Influence of full-contour zirconia surface roughness on wear of glass-ceramics.
The purpose of this study was to evaluate the influence of full-contour (Y-TZP) zirconia surface roughness (glazed vs. as-machined) on the wear behavior of glass-ceramics. Thirty-two full contour Y-TZP (Diazir®) specimens (hereafter referred to as zirconia sliders) (ϕ = 2 mm, 1.5 mm in height) were fabricated using CAD/CAM and sintered according to the manufacturer's instructions. Zirconia sliders were embedded in brass holders using acrylic resin and then randomly assigned (n = 16) according to the surface treatment received, that is, as-machined or glazed. Glass-ceramic antagonists, Empress/EMP and e.max/EX, were cut into tabs (13 × 13 × 2 mm(3) ), wet-finished, and similarly embedded in brass holders. Two-body pin-on-disk wear testing was performed at 1.2 Hz for 25,000 cycles under a 3 kg load. Noncontact profilometry was used to measure antagonist height (μm) and volume loss (mm(3) ). Qualitative data of the zirconia testing surfaces and wear tracks were obtained using SEM. Statistics were performed using ANOVA with a significance level of 0.05. As-machined yielded significantly higher mean roughness values (Ra = 0.83 μm, Rq = 1.09 μm) than glazed zirconia (Ra = 0.53 μm, Rq = 0.78 μm). Regarding glass-ceramic antagonist loss, as-machined zirconia caused significantly less mean height and volume loss (68.4 μm, 7.6 mm(3) ) for EMP than the glazed group (84.9 μm, 9.9 mm(3) ), while no significant differences were found for EX. Moreover, EMP showed significantly lower mean height and volume loss than EX (p < 0.0001). SEM revealed differences on wear characteristics between the glass-ceramics tested. e.max wear was not affected by zirconia surface roughness; however, Empress wear was greater when opposing glazed zirconia. Overall, surface glazing on full-contour zirconia did not minimize glass-ceramic wear when compared with as-machined zirconia.


Utilization of L-methionine sulfoxide, L-methionine sulfone and cysteic acid by the weanling rat.
Three experiments were conducted to test the ability of weanling rats to utilize the oxidized forms of the sulfur amino acids methionine and cysteine for growth. In the first two experiments, diets were fed which contained graded levels of methionine, methionine sulfoxide and methionine sulfone. The third experiment included a comparison of two dietary levels of cysteine and cysteic acid. The 2 week weight gain and food consumption data indicated that methionine sulfoxide was utilized for growth with only 60% of the efficiency of that achieved by rats fed methionine. Methionine sulfone was not utilized for growth. Analysis of plasma sulfur amino acids showed that the rat has a limited capacity to utilize methionine sulfoxide by effecting its reduction to methionine. Cysteic acid did not support weight gain. This amino acid appeared to be rapidly catabolized to taurine. It was concluded that methionine sulfone and cysteic acid cannot be utilized by the weanling rat. Methionine sulfoxide cannot fully meet the dietary requirement of the rat methionine because of its limited capacity to reduce this amino acid.


Variations in microbial assemblage between rhizosphere and root endosphere microbiomes contribute to host plant growth under cadmium stress.
In this study, we revealed that the variation in rhizosphere and root endosphere microbial assemblage between host plant ecotypes contribute to their differential abilities to withstand cadmium (Cd) stressors. Furthermore, our study found that phenolic compounds, such as benzenoids and flavonoids, could function as both essential carbon sources and semiochemicals, thereby contributing to the assemblage of rhizosphere microbiome to resist Cd stress. Our findings provide new insights into the mechanisms that drive the differential assemblage of rhizosphere and root endosphere microbiomes to enhance plant growth under abiotic stress.


A cost-utility analysis of the use of preoperative computed tomographic angiography in abdomen-based perforator flap breast reconstruction.
Computed tomographic angiography is a diagnostic tool increasingly used for preoperative vascular mapping in abdomen-based perforator flap breast reconstruction. This study compared the use of computed tomographic angiography and the conventional practice of Doppler ultrasonography only in postmastectomy reconstruction using a cost-utility model. Following a comprehensive literature review, a decision analytic model was created using the three most clinically relevant health outcomes in free autologous breast reconstruction with computed tomographic angiography versus Doppler ultrasonography only. Cost and utility estimates for each health outcome were used to derive the quality-adjusted life-years and incremental cost-utility ratio. One-way sensitivity analysis was performed to scrutinize the robustness of the authors' results. Six studies and 782 patients were identified. Cost-utility analysis revealed a baseline cost savings of $3179, a gain in quality-adjusted life-years of 0.25. This yielded an incremental cost-utility ratio of -$12,716, implying a dominant choice favoring preoperative computed tomographic angiography. Sensitivity analysis revealed that computed tomographic angiography was costlier when the operative time difference between the two techniques was less than 21.3 minutes. However, the clinical advantage of computed tomographic angiography over Doppler ultrasonography only showed that computed tomographic angiography would still remain the cost-effective option even if it offered no additional operating time advantage. The authors' results show that computed tomographic angiography is a cost-effective technology for identifying lower abdominal perforators for autologous breast reconstruction. Although the perfect study would be a randomized controlled trial of the two approaches with true cost accrual, the authors' results represent the best available evidence.


Sugar "allergy" and children's behavior.
Sixteen children whose behavior was said to become aggressive, overly active, loud, and noncompliant when ingesting sugar were tested. Sugar-free home diet was maintained and an "open" challenge to a large dose (3 g/kg) of candy bar sucrose was given. Subsequent behavior was noted by actometer, quantitative playroom observation using several standard behavioral tests, and ability to do maze drawings. No significant changes were found on the open challenge test. A slight change from baseline was noted in seven cases on three or four behavioral parameters. Five of these children agreed to a double-blind challenge test utilizing lemon-flavored slushes of sucrose, honey, tapioca starch, or aspartame, administered after a standard lunch free of sucrose. One child reacted to both sucrose and honey and another child reacted only to sucrose. These two children were challenged a second time. The child who reacted to honey again did so according to actometer readings, but this time not by Stony Brook test. To sugar, he reacted only at the 70-minute Stony Brook. The other child reacted to placebo instead of sucrose when rechallenged. The results indicate that high doses of sugar are not related to abnormal behavior. "Open" challenge was sufficient to rule out such a relationship in most instances. A repeated double-blind challenge confirmed the absence of a sugar effect in cases showing initial possibility of response.


Mitigated calcification of glutaraldehyde-fixed bovine pericardium by tannic acid in rats.
Bioprosthetic heart valves derived from glutaraldehyde (Glut)-fixed xenografts have been widely used to replace diseased cardiac valves. However, calcification and degeneration are common following their implantation. Inflammation is closely associated with calcification of Glut-fixed xenografts via macrophage infiltration. Tannic acid (TA) possesses anti-inflammatory effects. This study was designed to investigate the anti-calcification of TA treatment on the Glut-fixed bovine pericardium (BP) in a rat subdermal model. Fresh BP was divided into two groups (10 in each group) and separately subjected to different fixation procedures as follows: (1) Glut group: fixation with 0.6% Glut alone; (2) Glut/TA group: fixation with 0.6% Glut and subsequent 0.3% TA. Then the BP samples were subdermally implanted in juvenile male Sprague-Dawley rats and explanted 21 days after implantation. Each explanted BP sample was divided into three parts for calcium content analysis, von Kossa's staining and immunohistochemical staining, and reverse transcription-polymerase chain reaction study. The data from quantitative calcium analysis and von Kossa's staining showed that Glut-fixed BP developed significantly more calcification than Glut/TA-fixed BP ((90.3 +/- 32.5) mg/g dry weight vs (6.4 +/- 1.3) mg/g dry tissue, P < 0.01). Immunostaining demonstrated lower matrix metalloproteinase-9 and tenascin-C expression as well as macrophage infiltration into Glut/TA-fixed BP than in its Glut-fixed counterpart (P < 0.01 for all). Additionally, the reverse transcription-polymerase chain reaction study showed that higher levels of expression of matrix metalloproteinase-9 and tenascin-C mRNA occurred within Glut-fixed BP than within the Glut/TA-fixed ones (P < 0.01 for all). TA exerts excellent anti-calcification effects on Glut-fixed BP via inhibiting macrophage infiltration and expression of matrix metalloproteinase-9 and tenascin-C.


The Role of MicroRNAs in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is one of the most common cancers, leading to the second cancer-related death in the global. Although the treatment of HCC has greatly improved over the past few decades, the survival rate of patients is still quite low. Thus, it is urgent to explore new therapies, especially seek for more accurate biomarkers for early diagnosis, treatment and prognosis in HCC. MicroRNAs (miRNAs), small noncoding RNAs, are pivotal participants and regulators in the development and progression of HCC. Great progress has been made in the studies of miRNAs in HCC. The key regulatory mechanisms of miRNAs include proliferation, apoptosis, invasion, metastasis, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance and autophagy in HCC. And exosomal miRNAs also play important roles in proliferation, invasion, metastasis, and drug resistance in HCC by regulating gene expression in the target cells. In addition, some miRNAs, including exosomal miRNAs, can be as potential diagnostic and prediction markers in HCC. This review summarizes the latest researches development of miRNAs in HCC in recent years.


Identification and profiling of conserved and novel microRNAs in Laodelphax striatellus in response to rice black-streaked dwarf virus (RBSDV) infection.
MicroRNAs (miRNAs) are small non-coding endogenous RNA molecules that play important roles in various biological processes. This study examined microRNA profiles of Laodelphax striatellus using the small RNA libraries derived from virus free (VF) and rice black-streaked dwarf virus (RBSDV) infected (RB) insects. A total of 59 mature miRNAs (46 miRNA families) were identified as conserved insect miRNAs in both VF and RB libraries. Among these conserved miRNAs, 24 were derived from the two arms of 12 miRNA precursors. Nine conserved L. striatellus miRNAs were up-regulated and 12 were down-regulated in response to RBSDV infection. In addition, a total of 20 potential novel miRNA candidates were predicted in the VF and RB libraries. The miRNA transcriptome profiles and the identification of L. striatellus miRNAs differentially expressed in response to RBSDV infection will contribute to future studies to elucidate the complex miRNA-mediated regulatory network activated by pathogen challenge in insect vectors.


