TBNet: a context-aware graph network for tuberculosis diagnosis.
Tuberculosis (TB) is an infectious bacterial disease. It can affect the human lungs, brain, bones, and kidneys. Pulmonary tuberculosis is the most common. This airborne bacterium can be transmitted with the droplets by coughing and sneezing. So far, the most convenient and effective method for diagnosing TB is through medical imaging. Computed tomography (CT) is the first choice for lung imaging in clinics because the conditions of the lungs can be interpreted from CT images. However, manual screening poses an enormous burden for radiologists, resulting in high inter-observer variances. Hence, developing computer-aided diagnosis systems to implement automatic TB diagnosis is an emergent and significant task for researchers and practitioners. This paper proposed a novel context-aware graph neural network called TBNet to detect TB from chest CT images METHODS: Traditional convolutional neural networks can extract high-level image features to achieve good classification performance on the ImageNet dataset. However, we observed that the spatial relationships between the feature vectors are beneficial for the classification because the feature vector may share some common characteristics with its neighboring feature vectors. To utilize this context information for the classification of chest CT images, we proposed to use a feature graph to generate context-aware features. Finally, a context-aware random vector functional-link net served as the classifier of the TBNet to identify these context-aware features as TB or normal RESULTS: The proposed TBNet produced state-of-the-art classification performance for detecting TB from healthy samples in the experiments CONCLUSIONS: Our TBNet can be an accurate and effective verification tool for manual screening in clinical diagnosis.


Further characterization of the actin-related protein Act3p/Arp4 of S. cerevisiae through mutational analysis.
In the course of functional analysis of the yeast ARP4 (ACT3) gene, we further characterized the role of its protein product Arp4p in the cell. We report that although it is localized in the nucleus, Arp4p performs its function independently of binding to DNA directly. The roles of the core actin structure (the ATP-binding pocket) and a putative Nuclear Localization Signal (NLS) of Arp4p were tested by targeted mutagenesis. The results suggest that under normal conditions, the ATPase activity and the NLS are dispensable for the essential function of this protein in the cell. Furthermore, the use of reporter genes confirmed that Arp4p could be involved in some general mechanism of transcriptional regulation.


Seasonal variation of the distribution of PCBs in sediments and biota in a PCB-contaminated estuary.
To elucidate the effects of seasonal variation of precipitation on the distribution of polychlorinated biphenyls (PCBs) in estuarine sediments and benthic feeders, PCB concentrations of river surface sediments and mullet fish (Liza macrolepis) were investigated in the estuary of Er-Jen River near former PCB contamination sites before and after each wet season from 2002 to 2004. Analyses of grain size distribution and organic matter revealed that the pre-existing surface sediments were covered by and mixed with the soil particulates brought by surface runoff after each wet season. Obvious increment of PCB content and significantly elevated fraction (p<0.005) of light PCBs of the river mouth's sediments after each wet season indicated that the invading particles were rich in un weathered PCBs. PCBs previously buried in the surface soil of heavily contaminated sites were flushed into this estuary through surface runoff. The precipitation altered the PCB patterns in sediment organic matter, the dietary source of mullet, and consequently changed that of mullets accordingly, which all possessed significant greater fraction of light PCBs. In this study, it was demonstrated that seasonal summer precipitation affected the distribution of PCBs on surface sediments and the mullets of this estuary. PCB residuals retained in this region still pose potential threats to biota resided here.


Efficient sorption of polyphenols to soybean flour enables natural fortification of foods.
The present study demonstrated that defatted soybean flour (DSF) can sorb polyphenols from blueberry and cranberry juices while separating them from sugars. Depending on DSF concentration and juice dilution, the concentration of blueberry anthocyanins and total polyphenols sorbed to DSF ranged from 2 - 22 mg/g and 10 - 95 mg/g, respectively while the concentration of anthocyanins and proanthocyanidins in cranberry polyphenol-enriched DSF ranged from 2.5 - 17 mg/g and 21 - 101 mg/g, respectively. Blueberry polyphenols present in one serving of fresh blueberries (73g) were delivered in just 1.4 g of blueberry polyphenol-enriched DSF. Similarly, one gram of cranberry polyphenol-enriched DSF delivered the amount of proanthocyanidins available in three 240 ml servings of cranberry juice cocktail. The concentration of blueberry anthocyanins and total polyphenols eluted from DSF remained constant after 22 weeks of incubation at 37°C, demonstrating the high stability of the polyphenol-DSF matrix. LC-MS analysis of eluates confirmed DSF retained major cranberry and blueberry polyphenols remained intact. Blueberry polyphenol-enriched DSF exhibited significant hypoglycemic activities in C57bl/6J mice, and cranberry polyphenol-enriched DSF showed anti-microbial and anti-UTI activities in vitro, confirming its efficacy. The described sorption process provides a means to create protein-rich food ingredients containing concentrated plant bioactives without excess sugars, fats and water that can be incorporated in a variety of scientifically validated functional foods and dietary supplements.


Claudin-5a is essential for the functional formation of both zebrafish blood-brain barrier and blood-cerebrospinal fluid barrier.
Mammalian Claudin-5 is the main endothelial tight junction component maintaining blood-brain barrier (BBB) permeability, while Claudin-1 and -3 seal the paracellular space of choroid plexus (CP) epithelial cells contributing to the blood-cerebrospinal fluid barrier (BCSFB). In zebrafish, two paralogs of claudin-5a and -5b are expressed while their roles in the formation of BBB and BCSFB are unclear. The expression patterns of Claudin-5a and -5b in zebrafish brains were systematically analyzed by immunofluorescence (IF) assay. The developmental functions of Claudin-5a and -5b were characterized by generating of claudin-5a and -5b mutants respectively. Meanwhile, the cerebral inflammation and cell apoptosis in claudin-5a-/- were assessed by live imaging of transgenic zebrafish, RT-qPCR, IF, and TUNEL assay. The integrity of BBB and BCSFB was evaluated by in vivo angiographic and dye permeation assay. Finally, RT-qPCR, whole-mount RNA in situ hybridization (WISH), and transmission electron microscopy (TEM) analyses were performed to investigate the development of cerebral vessels and choroid plexus. We showed that Claudin-5a and -5b are both expressed in zebrafish cerebrovascular endothelial cells (ECs). In addition, Claudin-5a was strongly expressed in CP epithelial cells. Loss of Claudin-5b showed no effect on zebrafish vasculogenesis or BBB function. In contrast, the knockout of claudin-5a caused a lethal phenotype of severe whole-brain oedema, ventricular dilatation, and cerebral hernia in zebrafish larvae, although the cerebral vasculogenesis and the development of CP were not altered. In claudin-5a-/- , although ultrastructural analysis of CP and cerebral capillary showed intact integrity of epithelial and endothelial tight junctions, permeability assay indicated a disruption of both BBB and BCSFB functions. On the molecular level, it was found that ZO-1 was upregulated in the CP epithelium of claudin-5a-/-, while the notch and shh pathway responsible for CP development was not affected due to loss of Claudin-5a. Our findings verified a non-functional role of zebrafish Claudin-5b in the BBB and identified Claudin-5a as the ortholog of mammalian Claudin-5, contributing to the development and the functional maintenance of both BBB and BCSFB.


Reference values for serum levels of insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) in the West Black Sea region of Turkey.
The aim of this study was to determine the normal values of serum IGF-1 and IGFBP-3 in Turkish children and adults (1-79 years). The study included 571 healthy children and 625 healthy adults from the West Black Sea region of Turkey. Serum IGF-1 and IGFBP-3 concentrations were determined using a chemiluminescent immunometric assay on an Immulite 1000 analyzer. IGF-1 and IGFBP-3 levels tended to be higher in girls compared to boys among the children. The differences were statistically significant in puberty from age 12-14 years for IGF-1 and prepubertally from age 9-10 years for IGFBP-3. Peaks of serum IGF-1 levels were observed 2 years earlier in girls (14 years) than boys (16 years). The general pattern of IGFBP-3 was similar to IGF-1 during puberty. In adults, IGF-1 and IGFBP-3 levels decreased by age. There was no significant difference in IGF-1 and IGFBP3 values between men and women in any age group. This study established age- and sex-specific reference values for serum IGF-1 and IGFBP-3 in healthy Turkish children and adults.


