral nutrition, for 42 months on average, were studied. Daily vitamin supply for children above 2 years of age was: A 1050 ug, D 5.5 ug, E 10.2 mg plus 0.6 mg/g lipid (Intralipid), C 125 mg, B1 3.5 mg, B2 4.1 mg, B6 4.5 mg, biotine 69 mug; children who were younger than 2 years received half of these intakes. Water soluble vitamin status was only measured in children over 3 years old. Plasma levels remained stable and adequate for age, for most of the studied vitamins. Vitamin A concentration was inferior to 200 mug/l in 1 patient with hepatopathy. Plasma concentrations of vitamin E, which were initially below 6 mg/l in 4 patients, returned to normal during the study. Plasma levels of vitamin C were below 6.2 mg/l in several infants either temporarily (5 patients) or during the whole study period (2 patients). These results support a prolongation of the intervals between preparing batches of nutritional bags and also between deliveries. This results in a considerable reduction of costs, provided that plasma vitamin levels, specially vitamin C, are regularly monitored.


Headspace volatiles of marihuana and hashish: gas chromatographic analysis of samples of different geographic origin.
The sweet odor of marihuana is of interest for instrumental monitoring of illicit drug traffic and for applications in forensic work. Headspace volatiles of marihuana and hashish of different origin are examined by gas chromatography, and relative compositions of 24 samples are compared. No correlation between volatile make up and geography was found, but the profiling procedures are shown to be of use in the forensic problem of relating samples to a common source.


Purification and characterization of a 50,000 mol. wt glycoprotein antigen, and localization of determinants involved in cross-reactivity with carcinoembryonic antigen.
A 50,000 mol. wt glycoprotein antigen (50 k) was purified from metastatic colon tumor. The initial purification was monitored by cross-reactivity of the antigen with an unabsorbed antiserum against carcinoembryonic antigen (CEA, Mr 180,000). Six mg of antigen was obtained from 250 g of tissue, with a recovery of 14% and a relative purification of 143-fold. The amino acid composition of 50 k was similar to that of CEA. The carbohydrate content, primarily glucosamine and mannose, totaled about 25%. Immunodiffusion showed that 50 k lacked some of the CEA epitopes, and that normal spleen contained an antigen identical to 50 k. Radioimmunoassays showed that the high avidity anti-CEA antibodies in the unabsorbed antiserum were mainly cross-reactive with 50 k, probably via a similar but not identical antigenic site. The immunochemical properties of 50 k thus correspond to those of the non-specific cross-reacting antigen (NCA). The molecular size and carbohydrate composition reported for various NCA-like antigens have differed, so identity of 50 k an NCA cannot be established on this basis. Immunoreactive fragments of 50 k were prepared by digestion with each of three different proteolytic enzymes, and were purified by high performance liquid chromatography (HPLC). A polypeptide of 20,000-30,000 mol. wt containing about half of the 50 k determinants, was recovered in each case. Experiments with mixtures showed that the three purified fragments all contained the same subset of antigenic determinants. The fragment-localized subset represented most, if not all of the 50 k determinants involved in CEA cross-reactivity. Similarly, a CEA fragment was shown to contain essentially all of the CEA determinants involved in 50 k cross-reactivity. The fragments of 50 k and CEA were quite resistant to further proteolytic digestion, and comparison of a CEA fragment with a 50 k fragment by partial acid hydrolysis and HPLC peptide mapping failed to reveal structural homology to account for the cross-reactivity.