Transductional mapping of gene trmA responsible for the production of 5-methyluridine in transfer ribonucleic acid of Escherichia coli.
The gene trmA, responsible for the production of 5-methyluridine (ribothymidine) in transfer ribonucleic acid, has been located at 79 min on the chromosomal map of Escherichia coli K-12. In five-factor crosses the gene order was shown to be argH-trmA-rif-thiA-metA. The co-transduction frequency between argH and trmA was 65%. Furthermore, the trmA5 mutation was shown to be recessive, in agreement with the notion that the trmA gene is the structural gene for the transfer tibonucleic acid (5-methyluridine) methyltransferase.


Vitamin and mineral supplements: barriers and challenges for older adults.
Older adults are particularly vulnerable to deficiencies of calcium, vitamin D, and vitamin B12. Despite the availability of fortified foods in the United States, intakes of these nutrients among the elderly remain inadequate. Dietary supplements may be a convenient way to improve nutritional status within this population group. This article provides practical and evidence-based recommendations regarding the use of single vitamin/mineral and multivitamin/mineral (MVM) supplements in older adults and provides details on calcium and vitamin D, B12, E, and K. Some single-nutrient supplements have shown benefits for preventing or reducing risks for chronic diseases. Although MVM supplements have not been shown to prevent several major chronic diseases, they do substantially increase vitamin and mineral intakes and blood concentrations, thus improving overall micronutrient status. Older adults who use MVM and/or vitamin/mineral supplements to foster better nutritional and health status should read labels carefully and consult their health care provider to ensure appropriate dietary supplement use.


Progression from conduct disorder to antisocial personality disorder following treatment for adolescent substance abuse.
This study investigated the progression from conduct disorder to antisocial personality disorder among individuals treated for adolescent substance abuse. This issue is important because of the poor outcomes observed among individuals with antisocial pathology after treatment for alcohol and drug problems. The utility of factors assessed at the time of treatment in predicting progression to adult antisocial personality disorder was evaluated in the context of developmental models of antisocial behavior. This was a prospective longitudinal study of 137 substance-abusing adolescents (53 female and 84 male), whose average age was 15.9 years and who met the DSM-III-R criteria for conduct disorder. Consecutively admitted patients were recruited from two adolescent inpatient alcohol and drug treatment facilities. Participants were interviewed again 4 years after treatment. Four years after treatment, 61% of the study group met the DSM-III-R criteria for antisocial personality disorder. Results of a logistic regression analysis indicated that onset of deviant behavior at or before age 10, a greater diversity of deviant behavior, and more extensive pre-treatment drug use best predicted progression to antisocial personality disorder. At 4-year follow-up, the subjects with an antisocial personality disorder diagnosis exhibited more involvement with alcohol and drugs and poorer functioning across important life domains than the subjects without antisocial personality disorder. This study found a high rate of progression to antisocial personality disorder among substance-abusing adolescents and identified factors predictive of this progression. Careful assessment of conduct disorder history at the time of treatment may be valuable for treatment planning and intervention.


Visual Remapping.
Our visual system is fundamentally retinotopic. When viewing a stable scene, each eye movement shifts object features and locations on the retina. Thus, sensory representations must be updated, or remapped, across saccades to align presaccadic and postsaccadic inputs. The earliest remapping studies focused on anticipatory, presaccadic shifts of neuronal spatial receptive fields. Over time, it has become clear that there are multiple forms of remapping and that different forms of remapping may be mediated by different neural mechanisms. This review attempts to organize the various forms of remapping into a functional taxonomy based on experimental data and ongoing debates about forward versus convergent remapping, presaccadic versus postsaccadic remapping, and spatial versus attentional remapping. We integrate findings from primate neurophysiological, human neuroimaging and behavioral, and computational modeling studies. We conclude by discussing persistent open questions related to remapping, with specific attention to binding of spatial and featural information during remapping and speculations about remapping's functional significance.


The effect of chronic hypocholesterolemia in myeloproliferative disease on the distribution of plasma and erythrocyte tocopherol.
The presence of hypocholesterolemia and increased erythrocyte lipid peroxidation susceptibility in myeloproliferative disorders raised the possibility of coexistent tocopherol deficiency. Plasma and red blood cell (RBC) alpha-tocopherol, beta- + gamma-tocopherol, and free cholesterol were determined simultaneously by high performance liquid chromatography in 22 patients and 26 controls. Plasma alpha-tocopherol was correlated most highly with plasma free cholesterol and secondarily with RBC alpha-tocopherol in both groups. Plasma-free cholesterol and alpha-tocopherol were significantly reduced in myeloproliferative disease, although the ratio between the two remained normal. Erythrocyte tocopherol and free cholesterol concentrations were normal in myeloproliferative disease. High relative retention of tocopherol by erythrocytes was most pronounced in patients with the lowest plasma alpha-tocopherol and free cholesterol levels. The normal RBC tocopherol levels in these patients with chronic hypocholesterolemia indicate that the observed increase in RBC peroxidation susceptibility is not explainable by a deficiency of RBC vitamin E.


Beta-2-microglobulin adsorption and release in-vitro: influence of membrane material, osmolality and heparin.
We studied the effects of cuprammonium rayon (CR), polyacrylonitrile (PAN), polysulfone (PS), changes in osmolality, and heparin dosage on beta-2-microglobulin (b2M) handling in an in-vitro model that excluded convective transport and minimized diffusive transport. Both PAN and PS exhibited high adsorption capacity for b2M. Osmolality changes had no effect on b2M adsorption or release. CR membrane adsorption was minimal but increased slightly when higher heparin doses were used. In experiments with CR and high heparin doses (4 U/ml) b2M release occurred during the first 15 minutes of in-vitro dialysis, but this increase was inhibited by removing the leukocytes from the blood, indicating that b2M is released from leukocytes.


Sequence similarity of human caliciviruses and small round structured viruses.
The application of reverse transcription-polymerase chain reaction (RT-PCR) using primers directed to the RNA dependent RNA polymerase region within ORF1 of Norwalk virus (NV) showed that 31 percent of morphologically typical human caliciviruses (HuCV) and 57% of small round structured viruses (SRSVs) produced a product of 470 bp similar to the NV control, NV 8FIIa/68/US. Alignment of the amino acid sequences of morphologically typical HuCVs with previously published sequences for SRSVs, NV, and Snow Mountain agent (SMA) showed a high degree of homology (90-92%) with SMA and a lesser extent of homology with NV (60-61%). The amino acid sequence of two strains of HuCV, HuCV/3C/92/UK, and HuCV/5C/92/UK differed by only one or two amino acids respectively in the RNA dependent RNA polymerase region from that of two strains of SRSV obtained from children in the United Kingdom, SRSV/4S/90/UK and Japan, SRSV/OTH-25/89/J which were found to have identical amino acid sequences. The use of an EIA for detection of NV antigen employing antisera raised to recombinant NV protein indicated that HuCVs and SRSVs obtained from children and adults in the United Kingdom were antigenically distinct from the prototype Norwalk virus, NV/8fIIa/68/US.


Association Between Visual Function Response and Reduction of Inflammation in Noninfectious Uveitis of the Posterior Segment.
To examine the association between visual function response (VFR) and inflammation reduction in active noninfectious uveitis of the posterior segment (NIU-PS). Phase 3 SAKURA Study 1 randomized 347 subjects in a double-masked fashion to receive injections of intravitreal sirolimus 44 μg (n = 117); 440 μg (n = 114); or 880 μg (n = 116) every other month. Vitreous haze (VH) response, a measure of inflammation reduction, was defined as a VH score of 0 or 0.5+ at month 5 based on the modified Standardized Uveitis Nomenclature Scale. Visual function was assessed with best-corrected visual acuity (BCVA) and the National Eye Institute (NEI) Visual Function Questionnaire-25 (VFQ-25). In this post-hoc analysis, principal component analysis was used to reduce the information in the multidimensional visual function outcome to a restricted number of independently relevant VFR measures. Minimal clinically important differences (MCID) for the VFQ-25-derived components were based on the standard error of measurements. Overall VFR was defined as either a BCVA improvement of ≥2 lines, or an improvement exceeding the MCID in the VFQ-25 based visual function measures. The VFQ-25 composite score (VFQCS) and mental health subscale score (VFQMHS) were retained as relevant VFRs, with MCIDs of 4.3 and 11.7 points, respectively. A vitreous haze response was significantly associated with each VFR measure: VFQCS (odds ratio [OR] = 2.23; P = 0.0004); VFQMHS (OR = 2.84; P < 0.0001); BCVA (OR = 2.60; P = 0.0009), and overall VFR (OR = 2.65; P < 0.0001). Inflammation reduction to a VH score of 0 or 0.5+ was significantly associated with improved visual function. Achieving a VH response of 0 or 0.5+ is a patient-relevant outcome.


The Immediate Effect of Trigger Point Injection With Local Anesthetic Affects the Subsequent Course of Pain in Myofascial Pain Syndrome in Patients With Incurable Cancer by Setting Expectations as a Mediator.
A trigger point injection (TPI) with local anesthetic in myofascial pain syndrome (MPS) often has the immediate effect of a decrease in pain. It is unknown whether the immediate effect of a decrease in pain affects the subsequent course of pain. It is also unknown whether expectations of a decrease in pain mediate such effects. We aimed to clarify how the effect of a decrease in pain immediately after TPI with local anesthetic affected the subsequent course of pain, and whether it increased expectations of a decrease in pain. This was a prospective, single-center, observational clinical trial. Patients with incurable cancer who visited the palliative care department and received TPI with local anesthetic for MPS were prospectively examined. We evaluated whether the immediate effect of a TPI with local anesthetic affects the subsequent course of pain in MPS by setting expectations as a mediator, using path analysis. From 2018 to 2020, 205 patients with incurable cancer received TPI for MPS. Of these, 58.1% of patients reported an immediate effect of decreased pain. Compared with the non-immediate effect group, the immediate effect group had higher expectations of a decrease in pain, and the higher expectation was maintained at 7 days (p < 0.001). The percentage of patients with pain reduction at 7 days after TPI was 88.2% in the immediate effect group and 39.5% in the non-immediate effect group (p < 0.001). The immediate effect of decreased pain had the greatest influence on pain reduction at 7 days, both directly (β = 0.194) and indirectly through increased expectations (β = 0.293), as revealed by path analysis. The effect of a decrease in pain immediately after TPI with local anesthetic affected the subsequent course of MPS pain in patients with incurable cancer by setting expectations as a mediator. There were limitations to the discussion of these findings because this was an observational study.