High-Dose Chemotherapy With Autologous Stem Cell Transplantation in a Case of Refractory Peripheral T Cell Lymphoma With Tracheoesophageal Fistula: A Case Report.
A 46-year-old woman with a sore throat was diagnosed with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma that had spread from the piriform fossa to the cervical esophagus. Tracheoesophageal fistula developed after induction chemotherapy. Because conservative repair was not applicable, intensified chemotherapy, including autologous stem cell transplantation was performed with the fistula remaining open. Laryngopharyngectomy and cervical esophagectomy were performed 6 months after transplantation. The optimal strategy for refractory lymphoma with active tracheoesophageal fistula remains undetermined. To the best of our knowledge, this is the first report describing the successful treatment of a patient with tracheoesophageal fistula who received high-dose chemotherapy supported by autologous stem cell transplantation.


Genetic diversity in Echinococcus shiquicus from the plateau pika (Ochotona curzoniae) in Darlag County, Qinghai, China.
The metacestode of Echinococcus shiquicus has been recorded previously in the lung and liver of its intermediate host, the plateau pika (Ochotona curzoniae), but there is limited information regarding other organ sites. There is also limited evidence of intra-specific genetic variation within E. shiquicus. A PCR-amplified mitochondrial (mt) nad1 gene fragment (approximately 1400bp in size), with unique EcoRI and SspI restriction sites, was used to distinguish cysts or cyst-like lesions of E. shiquicus from E. multilocularis. Then, the complete mt nad1 and cox1 genes for the E. shiquicus isolates were amplified and sequenced. Phylogenetic tree and haplotype network analyses for the isolates were then generated based on a concatenated dataset of the nad1 and cox1 genes using the neighbour-joining (NJ) method and TCS1.21 software. Nineteen of eighty trapped pikas were found to harbor cysts (71 in total) when dissected at the survey site. Seventeen animals had cysts (fertile) present only in the lungs, one animal had fertile cysts in the lungs and spleen, and one individual had an infertile kidney cyst. Restriction endonuclease analysis of a fragment of the nad1 gene indicated all the cysts were due to E. shiquicus. Genetic diversity analysis revealed that the nad1 and cox1 genes varied by 0.1-1.2% and 0.1-1.0%, respectively. Haplotype network analysis of the concatenated nad1 and cox1 sequences of the isolates showed they were classified into at least 6 haplotypes, and different haplotype percentages ranged from 4.2% to 29.6%. Although, high haplotype diversity was evident in the study area, the complete nad1 and cox1 gene sequences obtained indicated that all samples represented isolates of E. shiquicus. The study has also provided a new PCR-restriction endonuclease-based method to rapidly distinguish E. shiquicus from E. multilocularis which provides a useful tool for epidemiological investigations where the two species overlap.


Relevance of vascular peroxisome proliferator-activated receptor γ coactivator-1α to molecular alterations in atherosclerosis.
Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is emerging as a novel factor that plays a critical role in integrating signalling pathways in the control of cellular and systemic metabolism. We investigated the role of vascular expression of PGC-1α and related factors, such as sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor γ (PPARγ) and adiponectin, during the atherosclerotic process. Endothelial function, vascular superoxide anion production and inflammatory mediators were also evaluated. This study was carried out in male New Zealand rabbits fed a diet containing 0.5% cholesterol and 14% coconut oil for 8 weeks. Animals developed mixed dyslipidaemia and atherosclerotic lesions, which were associated with endothelial dysfunction, aortic overproduction of superoxide anions and inflammation. Expression of PGC-1α, SIRT1, PPARγ and adiponectin was reduced (P<0.05) in aorta from atherosclerotic rabbits. Levels of PGC-1α were correlated negatively (P<0.05) with total cholesterol levels, aortic superoxide anion production and tumour necrosis factor-α expression, and positively (P<0.05) with maximal relaxation in response to acetylcholine. The observed results suggest that PGC-1α could be considered to be a link between the main atherosclerotic processes (endothelial dysfunction, oxidation and inflammation) and alterations of other factors involved in vascular wall integrity, such as SIRT1, PPARγ and adiponectin.


The efficiency of the Sudan-III-staining to identify wear particles of pmma-bone cement in tissue after total endoprostheses.
On the basis of the newly-formed capsular tissue of 80 cemented (Weber-Huggler, Müller-Charnley) and uncemented (ceramic/ceramic/titanium) total hip endoprostheses which had to be reoperated on because of aseptic loosening, the efficiency of the Sudan-III-staining reported in literature to identify polymethylmethacrylate (PMMA) bone cement particles is investigated, because the quantity as well as quality of the various wear products is discussed as possible factors of prostheses loosening. PMMA-, polyethylene and polyester particles show definite sudanophilia and orange-red coloration in the Sudan-III-stained frozen sections, so that only very large wear products utilizing the knowledge of the materials of the artificial joints used can be recognized by their forms, whereas the wear stored in the macrophages cannot be identified. Thus, Sudan-III-staining is not suitable for guaranteeing identification and determination of the amount of PMMA-wear.


Central-part laryngectomy after laryngotracheal separation to manage pharyngocutaneous fistula: A case report and retrospective analysis of 12 cases.
A 15-year-old girl presented with a 3-year-history of continuous outflow of saliva from a pharyngocutaneous fistula, located at 5 mm superior to her tracheal stoma. She was diagnosed with Miller-Dieker syndrome at birth. At 2 years of age, pediatric surgeons at our institution carried out laryngotracheal separation to prevent aspiration pneumonia. At the age of 12 years, she developed continuous saliva discharge from the fistula. We performed central-part laryngectomy and resection of the pharyngocutaneous fistula, which relieved her from the continuous saliva discharge. Central-part laryngectomy is less invasive and easier to perform than total laryngectomy. We hereby present a case and retrospective analysis of 12 patients, who underwent central-part laryngectomy.


Debriefing following trauma.
In this paper we address three areas. First we review the literature on clinical intervention using debriefing, second we examine who attends debriefings by looking at a study of the 1989 plane crash at Ramstein, Germany and lastly we examine the effect of natural debriefing, i.e., talking to family and friends on psychiatric outcome in disaster workers by looking at a study of the Sioux City, Iowa United plane crash, 1989. Our data suggest that those with high exposure and females were more likely to attend a debriefing. People most likely to talk about the disaster with spouse/significant other, coworker and/or another person were: those with acute PTSD, higher total and intrusive Impact of Event symptoms, older, married, those with higher levels of education and higher levels of disaster exposure. Better understanding of who attends formal debriefings will help identify potential high-risk groups. Similarly, whether talking about the disaster is associated with fewer or greater psychological symptoms is important to understanding the outcome, mechanisms, and risks of debriefing.


Popliteal pseudoaneurysm secondary to a tibial osteochondroma: diagnosis with multi-detector row computed tomographic angiography.
A 17-year-old male presented with right knee pain following mild trauma whilst playing badminton. He subsequently developed a popliteal pseudoaneurysm secondary to trauma from a tibial osteochondroma. This is a recognised though very rare occurrence. Its appearance is reported for the first time using multidetector row computed tomographic angiography (MDCTA). The clinical presentation and management of the popliteal pseudoaneurysm are outlined and the imaging findings are illustrated. There is increasing usefulness of MDCTA as an accessible, accurate, noninvasive clinical tool in the emergency diagnostic setting. Its use in the management of this unusual condition is demonstrated with emphasis on 3D, multi-planar reconstruction post-processing techniques.


Concomitant Reverse Hill-Sachs Lesion and Posterior Humeral Avulsion of the Glenohumeral Ligament: Treatment With Fresh Talus Osteochondral Allograft and Arthroscopic Posterior Humeral Avulsion of the Glenohumeral Ligament and Labrum Repair.
Chronic posterior glenohumeral joint instability can be a challenging clinical entity for patients and surgeons alike. In the setting of a posterior dislocation, a large anterior humeral impaction injury (reverse Hill-Sachs [HS]) may occur, leading to engagement of the humerus with the posterior glenoid bone, especially during internal rotation of the joint. A reverse HS is especially debilitating because of the significant portion of affected humeral head cartilage, and is made worse in the setting of ligamentous disruption such as a posterior humeral avulsion of the glenohumeral ligament (HAGL) lesions. Although several nonanatomic procedures to address these defects have been previously described, recent interest in anatomic reconstructions capable of restoring the cartilage surface of the humeral head has led to the use of bone grafts (autografts and allografts) to restore the articular contour of the humeral head in conjunction with anatomic repair of associated soft tissue injuries. We present our preferred technique for an anatomic repair of a posterior HAGL lesion in combination with reconstruction of an engaging reverse HS lesion using an unmatched hemitalar allograft.