Correlation between suppression of c-myc and antiproliferative effect of transforming growth factor-beta 1 in thyroid carcinoma cell growth.
The growth regulatory activity of transforming growth factor-beta 1 (TGF beta 1) was studied in a clonal strain of thyroid papillary carcinoma cell (NPA). Despite the presence of TGF beta 1 and its receptor messenger RNA in thyroid carcinoma, the molecular mechanism of TGF beta 1 action on cell growth of thyroid carcinoma has not yet been elucidated. Exogenously added TGF beta 1 inhibited DNA synthesis and cell growth in a dose- and time-dependent manner at concentrations of 0.1-10 ng/ml. TGF beta 1 inhibited not only basal but also fetal bovine serum-stimulated cell proliferation. Steady state levels of c-myc messenger RNA transcripts were inhibited by TGF beta 1 after 0.5-h treatment. Antisense, but not sense, c-myc oligodeoxynucleotides also caused suppression of NPA cell growth in a dose-responsive manner. Transfection studies of the 5'-up-stream flanking region (UFR) of c-myc/chloramphenicol acetyltransferase chimera genes suggest the presence of a TGF beta 1-responsive DNA element in the 2.3-kilobase c-myc 5'-UFR. Deletion mutant studies indicate the element lies between -106 to 70 relative to the P1 transcription start site. Studies with the gel mobility shift assay using 23-basepair double strand DNA showed the presence of at least two nuclear factors in NPA cell. TGF beta 1 treatment did not cause any alteration in TGF beta 1-induced mobility; however, the reduction of a positive band was selectively observed during 30 min to 2 h after treatment with TGF beta 1. In contrast, the position and intensity of another band were not altered by TGF beta 1 treatment. These results demonstrate that the inhibition of a nuclear factor binding to the c-myc 5'-UFR and subsequent suppression of c-myc gene expression are directly involved in the antiproliferative action of TGF beta 1 in NPA cell growth.


Perioperative outcomes and adverse events of robotic colorectal resections for inflammatory bowel disease: a systematic literature review.
The purpose of this study was to assess outcome measures and cost-effectiveness of robotic colorectal resections in adult patients with inflammatory bowel disease. The Cochrane Library, PubMed/Medline and Embase databases were reviewed, using the text "robotic(s)" AND ("inflammatory bowel disease" OR "Crohn's" OR "Ulcerative Colitis"). Two investigators screened abstracts for eligibility. All English language full-text articles were reviewed for specified outcomes. Data were presented in a summarised and aggregate form, since the lack of higher-level evidence studies precluded meta-analysis. Primary outcomes included mortality and postoperative complications. Secondary outcomes included readmission rate, length of stay, conversion rate, procedure time, estimated blood loss and functional outcome. The tertiary outcome was cost-effectiveness. Eight studies (3 case-matched observational studies, 4 case series and 1 case report) met the inclusion criteria. There was no reported mortality. Overall, complications occurred in 81 patients (54%) including 30 (20%) Clavien-Dindo III-IV complications. Mean length of stay was 8.6 days. Eleven cases (7.3%) were converted to open. The mean robotic operating time was 99 min out of a mean total operating time of 298.6 min. Thirty-two patients (24.7%) were readmitted. Functional outcomes were comparable among robotic, laparoscopic and open approaches. Case-matched observational studies comparing robotic to laparoscopic surgery revealed a significantly longer procedure time; however, conversion, complication, length of stay and readmission rates were similar. The case-matched observational study comparing robotic to open surgery also revealed a longer procedure time and a higher readmission rate; postoperative complication rates and length of stay were similar. No studies compared cost-effectiveness between robotic and traditional approaches. Although robotic resections for inflammatory bowel disease are technically feasible, outcomes must be interpreted with caution due to low-quality studies.


Initiation of teeth from the dental lamina in the ferret.
Mammalian tooth development is characterized by formation of primary teeth that belong to different tooth classes and are later replaced by a single set of permanent teeth. The first primary teeth are initiated from the primary dental lamina, and the replacement teeth from the successional dental lamina at the lingual side of the primary teeth. An interdental lamina connects the primary tooth germs together. Most mammalian tooth development research is done on mouse, which does not have teeth in all tooth classes, does not replace its teeth, and does not develop an interdental lamina. We have used the ferret (Mustela putorius furo) as a model animal to elucidate the morphological changes and gene expression during the development of the interdental lamina and the initiation of primary teeth. In addition we have analyzed cell-cell signaling taking place in the interdental lamina as well as in the successional lamina during tooth replacement. By 3D reconstructions of serial histological sections we observed that the morphogenesis of the interdental lamina and the primary teeth are intimately linked. Expression of Pitx2 and Foxi3 in the interdental lamina indicates that it has odontogenic identity, and there is active signaling taking place in the interdental lamina. Bmp4 is coexpressed with the stem cell factor Sox2 at its lingual aspect suggesting that the interdental lamina may retain competence for tooth initiation. We show that when tooth replacement is initiated there is Wnt pathway activity in the budding successional lamina and adjacent mesenchyme but no active Fgf or Eda signaling. Genes associated with human tooth replacement phenotypes, including Runx2 and Il11rα, are mostly expressed in the mesenchyme around the successional lamina in the ferret. Our results highlight the importance of the dental lamina in the mammalian tooth development during the initiation of both primary and replacement teeth.


Systemic lupus erythematosus in pregnancy.
Systemic lupus erythematosus is an inflammatory autoimmune disease that can affect multiple organ systems. The most popular theory regarding the origin of its clinical manifestations is that autoantibodies and circulating immune complexes become trapped in the capillaries of visceral structures.


Direct Evidence for Active Suppression of Salient-but-Irrelevant Sensory Inputs.
Researchers have long debated whether attentional capture is purely stimulus driven or purely goal driven. In the current study, we tested a hybrid account, called the signal-suppression hypothesis, which posits that stimuli automatically produce a bottom-up salience signal, but that this signal can be suppressed via top-down control processes. To test this account, we used a new capture-probe paradigm in which participants searched for a target shape while ignoring an irrelevant color singleton. On occasional probe trials, letters were briefly presented inside the search shapes, and participants attempted to report these letters. Under conditions that promoted capture by the irrelevant singleton, accuracy was greater for the letter inside the singleton distractor than for letters inside nonsingleton distractors. However, when the conditions were changed to avoid capture by the singleton, accuracy for the letter inside the irrelevant singleton was reduced below the level observed for letters inside nonsingleton distractors, an indication of active suppression of processing at the singleton location.


[PRIMARY MEDIASTINAL GERM CELL TUMOR ARISING IN A PATIENT WITH NEUROFIBROMATOSIS TYPE 1].
Neurofibromatosis type 1 (NF1) is a distinct genetic disorder due to the NF1 gene mutation which induces the aberrant activation of the RAS-signaling. Because RAS-related proteins function as oncogenic factors, NF1 patients frequently develop malignant tumors, especially of neural crest origin, such as peripheral nerve sheath. In addition, malignant tumors of the pancreas, colorectum, and lung have been reported to frequently arise in NF1 patients. However, the association between germ cell tumor and NF1 has not been clarified yet. A 29-year-old male with dyspnea was referred to our hospital because of the large mass in the anterior mediastinum and cervical lymph node swelling. The diagnosis was extragonadal germ cell tumor with cervical lymph node metastasis, and complete remission was obtained by multidisciplinary treatment consisted of combination chemotherapy and surgical resection. To our acknowledgement, this is the first case of extragonadal germ cell tumor in NF1 patients. We discuss the relevance between activation of the RAS-signaling and the development of germ cell tumor.


Proteomics analysis reveals a dynamic diurnal pattern of photosynthesis-related pathways in maize leaves.
Plant leaves exhibit differentiated patterns of photosynthesis rates under diurnal light regulation. Maize leaves show a single-peak pattern without photoinhibition at midday when the light intensity is maximized. This mechanism contributes to highly efficient photosynthesis in maize leaves. To understand the molecular basis of this process, an isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomics analysis was performed to reveal the dynamic pattern of proteins related to photosynthetic reactions. Steady, single-peak and double-peak protein expression patterns were discovered in maize leaves, and antenna proteins in these leaves displayed a steady pattern. In contrast, the photosystem, carbon fixation and citrate pathways were highly controlled by diurnal light intensity. Most enzymes in the limiting steps of these pathways were major sites of regulation. Thus, maize leaves optimize photosynthesis and carbon fixation outside of light harvesting to adapt to the changes in diurnal light intensity at the protein level.


Exploring the mechanism of Suanzaoren decoction in treatment of insomnia based on network pharmacology and molecular docking.
Objective: To explore the functional mechanisms of Suanzaoren decoction (SZRD) for treating insomnia using network pharmacology and molecular docking. Methods: The active ingredients and corresponding targets of SZRD were obtained from the Traditional Chinese Medicine Systems Pharmacology database, and then, the names of the target proteins were standardized using the UniProt database. The insomnia-related targets were obtained from the GeneCards, DisGeNET, and DrugBank databases. Next, a Venn diagram comprising the drug and disease targets was created, and the intersecting targets were used to draw the active ingredient-target network diagram using Cytoscape software. Next, the STRING database was used to build a protein-protein interaction network, followed by cluster analysis using the MCODE plug-in. The Database for Annotation, Visualization, Integrated Discovery (i.e., DAVID), and the Metascape database were used for Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. AutoDock Vina and Pymol software were used for molecular docking. Results: SZRD contained 138 active ingredients, corresponding to 239 targets. We also identified 2,062 insomnia-related targets, among which, 95 drug and disease targets intersected. The GO analysis identified 490, 62, and 114 genes related to biological processes, cellular components, and molecular functions, respectively. Lipid and atherosclerosis, chemical carcinogen-receptor activation, and neuroactive ligand-receptor interaction were the most common pathways in the KEGG analysis. Molecular docking demonstrated that the primary active components of SZRD for insomnia had good binding capabilities with the core proteins in PPI network. Conclusion: Insomnia treatment with SZRD involves multiple targets and signaling pathways, which may improve insomnia by reducing inflammation, regulating neurotransmitters.