Relationship between symptoms and dietary patterns in patients with functional dyspepsia.
Patients with functional dyspepsia (FD) often report that their symptoms are related to food ingestion. However, there is a lack of information about differences in eating patterns and nutrient intake between these patients and healthy individuals or the association with specific symptoms. We performed a prospective trial to evaluate the relationship between FD symptoms and dietary factors. Twenty patients with FD (17 women) and 21 healthy subjects (18 women) completed detailed diet diaries, recording all foods eaten, drinks consumed, and times of consumption, as well as the occurrence, timing, and severity of dyspeptic symptoms (ie, nausea, discomfort, fullness, bloating, upper-abdominal/epigastric pain) for 7 days. Data from the diet diaries were analyzed for the number of meals, light meals, snacks and drinks, energy intake, and macronutrient distribution. Patients with FD ate fewer meals (P < .01) and consumed less total energy (P = .1) and fat (P = .1) than healthy subjects. Their symptoms were modest in severity (score out of 10; 5 [range, 3-8]) and occurred within 31 minutes (range, 8-64 min) of eating. Fullness was related directly to the amount of fat ingested (z, 1.91; P < .05) and overall energy intake (z, 2.12; P < .05) and related inversely to the amount of carbohydrate ingested (z, -1.9; P = .05). Similarly, bloating was related to the amount of fat ingested (z, 1.68; P = .09). There was no significant relationship between symptom severity and any of the dietary variables measured. Management of patients with FD might be improved by instructing them to consume smaller meals with reduced fat content.


The effects of type beta transforming growth factor on proliferation and epidermal growth factor receptor expression in a human glioblastoma cell line.
Type beta transforming growth factor (B-TGF) is a potent growth inhibitor to many human tumor cell lines. Very little is known about the mechanism for this growth inhibitory action of B-TGF. We here report the effect of B-TGF on proliferation and epidermal growth factor receptor (R-EGF) expression in a human glioblastoma cell line named T-MG1. B-TGF inhibit the soft agar growth of T-MG1 cells. Maximum inhibition was 70%, achieved with 0.5 units B-TGF. B-TGF had no effect on monolayer growth of T-MG1 cells. T-MG1 cells contained abundant R-EGF, which could be divided into two subpopulations, one high affinity and one low affinity population of R-EGF. Treatment with B-TGF caused an initial decrease (0-6 h) in EGF-binding, followed by an increase in EGF-binding which reached maximum after 24 h exposure to B-TGF. Since addition of EGF to agar cultures gave no additional increase in inhibition by B-TGF and EGF alone had no inhibitory effect, we believe that binding of EGF to its receptor is not part of the pathway mediating the inhibitory effect of B-TGF. All neoplastic cells have lost some measure of growth control and the cellular elements involved are growth factors, growth factor receptors and oncogenes. T-MG1 cells contain abundant R-EGF and this may partly explain their malignant nature (malignant nature is here defined as ability to proliferate in agarose). Type alpha transforming growth factors, which in some cancer cells act as uncontrolled autocrine growth factors, were not found in protein extracts from T-MG1 cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Peptides and membrane fusion: towards an understanding of the molecular mechanism of protein-induced fusion.
Processes such as endo- or exocytosis, membrane recycling, fertilization and enveloped viruses infection require one or more critical membrane fusion reactions. A key feature in viral and cellular fusion phenomena is the involvement of specific fusion proteins. Among the few well-characterized fusion proteins are viral spike glycoproteins responsible for penetration of enveloped viruses into their host cells, and sperm proteins involved in sperm-egg fusion. In their sequences, these proteins possess a "fusion peptide, " a short segment (up to 20 amino acids) of relatively hydrophobic residues, commonly found in a membrane-anchored polypeptide chain. To simulate protein-mediated fusion, many studies on peptide-induced membrane fusion have been conducted on model membranes such as liposomes and have employed synthetic peptides corresponding to the putative fusion sequences of viral proteins, or de novo synthesized peptides. Here, the application of peptides as a model system to understand the molecular details of membrane fusion will be discussed in detail. Data obtained from these studies will be correlated to biological studies, in particular those that involve viral and sperm-egg systems. Structure-function relationships will be revealed, particularly in the context of protein-induced membrane perturbations and bilayer-to-nonbilayer transition underlying the mechanism of fusion. We will also focus on the involvement of lipid composition of membranes as a potential regulating factor of the topological fusion site in biological systems.


Long chain n-3 polyunsaturated fatty acids are not associated with circulating T-helper type 1 cells: Results from the Multi-Ethnic Study of Atherosclerosis (MESA).
T-helper type 1 (Th1) cells are pro-inflammatory and provide signals to immune cells. Animal models and in vitro human cell culture experiments have indicated that long chain n-3 polyunsaturated fatty acids (LCn3PUFAs) reduce Th1 cell levels; however, the association is unknown in healthy humans. We hypothesized that circulating levels and dietary intake of LCn3PUFAs have an inverse association with circulating levels of Th1 cells and studied 895 participants in the Multi-Ethnic Study of Atherosclerosis (age 61 ± 10 years at exam 1, 52% women, 44% white, 21% African-American, 24% Hispanic-American, 11% Chinese-American). Phospholipid LCn3PUFAs (% of total fatty acids), measured by gas chromatography, and intake of LCn3PUFAs, evaluated by food frequency questionnaire, were evaluated at exam 1 (2000-02) and defined as the sum of eicosapentaenoic and docosahexaenoic acids. Th1 cells were measured by flow cytometry at exam 4 (2005-07), expressed as a percentage of CD4+ lymphocytes that were interferon-γ+ (%Th1: CD4+IFN-γ+). Median (interquartile range) plasma LCn3PUFA, dietary LCn3PUFA, and %Th1 levels were 4.31% (3.40-5.82%), 0.09 (0.05-0.16) g/day, and 14.4% (9.8-20.0%), respectively. When the association of LCn3PUFA-quartiles with %Th1 was analyzed using general linear models, neither plasma nor dietary LCn3PUFAs were significantly associated with %Th1 (P-trend = 0.58 and 0.80, respectively), which remained even after adjusting for demographics, lifestyle factors, lipids, season, and cytomegalovirus titers. In this multi-ethnic U.S. population, circulating levels and dietary intake of LCn3PUFAs were not significantly associated with Th1 cell levels. Further research is needed to assess potential benefits of supplementation and much higher dietary consumption of LCn3PUFAs on Th1 cells.


Preparation of the Lanthanum-Aluminum-Amended Attapulgite Composite as a Novel Inactivation Material to Immobilize Phosphorus in Lake Sediment.
In this study, a green solvent-free drying production method was used to prepare an attapulgite clay/lanthanum and aluminum (ACLA) composite as a novel phosphorus (P) sorbent to immobilize P in lake sediment. The prepared sorbent contained around 5% La and 2% Al. The maximum P sorption capacity of ACLA can reach as high as 34.6 mg P/g and is higher than most clay-based P sorbents. The addition of ACLA into sediment can effectively reduce sediment mobile P and simultaneously induce elevated inert P forms of HCl-P and NaOH-rP, which also can increase the stability of P in sediment. Long-term sediment core incubation indicated that 72.2% of total phosphorus and 90.7% of soluble reactive phosphate (SRP), as well as 44.2% SRP fluxes, can be reduced with a dosage of 466 mg/m2 of ACLA when compared with the control treatment. The P binding mechanism by ACLA is assigned to the intersphere P complexes and is mainly because of the formation of rhabdophane and aluminum phosphate precipitation on ACLA. This is confirmed by results of the XPS and 31P NMR spectroscopy, which indicate that the La/Al coexisting novel P inactivation agents are a promising sorbent for lake sediment P control.


Electrorectography in chronic proctitis.
Rectal electrical activity, measured by electrorectography (ERG), was studied in 18 patients with chronic proctitis (11 ulcerative and 7 bilharzial proctitis). Mean age was 36.6 +/- 9.4 (SD) years. Eight healthy volunteers were included as controls. Monopolar recordings were made from silver-silver chloride electrodes situated 1 cm from the tip of the catheter, which was applied to the rectal mucosa. Signals from the electrode were displayed on a U-V recorder. Rectal neck and rectal pressures were recorded simultaneously. Pacesetter potentials (PP) were also recorded from all subjects. The healthy volunteers had a mean frequency of 2.6 +/- 0.6 cycles per minute (cpm), an amplitude of 2.4 +/- 0.5 mV, and a velocity of 4.3 +/- 0.5 cm/sec. The potentials had the same frequency and regular rhythm when the test was repeated and were followed randomly by bursts of action potentials (AP). The rectal pressure increased simultaneously with the AP. In the proctitis patients the PP frequency was higher than normal (mean 8.2 +/- 1.6 cpm in patients with bilharziasis and 8.9 +/- 2.1 cpm in those with ulcerative proctitis) (p < 0.001), whereas the amplitude and velocity were lower than normal (p < 0.05 and p < 0.01, respectively). APs had higher frequency and amplitude and were accompanied by higher rectal pressure than in the normal volunteers. The increased PP, or tachyrectia, may be due to rectal wall or rectosigmoid pacemaker irritation caused by proctitis, whereas the diminished amplitude and velocity may be caused by a diseased rectal wall. The increased AP frequency and amplitude seem to cause increased rectal contractile activity with a resulting tenesmus.(ABSTRACT TRUNCATED AT 250 WORDS)


Hypoglycemic effects of lactucin-8-O-methylacrylate of Parmentiera edulis fruit.
Hypoglycemic activity-guided fractionation together with chemical analysis led to the isolation of one guaianolide (lactucin-8-O-methylacrylate) from the chloroform extract of the dried fruits of Parmentiera edulis. Identification was based on spectroscopic methods. The compounds lowers blood sugar levels after administration to alloxan-diabetic mice.


Single-Stage Augmentation Mastopexy With Composite Reverse Inferior Muscle Sling Technique for Autologous Reinforcement of the Inferior Pole: Technical Refinements and Outcomes.
Single-stage augmentation mastopexy (SAM) is a common procedure, but revision rates are high. Muscle slings have been used in SAM, but despite satisfactory outcomes, most studies do not include objective or accurate measurements of implant/breast position. This article describes a surgical technique for SAM employing a composite reverse inferior muscle sling (CRIMS). The authors sought to assess outcomes from primary SAM procedures utilizing the CRIMS technique in a cohort of patients operated on by a single surgeon. Thirty-two patients (60 breasts) aged a mean of 43.1 ± 6.8 years underwent primary CRIMS mastopexy to treat severe ptosis (grade III-IV) in 25 patients (78.1%). The average implant volume was 255 cc (range, 215-335 cc). Three-dimensional imaging obtained from the Divina scanner system was employed to evaluate lower pole stretch and lower pole arc and to determine long-term ptosis. Four cases of complications were observed in 3 patients (9.3%), minor dehiscence in 2 and capsular contraction in 1, during a mean follow-up of 42 months. The value for lower pole stretch was 5.5% (P < 0.0001) between 10 days and 1 year, with the majority occurring early in the first 6 months, indicating that lower pole arc remained steady during the last months of follow-up. Advances in techniques have led to improvements in aesthetic outcomes following SAM, and CRIMS can play a helpful role. Our results show this procedure is suitable for patients with breast ptosis, with acceptable complication rates and the added bonus of implant stabilization within the pocket.


Antiviral activity of liposomal preparations of antibiotic geliomycin.
A liposomal preparation with maximally possible content of incorporated geliomycin was obtained. Its cytotoxicity was studied in a culture of human embryonal diploid fibroblasts. Antiviral activity was studied on a model of cytomegaloviral infection in vitro by the capacity to plaque formation. Liposomal geliomycin was 10-fold less toxic for human cells than the solution of the antibiotic in DMSO and exhibited antiviral activity towards cytomegaloviral infection at a concentration of 0.042 microg/ml.


Investigational antiepileptic drugs for the treatment of childhood seizure disorders: a review of efficacy and safety.
Pediatric epileptology is very different from adult epileptology. Although some epileptic disorders occur in both children and adults (e.g., localization-related epilepsy with complex partial seizures and primary generalized epilepsy with tonic-clonic seizures), other disorders can be called the catastrophic epilepsies of childhood (e.g., infantile spasms and the Lennox-Gastaut syndrome). They occur, or at least begin, exclusively in childhood and are often associated with mental retardation. Many of these pediatric disorders are notoriously unresponsive to currently available antiepileptic drugs (AEDs). Although there are undoubtedly many reasons for this, one possible explanation is that the methods used to screen potential AEDs use animal models of adult epilepsy. No screening program uses an animal model of seizures that begin during development and lead to functional decline.


Low vitamin D in dark-skinned immigrants is mainly due to clothing habits and low UVR exposure: a Danish observational study.
Low 25-hydroxyvitamin D3 (25(OH)D) among dark-pigmented persons has been observed. To elucidate the reason for this we examined sun behaviour, sun-exposed body area, solar UVR exposure and 25(OH)D levels in immigrants with dark pigmented skin and Danes with light pigmented skin. Clothing, sun behaviour, and diet were recorded daily during a Danish summer season (93 analysed days). Erythema-weighted UVR doses were measured by personal electronic UVR dosimeters (with erythema response, measurement every 5th second) and 25(OH)D was measured in 72 participants (33 dark-skinned and 39 light-skinned). The immigrants exposed 28% less skin area, received 70% less UVR dose, and had 71% less 25(OH)D increase during the summer. The UVR reactivity (Δ25(OH)D per joule accumulated UVR dose) was similar (P = 0.62) among the immigrants (0.53 nmol l-1 J-1) and the Danes (0.63 nmol l-1 J-1). In the groups combined, 25(OH)D levels after summer were mainly influenced by UVR dose to exposed skin (28.8%) and 25(OH)D start level (27.9%). Height and measured constitutive skin pigmentation were of minor influence: 3.5% and 3.2%, respectively. Sun exposure and clothing habits were the main reasons for lower 25(OH)D level after summer in the darker immigrants, as both groups had similar UVR reactivity.


Mouse Organotypic Brain Slice Cultures: A Novel Model for Studying Neuroimmune Responses to Cryptococcal Brain Infections.
Cryptococcal meningitis affects millions of people worldwide and is especially prevalent in regions with a high burden of HIV/AIDS. The study of the pathophysiology of this often fatal disease has been significantly hindered by the lack of reliable experimental models, especially at the level of the brain, which is the main organ of injury. Here we outline our novel protocol for the use of hippocampal organotypic brain slice cultures (HOCs) to study the host-fungal interactions during cryptococcal infections of the brain. HOCs are a powerful platform for investigating neuroimmune interactions as they allow for the preservation of all innate neuroglial cells including microglia, astrocytes, and neurons, all of which maintain their three-dimensional architecture and functional connectivity. We made HOCs from neonatal mice and infected these with a fluorescent strain of Cryptococcus neoformans for 24 h. Using immunofluorescent staining, we confirmed the presence and morphology of microglia, astrocytes, and neurons in HOCs prior to infection. Using fluorescent and light microscopy, we also confirmed that Cryptococcus neoformans encapsulates and buds in vitro, as it would in a host. Finally, we demonstrate that infection of HOCs with Cryptococcus neoformans results in close association of the fungal cells with host microglial cells. Our results demonstrate the utility of HOCs as a model to study the pathophysiology and host neuroimmune responses in neurocryptococcosis, which may assist in improving our collective understanding of the pathogenesis of this disease.


Long-term survival with stage IV poorly differentiated pancreatic adenocarcinoma.
Metastatic poorly differentiated adenocarcinoma of the pancreas has a poor outcome despite the use of various chemotherapy regimes. A 57-year-old woman presented with a 3-month history of generalised abdominal pain associated with weight loss. Computed tomography (CT) showed a large tumour in the head and body of pancreas, and needle biopsy confirmed a poorly differentiated adenocarcinoma. Laparoscopy revealed liver metastases in both lobes, again histologically shown to be poorly differentiated adenocarcinoma. Six cycles of cisplatin, epirubicin and infusional 5-fluorouracil were given. Five years later the patient remains completely well. Repeat CT scans show a complete radiological response. Previous studies using numerous chemotherapy regimes have not significantly altered the outcome of pancreatic cancer. To the best of our knowledge this is the longest surviving case of a patient with advanced metastatic adenocarcinoma (stage IV) of the pancreas treated with chemotherapy.


Beta estrogen receptor knockout (BERKO) mice present attenuated hippocampal CA1 long-term potentiation and related memory deficits in contextual fear conditioning.
Estrogen has marked effects on hippocampal synaptic plasticity. We demonstrate that male and female 3-month-old beta estrogen receptor knockout (BERKO) mice show profound memory impairment in a hippocampus-mediated fear-conditioning paradigm. Subsequently, hippocampal slices prepared from behaviorally naive female BERKO mice were examined electrophysiologically. These were found to have robust synaptic deficits, compared to slices from age-matched wild type controls, both in terms of their input-output curves and their expression of long-term-potentiation in area CA1. This report provides the first concrete evidence of significant hippocampal synaptic plasticity and memory deficits in the BERKO mouse.