Outcome of Conservative Versus Surgical Treatment of Humeral Shaft Fracture in Children and Adolescents: Comparison Between Nonoperative Treatment (Desault's Bandage), External Fixation and Elastic Stable Intramedullary Nailing.
The main objective of this study was to retrospectively evaluate the clinical and radiographic outcomes of displaced humeral shaft fractures in children treated by Desault's bandage (DB), external fixation (EF), and elastic stable intramedullary nailing (ESIN). During the study period, 36 consecutive children with displaced humeral shaft fracture were treated by DB (Group A), EF (Group B) or ESIN (Group C). All the patients underwent full-length preoperative and postoperative anteroposterior and lateral radiographs of the injured humerus. One year after the index surgery, patients were asked to answer the short version of the Disabilities of the Arm, Shoulder and Hand outcome questionnaire (Quick DASH). Ten patients (27.8%) were in Group A, 11 (30%) in Group B, and 15 (41.7%) in Group C. Mean age at the time of injury was 10.8±2.3 years (range, 8 to 15.2 y), 11.7±2.5 years (range, 6.8 to 15.9 y), and 12.7±2.2 years (range, 6.9 to 15.3 y) in Groups A, B, and C, respectively (P=0.08). Groups A, B, and C did not differ significantly in their demographics (P>0.05).Surgical treatment (Groups B and C) provided a better radiologic outcome than nonoperative treatment (Group A) (P=0.05). No statistically significant differences were observed for preoperative, postoperative and at last follow-up mean displacement between Groups B and C (P>0.05).Overall, 9 of 36 patients developed a complication: 2 in Group A (20%), 4 in Group B (37%), and 3 in Group C (20.1) (P=0.92).Mean Quick DASH score was 3±8.6 (range, 0 to 27.3), 1.4±2.9 (range, 0 to 9), and 1.2±4.7 (range, 0 to 18.2) in Groups A, B, and C, respectively. All the patients were able to resume previous physical and sport activities 4 to 6 months after the last fracture reduction procedure. Surgery is not contraindicated in children with displaced humeral shaft fractures. EF and ESIN provide a better radiologic outcome, less posttreatment pain and faster mobilization than DB. However, numerical differences, although statistically significant, were not clinically relevant for all variables but immobilization time. Nonoperative treatment was as efficacious as surgical treatment apart from the length of time for immobilization. Level III.


Clinicopathology and Diagnosis Delay in a 40-Year-Old with Mitochondrial Neurogastrointestinal Encephalomyopathy (MNGIE).
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive and fatal multisystem metabolic disorder. It presents with wide-ranging gastrointestinal and neurologic symptoms. It is caused by a mutation in the TYMP gene which impairs thymidine phosphorylase (TP) activity, therefore leading to the accumulation of thymidine and deoxyuridine in plasma and tissues. Thus, MNGIE can be diagnosed by findings of high levels of thymidine and deoxyuridine. Herein, we present the case of a 40-year-old male who presented with diarrhea, vomiting, and abdominal pain, severe weight loss, neurologic deficits, and distal motor weakness progressing over a period of 13 years. The combination of this broad clinical picture along with results of magnetic resonance imaging, electromyography, colonic biopsies, genetic testing, and elevated plasma and tissue thymidine and deoxyuridine levels confirmed the diagnosis of MNGIE. TYMP gene mutation impairs TP function. TP mutations in the nuclear DNA lead to mitochondrial DNA deletions causing mitochondrial failure and ultimately cell death. Treatment modalities are targeting the restoration of TP activity or aiming to decrease the high levels of thymidine and pyrimide. However, diagnosing this disease is still a challenge and often overdue. This patient's 13-year delay in diagnosis shows the importance of a complete neurological exam and muscle strength testing in patients with gastrointestinal symptoms. The diagnosis of MNGIE requires interdepartmental collaborative work for diagnosis delay prevention and for optimal patient care.


Current Understanding of Dietary Fiber and Its Role in Chronic Diseases.
Dietary fiber (DF) is an essential, albeit under-consumed, component in the North American diet. DF is thought to have anti-inflammatory disease-modifying effects via DF-related gut microbiota degradation products called short chain fatty acids. Thus far studies have shown the greatest associations between DF intake and risk reduction in obesity, improved weight loss outcomes, and risk reduction of cardiovascular disease (CVD). There is weak evidence associating DF intake and inflammatory bowel disease (IBD) risk, IBD remission, reduced risk of Crohn's disease (CD flares, and no evidence showing any benefit towards ulcerative colitis (UC) specifically. Evidence on DF intake and the risk reduction of colorectal cancer (CRC) has been equivocal. Studies were limited by a lack of randomization or in controlling fiber types and sources. Based on the current beneficial associations of DF on obesity management and CVD, counseling patients to increase DF intake may be a cost-effective measure to decrease the burden of chronic disease.


A singular noninterpenetrating coordination polymer with the Pt3O4 structure containing naked [Na+]4 units.
The homoleptic low-spin complex [Fe(L)3]2+ where L is the bisbidentate ligand 1,10-phenanthroline-5,6-dione, coordinates Na+ ions via exo-oriented dione groups defining a three-dimensional cationic network {[Fe(L)3]4Na3}11+}n with Pt3O4 topology. The large volume generated by the network is filled with 11 perchlorate ions, 7 "NaClO4" ionic pairs, and 9 H2O molecules. Singular [Na+]4 units, in which the Na+ ions are practically uncoordinated, are formed.


Adaptive steady-state optimization of biomass productivity in continuous fermentors.
An adaptive steady-state optimization algorithm is presented and applied to the problem of optimizing the production of biomass in continuous fermentation processes. The algorithm requires no modeling information but is based on an on-line identified linear model, locates the optimum dilution rate, and maintains the chemostat at its optimum operating condition at all times. The behavior of the algorithm is tested against a dynamic model of a chemostat that incorporates metabolic time delay, and it is shown that large disturbances in the subtrate feed concentration and the specific growth rate, causing a shift in the optimum, are handled well. The developed algorithm is also used to drive a methylotroph single-cell production process to its optimum.


In Defense of the Indefensible: A Very Naïve Approach to High-Dimensional Inference.
A great deal of interest has recently focused on conducting inference on the parameters in a high-dimensional linear model. In this paper, we consider a simple and very naïve two-step procedure for this task, in which we (i) fit a lasso model in order to obtain a subset of the variables, and (ii) fit a least squares model on the lasso-selected set. Conventional statistical wisdom tells us that we cannot make use of the standard statistical inference tools for the resulting least squares model (such as confidence intervals and p-values), since we peeked at the data twice: once in running the lasso, and again in fitting the least squares model. However, in this paper, we show that under a certain set of assumptions, with high probability, the set of variables selected by the lasso is identical to the one selected by the noiseless lasso and is hence deterministic. Consequently, the naïve two-step approach can yield asymptotically valid inference. We utilize this finding to develop the naïve confidence interval, which can be used to draw inference on the regression coefficients of the model selected by the lasso, as well as the naïve score test, which can be used to test the hypotheses regarding the full-model regression coefficients.


p53-Induced LINC00893 Regulates RBFOX2 Stability to Suppress Gastric Cancer Progression.
Long noncoding RNAs (lncRNAs) have been reported to regulate diverse tumorigenic processes. However, little is known about long intergenic non-protein coding RNA 00893 (LINC00893) and its role in gastric cancer (GC). Herein we investigated its biological functions and molecular mechanism in GC. LINC00893 was decreased in GC tissues but significantly elevated in AGS cells after treatment with Nutlin-3. In GC patients, it was found that low expression of LINC00893 was correlated with tumor growth, metastasis and poor survival. Functionally, overexpression of LINC00893 suppressed the proliferation, migration and invasion of GC cells. Mechanistically, LINC00893 regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins by binding to RNA binding fox-1 homolog 2 (RBFOX2) and promoting its ubiquitin-mediated degradation, thus suppressing the EMT and related functions of GC. In addition, the transcription factor p53 can regulate the expression of LINC00893 in an indirect way. Taken together, these results suggested that LINC00893 regulated by p53 repressed GC proliferation, migration and invasion by functioning as a binding site for RBFOX2 to regulate its stability and the expression of EMT-related proteins. LINC00893 acts as a tumor-inhibiting lncRNA that is induced by p53 in GC and regulates EMT by binding to RBFOX2, thus providing a novel experimental basis for the clinical treatment of GC.


Mitral valve repair in redo cardiac surgery.
An increasing number of patients are being referred for mitral valve repair in the redo cardiac surgery setting. The most common clinical scenarios involve prior coronary bypass surgery or aortic valve replacement, each presenting special challenges in terms of gaining valve exposure to enable repair while limiting dissection as much as possible. A right anterior thoracotomy approach is preferred in most patients, coupled with hypothermic fibrillatory arrest. A repeat sternotomy may be favored in select circumstances such as when there is a need for bypass grafting or moderate aortic insufficiency is present. Special attention to cannulation techniques, perfusion conditions, valve exposure, and de-airing maneuvers are all important to ensure good clinical results. Using a tailored approach we have performed mitral valve repair in 22 patients with a patent left internal mammary artery graft following coronary artery bypass grafting between July 1992 and February 2000 with acceptable morbidity and low mortality.


Spontaneous Intraoperative Rupture of a Large Interstitial Pregnancy: Laparoscopic Management.
We present a case of a large interstitial pregnancy which was intraoperatively ruptured, but was eventually laparoscopically treated. The patient experienced 9 weeks of amenorrhea, and a right cornual pregnancy measuring 6 cm was diagnosed. The patient consented on having a minimal surgical treatment, and a laparoscopic right cornuotomy was decided. During surgery, and prior to any manipulation to the uterus, there was a spontaneous rupture of the ectopic which resulted in excessive bleeding. Temporal pressure at the bleeding site and ligation of the superior branches of the right uterine artery allowed for a careful dissection of the right uterine cornua and achieved hemostasis. The surgery proceeded uneventfully thereafter. Although surgical intervention in such cases entails a high risk of hemorrhage, successful completion of the laparoscopy lies on the meticulous preoperative planning and the controlled precise surgical steps during the procedure.