Use of sirolimus in IPEX and IPEX-like children.
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome), a rare inflammatory disease caused by mutations of Foxp3, destroys the immunoregulatory environment of affected male infants. Data on optimal therapy are limited. We reviewed the effect of sirolimus use in our cohort of IPEX and IPEX-like patients (n = 7). Our patients exhibited features of enteropathy and recurrent infections with bacterial and viral pathogens. Before initiating sirolimus, six patients were treated with corticosteroids. Several also received other immunosuppressive agents. After starting sirolimus, six patients had improvement in diarrhea, and two were able to decrease corticosteroid dosages. Several also had significantly decreased number of infections after treatment. Of the three patients with post-treatment duodenal biopsies, two showed improvement in villous architecture. No significant adverse events occurred. Our experience suggests that sirolimus is a clinically effective and safe therapeutic option in IPEX and IPEX-like patients.


X-ray Photoelectron Fingerprints of High-Valence Ruthenium-Oxo Complexes along the Oxidation Reaction Pathway in an Aqueous Environment.
Recent advances in operando-synchrotron-based X-ray techniques are making it possible to address fundamental questions related to complex proton-coupled electron transfer reactions, for instance, the electrocatalytic water splitting process. However, it is still a grand challenge to assess the ability of the different techniques to characterize the relevant intermediates, with minimal interference on the reaction mechanism. To this end, we have developed a novel methodology employing X-ray photoelectron spectroscopy (XPS) in connection with the liquid-jet approach to probe the electrochemical properties of a model electrocatalyst, [RuII(bpy)2(py)(OH2)]2+, in an aqueous environment. There is a unique fingerprint of the extremely important higher-valence ruthenium-oxo species in the XPS spectra along the oxidation reaction pathway. Furthermore, a sequential method combining quantum mechanics and molecular mechanics is used to illuminate the underlying physical chemistry of such systems. This study provides the basis for the future development of in-operando XPS techniques for water oxidation reactions.


Short duration exposures to organic solvents: the relationship between neurobehavioral test results and other indicators.
Short duration exposure to solvents at even low concentrations can induce signs of mild toxicity such as mucous membrane irritation, tearing, nasal irritation, headache, and nausea. These irritant effects are often used as warning properties for potential solvent toxicities and have frequently been classified in the literature as pre-narcotic effects. With higher exposures the toxic effects are more pronounced and can include intoxication, incoordination, exhilaration, sleepiness, stupor, and the beginning stages of anesthesia. Collectively these effects are taken as indicators of narcosis. Offering recommendations for safe exposure limits for these shorter term exposures is made difficult because, (1) the mild toxic effects are often reported subjectively and tolerance usually develops, (2) the solvent concentration(s) cannot be documented in all cases, and (3) the effects are reversible when individuals are removed from exposure. Laboratory experiments involving controlled exposures to solvents using neurobehavioral performance tests represent one form of investigation that can provide meaningful information in this instance. The results can be viewed in two ways with reference to issues of safe exposure limits. One is to ensure that performance functions that can compromise safety are not affected by the exposure limits prescribed. The second is to consider performance changes due to short-term exposures as possible precursors of similar but more severe effects given longer term exposures. Thus, setting exposure limits to protect against these performance changes could possibly prevent the development of more serious cases of chronic solvent neurotoxicity. This paper compares solvent concentrations from short-duration exposure studies using neurobehavioral tests with the concentrations producing irritant and narcotic effects, as documented by the two main standards recommending bodies, the National Institute for Occupational Safety and Health and the American Conference of Governmental Industrial Hygienists. Comparisons are also made with the regulatory exposure limits established by the Occupational Safety and Health Administration. In general, the neurobehavioral changes which occur following short-duration exposures are reported at concentrations between those which produce irritant effects and narcosis. For the chemicals which have been tested, the performance changes measured by the present day neurobehavioral tests in use rarely occur at or below those limits recommended by the standards recommending bodies.


Effect of the surface charge of artificial model membranes on the aggregation of amyloid β-peptide.
The neurotoxicity effect of the β-amyloid (Aβ) peptide, the primary constituent of senile plaques in Alzheimer's disease, occurs through interactions with neuronal membranes. Here, we attempt to clarify the mechanisms and consequences of the interaction of Aβ with lipid membranes. We have used liposomes as a model of biological membrane, and have devoted particular attention to the bilayer charge effect. Our results show that insertion and surface association of peptide with membrane, increased in a membrane charge-dependent manner, lead to a reduction of Aβ soluble species, lag time elongation and an increase in the inter-molecular β-sheet ratio of amyloid fibrils. In addition, our findings suggest that the fine balance between peptide insertion and surface association modulates Aβ aggregation, influencing the amyloid fibrils concentration as well as their morphology.


When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function.
As a way of delineating different levels of cancer pain severity, we explored the relationship between numerical ratings of pain severity and ratings of pain's interference with such functions as activity, mood, and sleep. Interference measures were used as critical variable to grade pain severity. We explored the possibility that pain severity could be classified into groupings roughly comparable to mild, moderate, and severe. Our hypothesis was that mild, moderate, and severe pain would differentially impair cancer patients' function. We were able to identify boundaries among these categories of pain severity in terms of their interference with function. We also examined the extent to which cancer patients from different language and cultural groups differ in their self-reported interference as a function of pain severity level. We found optimal cutpoints that form 3 distinct levels of pain severity that can be defined on a 0-10-point numerical scale. We determined that, based on the degree of interference with cancer patients' function, ratings of 1-4 correspond to mild pain, 5-6 to moderate pain, and 7-10 to severe pain. Our analysis illustrates that the pain severity-interference relationship is non-linear. These cutpoints were the same for each of the national samples in our analysis, although there were slight differences in the specific interference items affected by pain. These cutpoints might be useful in clinical evaluation, epidemiology, and clinical trials.


The patentability of antibodies in the United States.
Recent US case law attempts to further clarify the written description, novelty and non-obviousness requirements as they apply to antibodies


A phase II study of 5-fluorouracil plus folinic acid in malignant gliomas in adults.
Fourteen patients with malignant gliomas were entered on a phase II study of 5-fluorouracil 300-370 mg/m2 plus folinic acid 200 mg/m2 x 5 days q4 weeks. To be eligible, patients could not have received more than 1 prior chemotherapy regimen. A single patient with a recurrent oligodendroglioma responded. Toxicity (predominantly stomatitis, diarrhea, and granulocytopenia) was tolerable and was similar to that seen in studies of 5-fluorouracil plus folinic acid in other tumor types. This regimen has minimal activity in recurrent malignant gliomas.


RANK, RANKL and OPG expressions in a permanent molar with a replacement resorption.
The aim of this study was to explore the expression of RANK, RANKL and OPG during ankylosis. Structural details and immunohistochemical investigations of the expression of RANK, RANKL and OPG in an extracted secondary retained permanent molar of a 12-year-old girl are reported. Woven and lamellar bones were observed in the thickness of the remodeled dental wall and a tertiary dentin was noticed around the pulp cavity. The resorbing multinucleated cells expressed TRAP and RANK but few of them also expressed RANKL. Both odontoblasts and osteoblasts expressed TRAP and RANK, but the expression of RANKL was limited to osteoblasts. OPG remained undetected. The present case reveals unusual expression of RANKL in the resorbing cells, TRAP and RANK in both osteoblasts and odontoblasts, and a failure of detection of OPG. These proteins could be involved in the pathogenesis of tooth ankylosis.


Expression of cyclooxygenase-2 in association with clinicopathological prognostic factors and molecular markers in epithelial ovarian cancer.
This study examines whether expression of COX-2 is associated with clinicopathological features and other molecular markers of ovarian cancer. Sixty-four paraffin-embedded tissue specimens were obtained from patients with ovarian cancer who received cytoreductive surgery and combination chemotherapy. Tissue specimens were subjected to immunohistochemical analysis using antibodies to COX-2, p53, and VEGF. Increased COX-2 expression significantly correlated with histologic type (mucinous 5.6% vs. non-mucinous 65.2%, P<0.001). COX-2 expression was also significantly associated with stage, tumor grade, residual disease status, and presence of ascites. COX-2 expression correlated positively with expression of p53 (P=0.006) and VEGF (P=0.025). Although survival was lower in patients with high COX-2 expression than in those without high COX-2 expression (P<0.001), only tumor grade and stage were independent prognostic indicators. In patients with non-mucinous cancer, COX-2 expression correlated with stage (P<0.001) and presence of ascites (P=0.033). Our results suggest that expression of COX-2 in ovarian cancers is specific to histologic type of tumor and is associated with poor clinicopathologic prognostic factors. Expression of COX-2 also correlates well with expression of p53 and VEGF.


Acetate as a carbon source for lipid synthesis in cultured cells.
Lipid synthesis from acetate and glucose has been studied in fibroblast cultures grown in lipid free medium containing various concentrations of acetate and glucose. Their role in lipid synthesis was evaluated by comparing the specific activities of total cell lipid, and sterol and fatty acid subfractions, to that of the carbon source in the medium. When glucose was present at 1000 microgram/ml (5.6 mM) and acetate at 100 microgram/ml (1.2 mM), the majority of the total cell lipid and subfractions were derived from glucose. As acetate concentrations increased, lipid synthesis from acetate increased, and glucose declined as a carbon source; in cells grown in the presence of 1000 microgram/ml (12 mM) acetate more of the lipid was derived from acetate than from glucose. When acetate was present at 1000 microgram/ml (12 mM) and glucose was varied from 1000 to 200 microgram/ml (5.6 to 1.1 mM), the relative amount of lipid synthesis from acetate was further increased. The data indicate that acetate can serve as a significant carbon source for lipid synthesis in cultured fibroblasts when it is presented to the cells at high extracellular concentrations relative to glucose.


Complications and Their Resolution in Recipients of Deceased and Living Donor Liver Transplants: Findings From the A2ALL Cohort Study.
The purpose of this study was to explore long-term complications in recipients of deceased donor liver transplant (DDLT) and living donor liver transplant (LDLT) in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). We analyzed 471 DDLTs and 565 LDLTs from 1998 to 2010 that were followed up to 10 years for 36 categories of complications. Probabilities of complications and their resolutions were estimated using the Kaplan-Meier method, and predictors were tested in Cox proportional hazards models. Median follow-up for DDLT and LDLT was 4.19 and 4.80 years, respectively. DDLT recipients were more likely to have hepatocellular carcinoma and higher disease severity, including Model for End-Stage Liver Disease score. Complications occurring with higher probability in LDLT included biliary-related complications and hepatic artery thrombosis. In DDLT, ascites, intra-abdominal bleeding, cardiac complications and pulmonary edema were significantly more probable. Development of chronic kidney disease stage 4 or 5 was less likely in LDLT recipients (hazard ratio [HR] 0.41, p = 0.02). DDLT and LDLT had similar risk of grade 4 complications (HR 0.89, p = 0.60), adjusted for other risk factors. Once a complication occurred, the time to resolution did not differ between LDLT and DDLT. Future efforts should be directed toward reducing the occurrence of complications after liver transplantation.


Comparison of United States and canadian glaucoma medication costs and price change from 2006 to 2013.
Objective. Compare glaucoma medication costs between the United States (USA) and Canada. Methods. We modelled glaucoma brand name and generic medication annual costs in the USA and Canada based on October 2013 Costco prices and previously reported bottle overfill rates, drops per mL, and wastage adjustment. We also calculated real wholesale price changes from 2006 to 2013 based on the Average Wholesale Price (USA) and the Ontario Drug Benefit Price (Canada). Results. US brand name medication costs were on average 4x more than Canadian medication costs (range: 1.9x-6.9x), averaging a cost difference of $859 annually. US generic costs were on average the same as Canadian costs, though variation exists. US brand name wholesale prices increased from 2006 to 2013 more than Canadian prices (US range: 29%-349%; Canadian range: 9%-16%). US generic wholesale prices increased modestly (US range: -23%-58%), and Canadian wholesale prices decreased (Canadian range: -38%-0%). Conclusions. US brand name glaucoma medications are more expensive than Canadian medications, though generic costs are similar (with some variation). The real prices of brand name medications increased more in the USA than in Canada. Generic price changes were more modest, with real prices actually decreasing in Canada.


Effects of fenbendazole and triclabendazole on the expression of cytochrome P450 1A and flavin-monooxygenase isozymes in bovine precision-cut liver slices.
Combinations of the anthelmintics fenbendazole (FBZ) and triclabendazole (TCBZ) have shown enhanced efficacy against the liver fluke Fasciola hepatica. This study aimed to measuring the constitutive expression of CYP1A1, CYP1A2, FMO1 and FMO3, thought to be involved in the metabolism of those compounds, by using an absolute quantitative real time (RT)-PCR approach in bovine precision-cut liver slices (PCLS). It also aimed to characterize the effects of FBZ and TCBZ (alone and in combination) on the expression and activity of the aforementioned isozymes. Both FMO1 and FMO3 were equally represented in control PCLS, whereas CYP1A2 was expressed more than CYP1A1 (P<0.05). PCLS cultured in the presence of beta naphthoflavone (β-NF; CYP1A inducer) had higher mRNA levels of CYP1A1, CYP1A2, FMO1 and FMO3 (P<0.05). No clear-cut evidence of transcriptional effects of the anthelmintics were recorded. After incubation of PCLS with FBZ, there was a significant increase (P<0.05) vs. controls and TBCZ was observed for CYP1A1. PCLS treated with FBZ showed a higher (P<0.05) expression of CYP1A2 compared to controls, TCBZ alone, and the combination FBZ+TCBZ. The gene expression profiles of FMO1 and FMO3 were not affected by the presence of the anthelmintics; the only exception was an upregulation of FMO3 by TCBZ alone. The observed transcriptional effects of the xenobiotics were not mirrored by increased enzyme activities using prototypical substrates of the isozymes under study. Although further confirmatory studies are needed, these results suggest that PCLS represent an alternative in vitro tool for studies on the expression, regulation and function of relevant xenobiotic-metabolizing enzymes in cattle.


[The seasonal dynamics of fleas (Siphonaptera) on bank voles (Clethrionomys glareolus) in the north part of Novgorod region].
The twelve flea species were revealed on bank voles. Only four of them (Amalaraeus penicillige, Ctenophthalmus uncinatus, Megabothris turbidus, Peromescopsylla bidentata) were abundant in some seasons of the year. Four other species (Ct. agyrtes, Hystrichopsylla talpae, P. silvatica, Rhadinopsylla integella) are the parasites of bank vole too but their numbers were always low in the study area. The four last species (Amphypsylla rossica, M. walkeri, Doratopsylla dasycnema, Palaeopsylla soricis) are not peculiar to bank vole. They occurs on it occasionally from other animals--the voules of Mucrotus and shrews. The most species diversity of fleas on bank vole was observed at the period from August to October, the least one--in late winter, spring and early summer. The total abundance indices of fleas on the voles (mean number of the insects per host) ranged in different months from 0.17 to 5.65. The time of minimum flea numbers was August-September. The peak abundance was reached in springtime (March-April).


Poly(N-isopropylacrylamide-co-N,N'-methylene bisacrylamide) monolithic column embedded with γ-alumina nanoparticles microextraction coupled with high-performance liquid chromatography for the determination of synthetic food dyes in soft drink samples.
The present work proposes a study of the synthesis of poly(N-isopropylacrylamide-co-N,N'-methylene bisacrylamide) monolithic column embedded with γ-alumina nanoparticles and its applications to the extraction of synthetic food dyes in soft drink samples. The monolithic column was synthesized inside fused silica capillaries using thermally initiated free-radical polymerization with N-isopropylacrylamide (NIPAAm) as the monomer, N,N'-methylene bisacrylamide (MBAAm) as the cross-linker, dimethylsulfoxide (DMSO) and dodecanol as the porogen. γ-Alumina nanoparticles were introduced to prevent the swelling of the organic polymer and enhance the loading capacity. In order to obtain optimum experimental conditions, sample pH, sample flow rate, sample volume, eluent flow rate were investigated. Under the optimum conditions, we obtained acceptable linearities, low limits of detection, and good intra-day/inter-day relative standard deviations. When applied to the determination of four synthetic food dyes (Tartrazine, Sunset Yellow, Allura Red, and Azorubine) in soft drink samples, satisfactory recoveries were obtained in the range of 90.4-109.2%.