Phylogeography of the wide-host range panglobal plant pathogen Phytophthora cinnamomi.
Various hypotheses have been proposed regarding the origin of the plant pathogen Phytophthora cinnamomi. P. cinnamomi is a devastating, highly invasive soilborne pathogen associated with epidemics of agricultural, horticultural and forest plantations and native ecosystems worldwide. We conducted a phylogeographic analysis of populations of this pathogen sampled in Asia, Australia, Europe, southern and northern Africa, South America, and North America. Based on genotyping-by-sequencing, we observed the highest genotypic diversity in Taiwan and Vietnam, followed by Australia and South Africa. Mating type ratios were in equal proportions in Asia as expected for a sexual population. Simulations based on the index of association suggest a partially sexual, semi-clonal mode of reproduction for the Taiwanese and Vietnamese populations while populations outside of Asia are clonal. Ancestral area reconstruction provides new evidence supporting Taiwan as the ancestral area, given our sample, indicating that this region might be near or at the centre of origin for this pathogen as speculated previously. The Australian and South African populations appear to be a secondary centre of diversity following migration from Taiwan or Vietnam. Our work also identified two panglobal, clonal lineages PcG1-A2 and PcG2-A2 of A2 mating type found on all continents. Further surveys of natural forests across Southeast Asia are needed to definitively locate the actual centre of origin of this important plant pathogen.


Renal involvement in plasma cell dyscrasias.
Monoclonal light chain-related renal diseases represent a unique collection of renal disorders with monoclonal light chain deposition underlying the pathogenesis of these disorders. Yet, despite this common pathogenic mechanism, each renal lesion is unique. In addition, these syndromes are unusual in that, unlike many other renal disorders, they are potentially reversible causes of renal failure. This review focuses on the pathogenesis of three light chain-related renal diseases: AL amyloidosis, granular light chain deposition disease, and cast nephropathy ("myeloma kidney"). Management of these renal lesions in relation to the different pathophysiologic mechanisms is also discussed. Treatment should be designed to decrease production of nephrotoxic light chains and to prevent the binding interaction between these light chains and the various structures of the nephron.


Divergent mating systems and parental conflict as a barrier to hybridization in flowering plants.
Parental conflicts can lead to antagonistic coevolution of the sexes and of parental genomes. Within a population, the resulting antagonistic effects should balance, but crosses between populations can reveal conflict. Parental conflict is less intense in self-pollinating plants than in outcrossers because outcrossing plants are pollinated by multiple pollen donors unrelated to the seed parent, while a self-pollinating plant is primarily pollinated by one individual (itself). Therefore, in crosses between plants with differing mating systems, outcrossing parents are expected to "overpower" selfing parents. We call this the weak inbreeder/strong outbreeder (WISO) hypothesis. Prezygotically, such overpowering can alter pollination success, and we argue that our hypothesis explains a common pattern of unilateral incompatibility, in which pollen from self-incompatible populations fertilizes ovules of self-compatible individuals but the reciprocal cross fails. A postzygotic manifestation of overpowering is aberrant seed development due to parent-of-origin effects such as genomic imprinting. We evaluate evidence for the WISO hypothesis by reviewing published accounts of crosses between plants of different mating systems. Many, but not all, of such reports support our hypothesis. Since parental conflicts can perturb fertilization and development, such conflicts may strengthen reproductive barriers between populations, contributing to speciation.


Proapoptotic protein PACT is expressed at high levels in colonic epithelial cells in mice.
The protein activator of RNA-activated protein kinase (PKR) is a proapoptotic protein called PACT. PKR is an interferon (IFN)-induced serine-threonine protein kinase that plays a central role in IFN's antiviral and antiproliferative activities. PKR activation in cells leads to phosphorylation of the alpha-subunit of the eukaryotic protein synthesis initiation factor (eIF)2alpha, inhibition of protein synthesis, and apoptosis. In the absence of viral infections, PKR is activated by its activator PACT, especially in response to diverse stress signals. Overexpression of PACT in cells causes enhanced sensitivity to stress-induced apoptosis. We examined PACT expression in different mouse tissues and evaluated its possible role in regulating apoptosis. PACT is expressed at high levels in colonic epithelial cells, especially as they exit the cell cycle and enter an apoptotic program. PACT expression also coincides with the presence of active PKR and phosphorylated eIF2alpha. These results suggest a possible role of PACT-mediated PKR activation in the regulation of epithelial cell apoptosis in mouse colon. In addition, transient overexpression of PACT in a nontransformed intestinal epithelial cell line leads to induction of apoptosis, further supporting PACT's role in inducing apoptosis.


Icariin Promotes Osteogenic Differentiation in a Cell Model with NF1 Gene Knockout by Activating the cAMP/PKA/CREB Pathway.
Neurofibromatosis type 1 is a rare autosomal dominant genetic disorder, with up to 50% of patients clinically displaying skeletal defects. Currently, the pathogenesis of bone disorders in NF1 patients is unclear, and there are no effective preventive and treatment measures. In this study, we found that knockout of the NF1 gene reduced cAMP levels and osteogenic differentiation in an osteoblast model, and icariin activated the cAMP/PKA/CREB pathway to promote osteoblast differentiation of the NF1 gene knockout cell model by increasing intracellular cAMP levels. The PKA selective inhibitor H89 significantly impaired the stimulatory effect of icariin on osteogenesis in the NF1 cell model. In this study, an osteoblast model of NF1 was successfully constructed, and icariin was applied to the cell model for the first time. The results will help to elucidate the molecular mechanism of NF1 bone disease and provide new ideas for the clinical prevention and treatment of NF1 bone disease and drug development in the future.


Cost consequence analysis of use of a balloon expandable vascular access system and standard vascular sheath for transcatheter aortic valve implantation.
Vascular complications are an important complication of transcatheter aortic valve implantation and are associated with increased morbidity and mortality as well as cost. The Solopath device is an expandable vascular access system that has previously been shown to be associated with lower rates of vascular complications. This study sought to evaluate the impact of the use of this system on vascular complications and costs in a decision model analysis. A cost-consequence analysis was undertaken utilizing event rate data from the PARTNER trials and a published retrospective analysis of the Solopath device. The decision model estimated costs and benefits in a hypothetical cohort of patients with aortic stenosis undergoing TAVI using either a standard sheath or Solopath. The modeled analysis compared the occurrence of vascular complications and mortality at 30 days and 1 year using TreeAge Pro. The decision model demonstrated that use of the Solopath sheath resulted in 36 fewer major vascular complications, three fewer deaths at 30 days, and five fewer deaths at 1 year, resulting in a discounted cost savings of $846 CDN. Results were sensitive to decreasing rates of vascular complications with newer generation devices, however maintained modest cost-savings. Reduction in vascular complications is an important part of improving care for TAVI patients. The Solopath vascular access device offers an alternative to standard sheaths with a potential reduction in complications and cost-savings.


Methane production in an anaerobic osmotic membrane bioreactor using forward osmosis: Effect of reverse salt flux.
This study investigated the impact of reverse salt flux (RSF) on microbe community and bio-methane production in a simulated fertilizer driven FO-AnMBR system using KCl, KNO3 and KH2PO4 as draw solutes. Results showed that KH2PO4 exhibited the lowest RSF in terms of molar concentration 19.1mM/(m2.h), while for KCl and KNO3 it was 32.2 and 120.8mM/(m2.h), respectively. Interestingly, bio-methane production displayed an opposite order with KH2PO4, followed by KCl and KNO3. Pyrosequencing results revealed the presence of different bacterial communities among the tested fertilizers. Bacterial community of sludge exposed to KH2PO4 was very similar to that of DI-water and KCl. However, results with KNO3 were different since the denitrifying bacteria were found to have a higher percentage than the sludge with other fertilizers. This study demonstrated that RSF has a negative effect on bio-methane production, probably by influencing the sludge bacterial community via environment modification.


Direct real-time observation of E- and P-selectin-mediated rolling on cutaneous lymphocyte-associated antigen immobilized on Western blots.
Human memory T cells associated with cutaneous inflammatory responses are characterized by their expression of cutaneous lymphocyte-associated Ag (CLA), a carbohydrate determinant differentially expressed on P-selectin glycoprotein ligand-1 (PSGL-1). Although expression of the CLA epitope on PSGL-1 (CLA(+) PSGL-1) by memory T cells is associated with acquisition of E-selectin ligand activity, it is not known whether CLA(+) PSGL-1, itself, is a ligand for E-selectin on human T cells or whether other glycoproteins, with or without CLA modification, support E-selectin-dependent rolling in shear flow. To address this issue, we developed a method for real-time analysis of functional adhesive interactions between selectin-bearing cells in shear flow with leukocyte ligands resolved by SDS-PAGE and immobilized on standard Western blots. The results of these studies provide direct evidence that CLA(+) PSGL-1 is a functional ligand for both E- and P-selectin, confirm that the P-selectin ligand activity of PSGL-1 is independent of CLA modification, and identify a distinct, non-PSGL-1 E-selectin ligand on CLA-positive human memory T cells.


A mechanistic overview of translation initiation in eukaryotes.
Translation initiation in eukaryotes is a complex and highly regulated process requiring the action of at least 12 protein factors. The pathway is distinguished by the formation of a pre-initiation complex that recruits the 5' end of the mRNA and scans along it to locate the start codon. During the past decade, a combination of genetics, biochemistry and structural studies has begun to illuminate key molecular events in this critical phase of gene expression. Here, we outline our current understanding of eukaryotic translation initiation and discuss important outstanding challenges.


Language development in Down syndrome: from the prelinguistic period to the acquisition of literacy.
Down syndrome (DS) is associated with abnormalities in multiple organ systems and a characteristic phenotype that includes numerous behavioral features. Language, however, is among the most impaired domains of functioning in DS and, perhaps, also the greatest barrier to independent meaningful inclusion in the community. In this article, we review what is known about the extent, nature, and correlates of the language and related problems of individuals with Down syndrome. In doing so, we focus largely on the syndrome-specific features of the language phenotype, although we also consider within-syndrome variation. The review focuses on the prelinguistic foundations of language and the major components of language (i.e., vocabulary, syntax, and pragmatics). We also consider two topics in the treatment and education of individuals with DS: prelinguistic communication intervention and the acquisition of literacy skills.


Sensitivity to abscisic acid modulates positive interactions between Arabidopsis thaliana individuals.
The ability of abscisic acid (ABA) to modulate positive interactions between Arabidopsis thaliana individuals under salinity stress was investigated using abi1-1 (insensitive to ABA), era1-2 (hypersensitive to ABA) mutant and wild type plants. The results showed that sensitivity to ABA affects relative interaction intensity (RII) between Arabidopsis thaliana individuals. The neighbor removal experiments also confirmed the role of phenotypic responses in linking plant-plant interactions and sensitivity to ABA. For abi1-1 mutants, the absolute value differences between neighbor removal and control of stem length, root length, leaf area, leaf thickness, flower density, above biomass/belowground biomass (A/U), photosynthetic rate, stomatal conductance, leaf water content and water-use efficiency were smaller than those of the wild type, while for era1-2 mutants, these absolute value differences were larger than those of the wild type. Thus, it is suggested that positive interactions between Arabidopsis thaliana individuals are at least partly modulated by different sensitivity to ABA through different physiological and phenotypic plasticity.