Alterations in the high density lipoprotein phenotype and HDL-associated enzymes in subjects with metabolic syndrome.
Patients with metabolic syndrome (MetS) usually have low high density lipoprotein cholesterol (HDL-C) levels. We determined the HDL distribution profile as well as the HDL-related lipoprotein associated phospholipase A(2) (HDL-LpPLA(2)) and paraoxonase-1 (PON1) activities in subjects with MetS (n = 189) but otherwise healthy. Age and sex-matched individuals (n = 166) without MetS served as controls. The lower HDL-C concentration in MetS patients was due to a reduction in both large and small HDL subclasses (P < 0.001 and P < 0.05, respectively). As the number of MetS components increased, the HDL phenotype comprised of a greater percentage of small HDL-3 and less large HDL-2 subclasses, resulting in a decreased HDL-2/HDL-3 ratio (P < 0.001 for all trends). Multivariate analysis revealed that HDL-2 levels and the HDL-2/HDL-3 ratio significantly and independently correlated with HDL-C (positively) and TG (negatively) levels. HDL-3 concentration significantly and independently positively correlated with HDL-C and TG levels. HDL-LpPLA(2) activity was decreased in MetS patients (P < 0.01), a phenomenon that may contribute to the defective antiatherogenic activity of HDL in MetS. PON1 activity did not differ between groups. We conclude that MetS, in addition to the decrease in HDL-C concentration, is associated with alterations in the HDL phenotype, which is comprised of a greater percentage of small HDL subclasses. Furthermore, HDL-LpPLA(2) activity is decreased in MetS patients.


Characterization of sildenafil citrate tablets of different sources by near infrared chemical imaging and chemometric tools.
The chemical imaging technique by near infrared spectroscopy was applied for characterization of formulations in tablets of sildenafil citrate of six different sources. Five formulations were provided by Brazilian Federal Police and correspond to several trademarks of prohibited marketing and one was an authentic sample of Viagra. In a first step of the study, multivariate curve resolution was properly chosen for the estimation of the distribution map of concentration of the active ingredient in tablets of different sources, where the chemical composition of all excipients constituents was not truly known. In such cases, it is very difficult to establish an appropriate calibration technique, so that only the information of sildenafil is considered independently of the excipients. This determination was possible only by reaching the second-order advantage, where the analyte quantification can be performed in the presence of unknown interferences. In a second step, the normalized histograms of images from active ingredient were grouped according to their similarities by hierarchical cluster analysis. Finally it was possible to recognize the patterns of distribution maps of concentration of sildenafil citrate, distinguishing the true formulation of Viagra. This concept can be used to improve the knowledge of industrial products and processes, as well as, for characterization of counterfeit drugs.


Self-assembled vesicles of monocarboxylic acids and alcohols: conditions for stability and for the encapsulation of biopolymers.
We tested the ability of saturated n-monocarboxylic acids ranging from eight to 12 carbons in length to self-assemble into vesicles, and determined the minimal concentrations and chain lengths necessary to form stable bilayer membranes. Under defined conditions of pH and concentrations exceeding 150 mM, an unbranched monocarboxylic acid as short as eight carbons in length (n-octanoic acid) assembled into vesicular structures. Nonanoic acid (85 mM) formed stable vesicles at pH 7.0, the pK of the acid in bilayers, and was chosen for further testing. At pH 6 and below, the vesicles were unstable and the acid was present as droplets. At pH ranges of 8 and above clear solutions of micelles formed. However, addition of small amounts of an alcohol (nonanol) markedly stabilized the bilayers, and vesicles were present at significantly lower concentrations (approximately 20 mM) at pH ranges up to 11. The formation of vesicles near the pK(a) of the acids can be explained by the formation of stable RCOO(-)...HOOCR hydrogen bond networks in the presence of both ionized and neutral acid functions. Similarly, the effects of alcohols at high pH suggests the formation of stable RCOO(-)...HOR hydrogen bond networks when neutral RCOOH groups are absent. The vesicles provided a selective permeability barrier, as indicated by osmotic activity and ionic dye capture, and could encapsulate macromolecules such as DNA and a protein. When catalase was encapsulated in vesicles of decanoic acid and decanol, the enzyme was protected from degradation by protease, and could act as a catalyst for its substrate, hydrogen peroxide, which readily diffused across the membrane. We conclude that membranous vesicles produced by mixed short chain monocarboxylic acids and alcohols are useful models for testing the limits of stabilizing hydrophobic effects in membranes and for prebiotic membrane formation.


Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo.
Deletion of the INK4a/ARF locus at 9p21 is detected with high frequency in human melanoma. Within a short genomic distance, this locus encodes several proteins with established tumor-suppressor roles in a broad spectrum of cancer types. Several lines of evidence support the view that p16INK4a and p19ARF exert the tumor-suppressor activities of this locus, although their relative importance in specific cancer types such as melanoma has been less rigorously documented on the genetic level. Here, we exploit a well-defined mouse model of RAS-induced melanomas to examine the impact of germline p16INK4a or p19ARF nullizygosity on melanoma formation. We demonstrate that loss of either Ink4a/Arf product can cooperate with RAS activation to produce clinically indistinguishable melanomas. In line with the common phenotypic end point, we further show that RAS+ p16INK4a-/- melanomas sustain somatic inactivation of p19ARF-p53 and, correspondingly, that RAS+ p19ARF-/- melanomas experience high-frequency loss of p16INK4a. These genetic studies provide definitive proof that p16INK4a and p19ARF cooperate to suppress the development of melanoma in vivo.


Survival strategy of Cronobacter sakazakii against ampicillin pressure: Induction of the viable but nonculturable state.
In a viable but nonculturable (VBNC) state, bacteria are no longer culturable on standard laboratory media, but still, remain a pathogenic potential and present possible health risks. In this study, we investigated ampicillin's ability, which is commonly used in dairy cattle disease treatment, to induce Cronobacter sakazakii into the VBNC state. After treatment with ampicillin, the counts of culturable cells decreased from 108 CFU/mL to an undetected level 7-30 days post-treatment. Meanwhile, viable cells were still approximately 104-105 cells/mL, and could be resuscitated under appropriate conditions. Fluorescence microscopy showed that VBNC cell maintained apparent cellular integrity, but that the morphology of VBNC cells differed visibly from that of normal cells. Moreover, the respiratory chain activity of VBNC cells were confirmed by flow cytometry (FCM) analysis, suggesting that cells in a VBNC state were physiologically active. Finally, transcriptomics analysis and real-time PCR (qPCR) validation were used to explore the underlying mechanisms of VBNC cell formation. Over-expression of relA, lon, ppx, and ppk in the toxin-antitoxin (TA) trigger system contributed to VBNC cell formation. In the TA trigger system, RelA and exopolyphosphatases/guanosine pentaphosphate phosphohydrolases (PPX/GPPA) synthesize ppGpp, which activates polyphosphate kinase (PPK), the cellular enzyme that accumulates plyphosphate (PolyP). PolyP combines with and stimulates Lon to degrade the antitoxins, thereby activating the toxins that induce a VBNC state. The results of our research will facilitate a better understanding of the survival strategies that bacteria develop to deal with ampicillin pressure and the health risks associated with VBNC Cronobacter sakazakii induced by antibiotics.


Effects of orexins on energy balance and thermoregulation.
Intracerebroventricular injections of 10-20-microg orexin-A induce food intake in rats for about 30 min, or enhance fasting-induced hyperphagia. In thermoregulatory studies, an amount of 2 microg of the peptide causes hypometabolism and hypothermia in the same period. The thermoregulatory reaction can be demonstrated at moderately cool environments, mainly after slight food deprivation. Both the ingestive and the thermoregulatory reactions are more pronounced in cold-adapted animals. Pretreatment with D-Tyr27,36,D-Thr32-NPY(27-36), a peptide-antagonist of NPY, prevents the hypothermia. It is concluded that, probably through NPY activation, orexin-A is involved primarily in the regulation of energy status of the body (as an anabolic agent), and not simply in the regulation of either food intake or body temperature. This anabolic response is followed by a late and more sustained catabolic phase characterized by absence of food intake, increased metabolism and dose-dependent hyperthermia, which hyperthermia cannot be suppressed by the NPY-antagonist. In contrast to orexin-A, neither hyperphagia nor suppression of refeeding hyperphagia, but dose-dependent hyperthermia follows injections of orexin-B, suggesting that this peptide has neither coordinated anabolic nor coordinated catabolic effects on energy balance.


Cellular extrusion bioprinting improves kidney organoid reproducibility and conformation.
Directed differentiation of human pluripotent stem cells to kidney organoids brings the prospect of drug screening, disease modelling and the generation of tissue for renal replacement. Currently, these applications are hampered by organoid variability, nephron immaturity, low throughput and limited scale. Here, we apply extrusion-based three-dimensional cellular bioprinting to deliver rapid and high-throughput generation of kidney organoids with highly reproducible cell number and viability. We demonstrate that manual organoid generation can be replaced by 6- or 96-well organoid bioprinting and evaluate the relative toxicity of aminoglycosides as a proof of concept for drug testing. In addition, three-dimensional bioprinting enables precise manipulation of biophysical properties, including organoid size, cell number and conformation, with modification of organoid conformation substantially increasing nephron yield per starting cell number. This facilitates the manufacture of uniformly patterned kidney tissue sheets with functional proximal tubular segments. Hence, automated extrusion-based bioprinting for kidney organoid production delivers improvements in throughput, quality control, scale and structure, facilitating in vitro and in vivo applications of stem cell-derived human kidney tissue.