[Syncope in Young Elite Athletes].
Syncope - one of the most common syndrome in the general population - may be a manifestation of diseases associated with risk of sudden death. To evaluate the prevalence, pathogenesis particular syncope, near syncope in children involved in elite sport. The study involved 500 young elite athletes aged 9-18 years (mean age 16.1+/-2.2 years), member of Russian national teams.


Design, synthesis, and antiviral, fungicidal, and insecticidal activities of tetrahydro-β-carboline-3-carbohydrazide derivatives.
According to our previous research on the antiviral activity of β-carboline and tetrahydro-β-carboline derivatives, using (1S,3S)-1-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carbohydrazide (1) as a lead compound, series of novel tetrahydro-β-carboline derivatives containing acylhydrazone moiety were designed, synthesized, and first evaluated for their biological activities. Most of these compounds exhibited excellent antiviral activity both in vitro and in vivo. The in vivo inactivation, curative, and protection activities of compounds 8, 9, 12, 16, 28, 29, and 30 were much higher than that of ribavirin (37.6%, 39.4%, and 37.9% at 500 μg/mL) and the lead compound (40.0%, 42.3%, and 39.6% at 500 μg/mL). Especially, the in vitro and in vivo activities of compound 16 (36.9%, 33.6%, 30.2%, and 35.8%) at 100 μg/mL, which were very close to that of ribavirin (40.0% for in vitro activity) at 500 μg/mL. Compounds 9 and 29 were chosen for the field trials of antiviral efficacy against TMV (tobacco mosaic virus); the results exhibited that both compounds, especially compound 29, showed better activities than control plant virus inhibitors. At the same time, the fungicidal results showed that compounds 6, 9, and 11 exhibited good fungicidal activities against 14 kinds of phytopathogens. Additionally, compounds 3 and 23 exhibited moderate insecticidal activity against the four tested species of insects.


Superparamagnetic reconstituted high-density lipoprotein nanocarriers for magnetically guided drug delivery.
Current cancer chemotherapy is frequently associated with short- and long-term side effects, affecting the quality of life of cancer survivors. Because malignant cells are known to overexpress specific surface antigens, including receptors, targeted drug delivery is often utilized to reduce or overcome side effects. The current study involves a novel targeting approach using specifically designed nanoparticles, including encapsulation of the anti-cancer drug valrubicin into superparamagnetic iron oxide nanoparticle (SPION) containing reconstituted high-density lipoprotein (rHDL) nanoparticles. Specifically, rHDL-SPION-valrubicin hybrid nanoparticles were assembled and characterized with respect to their physical and chemical properties, drug entrapment efficiency and receptor-mediated release of the drug valrubicin from the nanoparticles to prostate cancer (PC-3) cells. Prussian blue staining was used to assess nanoparticle movement in a magnetic field. Measurements of cytotoxicity toward PC-3 cells showed that rHDL-SPION-valrubicin nanoparticles were up to 4.6 and 31 times more effective at the respective valrubicin concentrations of 42.4 µg/mL and 85 µg/mL than the drug valrubicin alone. These studies showed, for the first time, that lipoprotein drug delivery enhanced via magnetic targeting could be an effective chemotherapeutic strategy for prostate cancer.


Side-chain effects in molecular electronic devices.
We discuss the effect of an abundant structural element of molecules on the transmission probabilities of molecular electronic devices. We show that an attachment of side chains to a molecular conductor may lead to zero transmission probabilities. The gaps in the transmission-probability appear approximately at the eigenvalues of the isolated side chains, provided that the corresponding eigenstates are not localized away from the molecular conductor. Simple Hückel-type calculations serve to illustrate the described effect. Furthermore, we show that complex transmission-probability curves, obtained with Kohn-Sham density-functional theory, also exhibit the described side-chain effect.


[Depressive states in adolescents].
The review was carried out on clinical pictures, premorbid character, fixation point, and family dynamics of depressive adolescents. Depression is one of the most common, but still not clearly defined, emotional reactions in adolescence. Object loss as a result of emotional development would exercise great influence on the still developing psychic structure. Through this review, the author has arrived at the conclusion that, the loss of infantile object, affecting the individual at different developmental levels, produced different clinical manifestations. The author takes into account not only the object loss but also the degree of ego integration of the adolescent individual, and family as a container.


Yes-associated protein 1 promotes the differentiation and mineralization of cementoblast.
Yes-associated protein 1 (YAP1) transcriptional coactivator is a mediator of mechanosensitive signaling. Cementum, which covers the tooth root surface, continuously senses external mechanical stimulation. Cementoblasts are responsible for the mineralization and maturation of the cementum. However, the effect of YAP1 on cementoblast differentiation remains largely unknown. In this study, we initially demonstrated that YAP1 overexpression enhanced the mineralization ability of cementoblasts. YAP1 upregulated the mRNA and protein expression of several cementogenesis markers, such as alkaline phosphatase (ALP), runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and dentin matrix acidic phosphoprotein 1 (DMP1). The YAP1 overexpression group showed higher intensities of ALP and Alizarin red stain than the YAP1-knockdown group. Unexpectedly, a sharp increase in the expression of dentin sialophosphoprotein (DSPP) was induced by the overexpression of YAP1. Knockdown of YAP1 suppressed DSPP transcriptional activity. YAP1 overexpression activated Smad-dependent BMP signaling and slightly inhibited Erk1/2 signaling pathway activity. Treatment with specific BMP antagonist (LDN193189) prevented the upregulation of the mRNA levels of ALP, RUNX2, and OCN, as well as intensity of ALP-stained and mineralized nodules in cementoblasts. The Erk1/2 signaling pathway inhibitor (PD 98,059) upregulated these cementogenesis markers. Thus, our study suggested that YAP1 enhanced cementoblast mineralization in vitro. YAP1 exerted its effect on the cementoblast partly by regulating the Smad-dependent BMP and Erk1/2 signaling pathways.


Nonfacial Reconstructive Techniques.
Nonfacial reconstruction encompasses several anatomic locations with varied topography, skin quality, and tissue reservoirs. Patients also have varied mobility concerns and wound care needs when managing wounds in these areas. This article includes techniques and approaches from the dermatologic surgery, plastic surgery, and podiatric surgery literature in an effort to provide a comprehensive overview of the subject matter. Functionally and esthetically acceptable reconstructions of nonfacial surgical wounds can be accomplished with a variety of techniques based on the characteristics of the wound and unique needs of the patient.


A Novel Inverse Solution of Contact Force Based on a Sparse Tactile Sensor Array.
High-density tactile sensing has been pursued for humanoid robotic hands to obtain contact force information while the elastomer skin cover is traditionally considered to impair the force discrimination. In this work, we try to utilize the diffusion effect of the elastomer cover to identify an arbitrary contact force load just based on a sparse tactile sensor array. By numerical analysis, we proved the monotonous relation between the Pearson's correlation coefficient and the relative distance of two single-force loads. Then, we meshed the elastomer surface and conducted the calibration load process to establish the calibration database of the sensing outputs. Afterwards, we applied the correlation method to the database and the sensing output of the unknown load to determine its location and intensity. For validation tests of the proposed method, we designed and fabricated a 3 × 3 sparse tactile sensor array with flat elastomer cover and established an automatic three-axis loading system. The validation tests were implemented including 100 random points with force intensity ranging from 0.1 to 1 N. The test results show that the method has good accuracy of detecting force load with the mean location error of 0.46 mm and the mean intensity error of 0.043 N, which meets the basic requirements of tactile sensing. Therefore, it is feasible for the sparse tactile sensor array to realize high-density load detection.


A critical assessment of methods of measuring metabolite concentrations by NMR spectroscopy.
Many NMR studies are made by scientists and clinicians in order to measure metabolite levels. There is a growing need to obtain absolute quantification of these metabolites. We have therefore reviewed the methods that are available and those which are being developed, for studies in vivo and on isolated tissues. We describe the following methods and assess their advantages and limitations: (1) Conventional spectroscopy and area ratios, (2) Tissue extracts, (3) External capillary, (4) Internal endogenous marker, (5) Internal exogenous marker, (6) External marker in bath, (7) Reference to internal 1H water concentration, (8) Gradient-localized spectroscopy and (9) Fourier series analysis localization. The relevant biological and technical aspects associated with quantification of metabolite concentrations are also discussed. This includes NMR visibility, origin of the NMR signals, definitions of concentration, influence of the RF coil, data collection and data analysis.


How mothers choose babymilk brands.
Babymilks which had been on the market for many years were the most highly regarded by the women. Midwives had a greater influence in brand choice than health visitors, although overall the women's sisters appeared to be the most influential. Women expressed a need for more information regarding the nutritional content and differences between various babymilks, but from an unbiased source. The effect of subliminal advertising on the postnatal wards (i.e. by using ready-to-feed bottles of babymilk) was highly significant. There is no doubt that there is deliberate confusion of brand name advertising with impartial information.


The effect of atrophied pancreas as shown in the preoperative imaging on the leakage rate after pancreaticoduodenectomy.
The soft texture of the pancreas parenchyma may influence the incidence of pancreatic leakage after pancreaticoduodenectomy (PD). One possible method to assess pancreatic texture and atrophy, is via computed tomography (CT) scan of the abdomen. The purpose of our study was to evaluate the relation between the preoperative CT scan and the incidence of pancreatic fistula after PD. A retrospective single-center study including patients who underwent PD for a benign and malignant tumor of the periampullary region between the years 2000 and 2016. Demographic and imaging data were analysed and a correlation with the post-operative leak was evaluated. Pancreatic leak was documented in 34 out of 154 (22.1%) patients. All the leakage cases occurred in the preserved pancreas group (33.1% of the total preserved pancreas group alone). No leak was documented in the atrophic pancreas group. This difference between the two groups was found to be statistically significant (p ≤ 0.00001). Atrophic pancreas in the preoperative CT scan may be protective against leakage after PD. These findings may help the surgeon to risk stratify patients accordingly. In addition, the findings suggest that patients with a preserved pancreas may require more protective methods to prevent leakage.


Actin cytoskeleton organization and posttranscriptional regulation of endothelial nitric oxide synthase during cell growth.
Posttranscriptional regulation of endothelial nitric oxide synthase (eNOS) expression is an important mechanism by which endothelial cells respond to various physiological and pathophysiological stimuli. Previously, we showed that eNOS expression was dramatically altered by the state of cell growth and that the mechanism responsible for this regulation was entirely posttranscriptional, occurring via changes in eNOS mRNA stability. The present study identifies a role for actin cytoskeleton organization in the posttranscriptional regulation of eNOS during cell growth and examines the relationship between the state of actin polymerization and eNOS expression. We identified monomeric actin (globular [G]-actin) as the major component of a 51-kDa ribonucleoprotein that binds to the eNOS mRNA 3' untranslated region in UV-crosslinking analysis. Binding activity of the ribonucleoprotein complex correlated with the relative concentration of G-actin versus filamentous actin (F-actin). ENOS transcripts colocalized with cytoplasmic G-actin in cells subjected to fluorescence in situ hybridization and G-actin fluorescence staining. In subcellular fractionation studies, eNOS transcripts were enriched in the free polysomal fraction of nonproliferating cells and enriched in the cell matrix-associated polysomal fraction of proliferating cells. Furthermore, an inverse relationship between the concentration of G-actin and eNOS expression was observed in endothelial cells subjected to pharmacological alteration of their cytoskeleton; lower G/F-actin ratios correlated with increased eNOS expression. Our findings provide some insight into how endothelial cells may use the dynamic organization of the actin cytoskeleton to regulate expression of an enzyme that is crucial to vascular homeostasis.


Synergistic activity of recombinant human endostatin in combination with adriamycin: analysis of in vitro activity on endothelial cells and in vivo tumor progression in an orthotopic murine mammary carcinoma model.
Current combination treatment strategies in malignancy are designed to evaluate the use of cytotoxic drugs and antiangiogenic agents. Endostatin, a fragment of collagen XVIII, specifically inhibits proliferation, migration, and differentiation of endothelial cells in vitro as well as angiogenesis and tumor progression in in vivo models. In this study, we determine the antitumor effect of rhEndostatin administered alone or in combination with Adriamycin against established orthotopic murine mammary carcinoma. Mice bearing orthotopically established DA-3 mammary adenocarcinoma tumors received varying doses of rhEndostatin alone and in combination with Adriamycin to assess tumor growth inhibition. Additional studies of this in vivo combination included a determination of Adriamycin-induced cardiotoxicity and in vitro effects on human umbilical vein endothelial cell proliferation and cord formation. For single-agent activity, optimal tumor growth inhibition was observed after s.c. administration of 50 mg/kg/day rhEndostatin or 5 mg/kg Adriamycin injected i.v. every 4 days. Combination of Adriamycin with optimal or suboptimal doses of rhEndostatin resulted in synergistic inhibition of DA-3 tumor growth. Importantly, unlike other antiangiogenic agents, rhEndostatin did not exacerbate the cardiotoxicity of Adriamycin. The synergistic interaction between rhEndostatin and Adriamycin was also observed in vitro for inhibition of human umbilical vein endothelial cell proliferation and inhibition of cord formation. These data suggest that the synergy observed with rhEndostatin in combination with Adriamycin is exerted at the level of the endothelial cell and can result in enhanced tumor growth inhibition. The potential benefit of Adriamycin used in combination with rhEndostatin is being considered for clinical evaluation.


High affinity of nonesterified polyunsaturated fatty acids for rat alpha-fetoprotein (AFP).
We have recently demonstrated that a mixture of nonesterified long chain fatty acids, mainly polyunsaturated, which are extracted under certain conditions from either whole mammalian sera or from pure rat alpha 1-fetoprotein (AFP), interfere with rat AFP-estrogen interaction. We present here a quantitative study of the association constants for the binding to AFP of these different fatty acids. We show important differences among them, the polyunsaturated ones displaying higher association constants (Ka approximately 10(7) -- 10(8) M-1) than the monounsaturated (Ka approximately 10(6) M-1) or the saturated (Ka approximately 10(4) -- 10(5) M-1) compounds. Moreover, though all the fatty acids identified in rat serum or rat AFP extract are more or less tightly bound by rodent AFP, only some of them can compete for exogeneous estrogens complexed to this highly estrophilic macromolecule.


CD137 Plays Both Pathogenic and Protective Roles in Type 1 Diabetes Development in NOD Mice.
We previously reported that CD137 (encoded by Tnfrsf9) deficiency suppressed type 1 diabetes (T1D) progression in NOD mice. We also demonstrated that soluble CD137 produced by regulatory T cells contributed to their autoimmune-suppressive function in this model. These results suggest that CD137 can either promote or suppress T1D development in NOD mice depending on where it is expressed. In this study, we show that NOD.Tnfrsf9-/- CD8 T cells had significantly reduced diabetogenic capacity, whereas absence of CD137 in non-T and non-B cells had a limited impact on T1D progression. In contrast, NOD.Tnfrsf9-/- CD4 T cells highly promoted T1D development. We further demonstrated that CD137 was important for the accumulation of β cell-autoreactive CD8 T cells but was dispensable for their activation in pancreatic lymph nodes. The frequency of islet-infiltrating CD8 T cells was reduced in NOD.Tnfrsf9-/- mice in part because of their decreased proliferation. Furthermore, CD137 deficiency did not suppress T1D development in NOD mice expressing the transgenic NY8.3 CD8 TCR. This suggests that increased precursor frequency of β cell-autoreactive CD8 T cells in NY8.3 mice obviated a role for CD137 in diabetogenesis. Finally, blocking CD137-CD137 ligand interaction significantly delayed T1D onset in NOD mice. Collectively, our results indicate that one important diabetogenic function of CD137 is to promote the expansion and accumulation of β cell-autoreactive CD8 T cells, and in the absence of CD137 or its interaction with CD137 ligand, T1D progression is suppressed.


Soybean cell enlargement oscillates with a temperature-compensated period length of ca. 24 min.
Rate of enlargement of epidermal cells from soybean, when measured at intervals of 1 min using a light microscope equipped with a video measurement system, oscillated with a period length of about 24 min. This oscillation parallels the 24-min periodicity observed for the oxidation of NADH by the external plasma membrane NADH oxidase. The increase in length was not only non-linear, but intervals of rapid increase in area alternated with intervals of rapid decrease in area. The length of the period was temperature compensated, and was approximately the same when measured at 14, 24 and 34 degrees C even though the rate of cell enlargement varied over this same range of temperatures. These observations represent the first demonstration of an oscillatory growth behavior correlated with a biochemical activity where the period length of both is independent of temperature (temperature compensated) as is the hallmark of clock-related biological phenomena.


Case report: diabetes mellitus as a predisposing factor in the development of pyomyositis.
Pyomyositis is an uncommon infection in temperate climates, usually resulting from Staphylococcus aureus infection of skeletal muscle. In this report, the authors describe a patient with untreated Type 2 diabetes mellitus who suffered nonpenetrating blunt trauma to his left anterior thigh, and S. aureus pyomyositis and secondary osteomyelitis of his proximal tibia and patella subsequently developed as a result of delayed diagnosis and treatment. Patients with diabetes mellitus are at increased risk for the development of pyomyositis because of more frequent S. aureus colonization of skin, nasal mucosa, and oropharynx; a delay in definitive treatment can lead to significant morbidity in these patients. Computed tomography or magnetic resonance imaging may be helpful in the diagnosis of pyomyositis. An anemia of chronic disease may result from this disorder, which resolves with treatment.


Fish odour triggers conspecific attraction behaviour in an aquatic invertebrate.
Group living has evolved as an adaptation to predation in many animal species. In a multitude of vertebrates, the tendency to aggregate varies with the risk of predation, but experimental evidence for this is less well known in invertebrates. Here, we examine the tendency to aggregate in the freshwater amphipod Gammarus pulex in the absence and presence of predator fish odour. Without fish odour, the gammarids showed no significant tendency to aggregate. In contrast to this, in fish-conditioned water, they significantly preferred to stay close to conspecifics. Predation risk can, thus, influence gammarids social behaviour.


[A review of the mammalian Mallophaga of Europe].
The paper reviews the present knowledge of the Mallophaga of European mammals. 50 species and subspecies have been listed in a checklist and a host-parasite list. 32 of them are still found in Europe. There have been no records so far of 21 hosts listed as hypothetical mallophagian hosts. Eight extinct or exterminated forms of mammals in Europe are listed as hypothetical hosts of chewing louse.


Toward a Complex Network of Risks for Psychosis: Combining Trauma, Cognitive Biases, Depression, and Psychotic-like Experiences on a Large Sample of Young Adults.
Although the linkage between traumatic life events and psychotic-like experiences (PLEs) is well established, the knowledge of potential mechanisms of this relationship is scarce. The aim of the present study was to better understand the structure of connections between traumatic life events and PLEs by considering at the same time the role of cognitive biases and depressive symptoms in the population of young adults (18-35 years of age, M = 26.52, SD = 4.74, n = 6772). Our study was conducted within a framework of network analysis. PLEs were measured with the Prodromal Questionnaire (PQ-16), cognitive biases were measured with nine items from the Davos Assessment of Cognitive Biases Scale-18 (DACOBS-18), depressive symptoms were assessed with the Center for Epidemiologic Studies-Depression Scale (CESD-R) and exposure to traumatic life events was measured with a combination of Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and Traumatic Experience Checklist (TEC). The results present a network of all nodes being interconnected within and between domains, with no isolated factors. Exposures to sexual trauma were the most central node in the network. Pathways were identified from trauma to PLEs via cognitive biases and depressive symptoms. However, the shortest pathway between the most central traumatic life event and PLEs was through other traumatic life events, without cognitive biases or depressive symptoms along the way. Our findings suggest the importance of environmental adversities as well as dysfunctional information processing and depression in the network of psychosis risks.


Bulk sensitive hard x-ray photoemission electron microscopy.
Hard x-ray photoelectron spectroscopy (HAXPES) has now matured into a well-established technique as a bulk sensitive probe of the electronic structure due to the larger escape depth of the highly energetic electrons. In order to enable HAXPES studies with high lateral resolution, we have set up a dedicated energy-filtered hard x-ray photoemission electron microscope (HAXPEEM) working with electron kinetic energies up to 10 keV. It is based on the NanoESCA design and also preserves the performance of the instrument in the low and medium energy range. In this way, spectromicroscopy can be performed from threshold to hard x-ray photoemission. The high potential of the HAXPEEM approach for the investigation of buried layers and structures has been shown already on a layered and structured SrTiO3 sample. Here, we present results of experiments with test structures to elaborate the imaging and spectroscopic performance of the instrument and show the capabilities of the method to image bulk properties. Additionally, we introduce a method to determine the effective attenuation length of photoelectrons in a direct photoemission experiment.


A professional development model: rewarding excellence in nursing practice.
Change continues to be the only constant in health care. The array of rapid and complex changes in the provision of health care services is dramatically affecting the development needs of professional nursing staff. The model presented describes a theoretical framework designed to support the philosophy of both continuous learning and professional development of nurses and also provides a structure for systematic implementation of objectives, content, and learning activities. Linking of professional development models with reward systems is rapidly becoming a successful strategy for organizations in achieving cost-quality outcomes. This model provides a map for staff and management to support, recognize, and reward professional development.


Lipolytic degradation of human very low density lipoproteins by human milk lipoprotein lipase: the identification of lipoprotein B as the main lipoprotein degradation product.
Although the direct conversion of very low density lipoproteins (VLDL) into low density (LDL) and high density (HDL) lipoproteins only requires lipoprotein lipase (LPL) as a catalyst and albumin as the fatty acid acceptor, the in vitro-formed LDL and HDL differ chemically from their native counterparts. To investigate the reason(s) for these differences, VLDL were treated with human milk LPL in the presence of albumin, and the LPL-generated LDL1-, LDL2-, and HDL-like particles were characterized by lipid and apolipoprotein composition. Results showed that the removal of apolipoproteins B, C, and E from VLDL was proportional to the degree of triglyceride hydrolysis with LDL2 particles as the major and LDL1 and HDL + VHDL particles as the minor products of a complete in vitro lipolysis of VLDL. In comparison with native counterparts, the in vitro-formed LDL2 and HDL + VHDL were characterized by lower levels of triglyceride and cholesterol ester and higher levels of free cholesterol and lipid phosphorus. The characterization of lipoprotein particles present in the in vitro-produced LDL2 showed that, as in plasma LDL2, lipoprotein B (LP-B) was the major apolipoprotein B-containing lipoprotein accounting for over 90% of the total apolipoprotein B. Other, minor species of apolipoprotein B-containing lipoproteins included LP-B:C-I:E and LP-B:C-I:C-II:C-III. The lipid composition of in vitro-formed LP-B closely resembled that of plasma LP-B. The major parts of apolipoproteins C and E present in VLDL were released to HDL + VHDL as simple, cholesterol/phospholipid-rich lipoproteins including LP-C-I, LP-C-II, LP-C-III, and LP-E. However, some of these same simple lipoprotein particles were present after ultracentrifugation in the LDL2 density segment because of their hydrated density and/or because they formed, in the absence of naturally occurring acceptors (LP-A-I:A-II), weak associations with LP-B. Thus, the presence of varying amounts of these cholesterol/phospholipid-rich lipoproteins in the in vitro-formed LDL2 appears to be the main reason for their compositional difference from native LDL2. These results demonstrate that the formation of LP-B as the major apolipoprotein B-containing product of VLDL lipolysis only requires LPL as a catalyst and albumin as the fatty acid acceptor. However, under physiological circumstances, other modulating agents are necessary to prevent the accumulation and interaction of phospholipid/cholesterol-rich apolipoprotein C- and E-containing particles.


High-Temperature Short-Time Preserves Human Milk's Bioactive Proteins and Their Function Better Than Pasteurization Techniques With Long Processing Times.
Donor human milk is generally processed by holder pasteurization (HoP) at 62. 5°C for 30 min. This temperature-time combination is sufficient for eliminating pathogens in donor milk, but also negatively affects several bioactive milk components. Long heating up times may further affect the bioactive properties of pasteurized milk. High-Temperature-Short-Time (HTST), a treatment with shorter processing times (72°C for 15 sec), was investigated as a suitable alternative to HoP. In addition, pasteurization methods that follow the same temperature regime but with varying heating up times were compared. Human milk samples from four different donors were combined into one pool, which was then used to perform all analyses. The effects of these methods on the levels and functionality of immunoglobulin A, lactoferrin, lysozyme and bile salt-stimulated lipase, were evaluated with LC-MS/MS-based proteomics and activity assays, while the pasteurization efficacy was evaluated with an alkaline phosphatase test. HoP, a treatment with long processing times, times, caused the highest reduction in all proteins studied (reduced by 50-98%). Compounds such as lactoferrin and bile salt-stimulated lipase that are more sensitive to heat treatments were better retained with HTST, but their levels and functionality were still significantly lower than those of untreated donor milk (52 and 81% reduction of lactoferrin and bile salt-stimulated lipase activity, respectively). Our findings showed that a treatment with considerably shorter processing times, such as HTST, may reduce the thermal damage caused to the bioactive proteins compared to HoP, without affecting pasteurization efficacy. Since the vast majority of the donor human milk banks that are currently operating on a global level apply HoP to donor milk, our findings may provide relevant information for the optimization of donor milk processing.


Biomimetic stimulus-responsive star diblock gelators.
Novel biomimetic gelators with star diblock copolymer architectures have been synthesized by atom-transfer radical polymerization (ATRP). Two types of trifunctional ATRP initiator were used to polymerize 2-(methacryloyloxy)ethyl phosphorylcholine [MPC] at 20 degrees C, followed by sequential monomer addition of various tertiary amine methacrylates or mixtures thereof. Poor living character was achieved using an amide-based trifunctional initiator, but the analogous triester initiator gave reasonably well-defined thermo-responsive and pH-responsive star diblock copolymers. The most effective thermo-responsive gelators were obtained by the statistical terpolymerization of 2-(dimethylamino)ethyl methacrylate [DMA], 2-(diethylamino)ethyl methacrylate [DEA], and a monomethoxy-capped poly(propylene oxide) methacrylate [PPOMA], whereas pH-responsive gelators were prepared using 2-(diisopropylamino)ethyl methacrylate [DPA] as the second monomer. Star diblock copolymer gelators that were both thermo-responsive and pH-responsive were obtained by the statistical copolymerization of DMA with DPA. Copolymer compositions were assessed by 1H NMR spectroscopy, and the molecular weight distributions of the three-arm star MPC homopolymer precursors were assessed by aqueous gel permeation chromatography. Static light scattering was used to obtain weight-average molecular weights of selected star diblock copolymers and rheological measurements and variable-temperature 1H NMR were used to probe the onset of gelation.


Steady-state and time-dependent thermodynamic modeling of the effect of intravenous infusion of warm and cold fluids.
Hypothermia results in vital sign lability, coagulopathy, wound infections, and other sequelae. Normothermia can be restored by several modalities, including passive blanket heating, warm forced-air devices, and active fluid warming (AFW). In AFW, intravenously administered fluids are heated to 40 to 45 °C to minimize net thermal losses and to raise body temperature. Clinical studies have demonstrated the efficacy of AFW as part of a strategy encompassing several methods, but the isolated contribution of AFW to warming has not been theoretically examined in detail. A calorimetric model is derived to determine the functional dependence of warming on patient weight, hypothermia severity, infusion temperature, and volume infused. A second heat transfer model is derived to describe the time-dependent temperature changes of the periphery and core after warmed-fluid infusion. There is an inverse linear relationship between the patient's initial temperature and the amount of warming achieved with a given volume. In contrast, as the temperature of the infusion approaches the desired final temperature, the volume required for a fixed temperature change increases nonlinearly. For weight-based boluses, the temperature change scales appropriately with patient mass. Infusion of 2 L of room-temperature crystalloid results in a decrease in body temperature of approximately one-third degree Celsius in the average normothermic adult. For the heat transfer model, previously reported rates of temperature drop and recovery after the intravenous infusion of cold fluids are qualitatively reproduced with a blood mixing time of approximately 15 minutes. Our calculations reveal that AFW has a larger measurable beneficial effect for patients with more severe hypothermia, but true rewarming of the patient with AFW alone would require prohibitively large fluid volumes (more than 10 L of 40 °C fluid) or dangerously hot fluid (20 mL/kg of 80 °C fluid for a 1 °C increase). The major beneficial effect of AFW is the prevention of further net heat loss.


Impact of Switching on Pharmacokinetics of Therapeutic Biologics and Interchangeability Assessment-A Simulation Study.
The risk in terms of safety or diminished efficacy of switching between an originator biological product and a proposed interchangeable product is an important consideration for interchangeability evaluation in the regulatory framework. This simulation study evaluated the impact of several switching study design scenarios on the pharmacokinetic (PK) assessment between a virtual originator biological product and a virtual proposed interchangeable product. Our results show that (1) at least 3 switches are needed to optimize the detection of potential PK differences, (2) the initial incidence of antidrug antibodies after treatment with the reference product in the lead-in period is a significant covariate affecting the PK results, and (3) the area under the concentration-time curve is more sensitive than peak concentration in assessing the impact of switching on PK similarity. Our simulation work illustrates that a range of factors should be carefully considered when designing a switching study for the assessment of interchangeability between 2 biological products.


Incidence of asthma in children in Tuzla Canton--Bosnia and Herzegovina.
Asthma is one of the most common chronic diseases whose incidence shows constant growth in childhood. The objective of this work was to look into asthma incidence in children in relation to their age group and sex in a retrospective study, at Tuzla Canton area. The study comprised children of both sexes, age 0-14 who fell sick with asthma within the period from January 1st 2003 to December 31st 2007. The overall incidence and the incidence in relation to age group and sex was calculated as the number of children suffering from asthma, within the age group 0-14 years per 1000 children of the same age group in the Tuzla Canton. Asthma was diagnosed in 277 children (66.1% male and 33.9% female). The difference between asthma frequency in boys and girls was significant (chi2 = 56.16; df = 1; p < 0.0001). The average difference in proportion between the boys and girls was 32.2% (95% CI = 24.32-40.08). From this sample group the boys had a 3.8 times greater risk (OR = 3.79; %95 CI = 2.67-5.39) of contracting asthma. The average rate of incidence of asthma for both sexes in the observed period was 0.67/1000 (95% CI; 0.6-0.7; for boys 0.86/1000; for girls 0.47/1000). There was a statistically significantly higher incidence of asthma in boys in relation to girls (t = 6.3836, df = 32; p < 0.0001). The epidemiological data obtained could be useful for early detection and adequate treatment of children with asthma in the mentioned area.