Severe hypertriglyceridemia and pancreatitis following hormone replacement prior to cryothaw transfer.
A case of acute pancreatitis with severe hypertriglyceridemia occurred following use of intramuscular estradiol valerate during endometrial preparation for cryopreserved embryos. A 30-year-old woman with primary infertility and a past history of well-controlled hypothyroidism, underwent endometrial development with intramuscular estradiol valerate in preparation for the transfer of cryopreservred embryos. Initial hospitalization, discontinuation of all estrogens, aggressive intravenous fluid hydration, and initiation of low-fat diet with additional gemfibrozil treatment resulted in complete resolution of all symptoms related to the pancreatitis including the hyperlipidemia. A subsequent cryothaw cycle using oral estradiol resulted in a viable pregnancy with only mild increases in the patient's triglyceride and cholesterol levels noted throughout her 38-week gestation. Estradiol valerate, a commonly used form of estrogen for endometrial preparation during cryothaw cycles, may cause severe hypertriglyceridemia and acute pancreatitis in certain predisposed individuals. Oral and transdermal estrogens should be the preferred method of endometrial preparation in patients at high risk for lipid metabolism disorders, such as patients with polycystic ovarian syndrome and familial hypertriglyceridemia. These estrogens are more rapidly metabolized and have a shorter half life compared to that of estradiol valerate.


Evacuation of the pleural cavity with an infant feeding catheter following en bloc resection of hepatocellular carcinoma and involved diaphragm--an institutional experience.
En block resection of hepatocellular carcinoma and the involved diaphragm will, towards the end of operation, require evacuation of the pleural cavity, usually with a chest drain. We describe our method and experience of evacuating the pleural cavity, at the time of diaphragmatic repair, with an infant feeding catheter without the need of a chest drain. We have found the method safe and efficacious.


Bronchoalveolar lavage fluid level of carcinoembryonic antigen in the diagnosis of peripheral lung cancer.
The objective of this study was to verify whether the assay of carcinoembryonic antigen (CEA) in bronchoalveolar lavage fluid (BALF) can increase the sensitivity and specificity of serum CEA for the diagnosis of lung cancer. We examined 72 subjects, 53 males and 19 females, 18 affected with peripheral lung cancer (10 adenocarcinoma, 6 squamous cell carcinoma, 1 small cell lung cancer, 1 adenosquamous carcinoma), 19 with acute pneumonia, 14 with chronic obstructive pulmonary disease (COPD), 6 with interstitial lung disease (ILD), and 15 healthy subjects. CEA was assayed in blood and in BALF using microparticle enzyme immunoassay (MEIA) (IMX Abbott). The mean serum CEA value in the lung cancer group did not differ from that in each group of non-neoplastic subjects, neither was it different from that in healthy subjects. The mean BALF CEA in patients with lung cancer, pneumonia, and COPD was significantly increased compared with that in healthy subjects, whereas there was no difference between the three groups of patients. The ratio of BALF CEA was not significantly different in the three groups of patients. There were no differences according to the histological type of the tumour (adenocarcinoma or squamous cell carcinoma). Based on the results in healthy subjects, the upper limits of normal were defined for serum CEA, BALF CEA, and CEA/albumin ratio. Thus, the sensitivity of BALF CEA in detecting lung cancer (50%) was higher than that of serum CEA (33%), although clinically not useful. In addition, BALF CEA had only 59% specificity compared to 100% of serum CEA. The diagnostic accuracy was 79% for serum CEA and 56% for BALF CEA.(ABSTRACT TRUNCATED AT 250 WORDS)


Detour of prenostodione synthesis towards pyrazolones for antibacterial activity.
Our attempts to prepare indolyl acid (3), enroute to prenostodione (2), from phenyl-hydrazine following a reported procedure of Fischer-Indole synthesis rather lead to ethyl 2-(5-oxo-1-phenyl-2,5-dihydro-1H-pyrazol-3-yl)acetate as a major product, which underwent facile condensation with aldehydes to provide the pyrazolones. Intrigued by the opportunity for the diversity oriented synthesis of substituted pyrazolones, we have developed a facile one pot approach for pyrazolones and screened for antibacterial activity and, herein, results are reported.


Level A IVIVC for immediate release tablets confirms in vivo predictive dissolution testing for ibuprofen.
A bioequivalence study comparing two fixed dose combination tablets containing 200 mg ibuprofen and 30 mg pseudoephedrine hydrochloride showed bioequivalence for pseudoephedrine AUC and Cmax, but the reference product showed higher Cmax than the test product in fasted conditions. The main difference between products was the presence of tribasic calcium phosphate in the reference tablet, resulting in an increased surface pH of the dissolving ibuprofen particles under gastric and intestinal conditions and, consequently, higher solubility of ibuprofen. A mechanistic model based on mass balance and ionization equilibria was used to calculate the pH of the particle surface under different buffer conditions. The discrepancies in surface pH between test and reference tablet were pronounced in 0.1 M and 0.01 M hydrochloric acid and in diluted maleate 7 mM pH 6.5 and phosphate 5 mM pH 6.7 buffers (but negligible in compendial phosphate buffer pH 6.8. Only those dissolution tests using pre-treatment in acidic conditions could be used to build a one-step in vitro-in vivo correlation (IVIVC). This work shows the potential of these discriminatory and in vivo predictive dissolution methods to obtain IVIVCs for BCS class IIa drugs and for extending BCS biowaivers to BCS class IIa drugs.


Genetic matching for time-dependent treatments: a longitudinal extension and simulation study.
Longitudinal matching can mitigate confounding in observational, real-world studies of time-dependent treatments. To date, these methods have required iterative, manual re-specifications to achieve covariate balance. We propose a longitudinal extension of genetic matching, a machine learning approach that automates balancing of covariate histories. We examine performance by comparing the proposed extension against baseline propensity score matching and time-dependent propensity score matching. To evaluate comparative performance, we developed a Monte Carlo simulation framework that reflects a static treatment assigned at multiple time points. Data generation considers a treatment assignment model, a continuous outcome model, and underlying covariates. In simulation, we generated 1,000 datasets, each consisting of 1,000 subjects, and applied: (1) nearest neighbour matching on time-invariant, baseline propensity scores; (2) sequential risk set matching on time-dependent propensity scores; and (3) longitudinal genetic matching on time-dependent covariates. To measure comparative performance, we estimated covariate balance, efficiency, bias, and root mean squared error (RMSE) of treatment effect estimates. In scenario analysis, we varied underlying assumptions for assumed covariate distributions, correlations, treatment assignment models, and outcome models. In all scenarios, baseline propensity score matching resulted in biased effect estimation in the presence of time-dependent confounding, with mean bias ranging from 29.7% to 37.2%. In contrast, time-dependent propensity score matching and longitudinal genetic matching achieved stronger covariate balance and yielded less biased estimation, with mean bias ranging from 0.7% to 13.7%. Across scenarios, longitudinal genetic matching achieved similar or better performance than time-dependent propensity score matching without requiring manual re-specifications or normality of covariates. While the most appropriate longitudinal method will depend on research questions and underlying data patterns, our study can help guide these decisions. Simulation results demonstrate the validity of our longitudinal genetic matching approach for supporting future real-world assessments of treatments accessible at multiple time points.


Frailty in relation to the risk of carotid atherosclerosis and cardiovascular events in Chinese community-dwelling older adults: A five-year prospective cohort study.
To investigate the frailty, as estimated by accumulated health deficits, in association with the symptomatic carotid atherosclerosis and in relation to five-year cardiovascular (CVD) outcomes. This is a five-year prospective cohort study. Secondary analysis of data from the Beijing Longitudinal Study on Aging. Community-dwelling people aged 55+ years (n = 1257) have been followed between 2009 and 2014, and having carotid ultrasonography examinations with no CVD events at baseline. Frailty was quantified using the deficit accumulation-based frailty index (FI), constructed from 37 health deficits assessed at baseline. The association between the degree of frailty and carotid atherosclerosis was examined using odds ratios (OR) with multivariate logistic regression analyses. Effects of frailty on the probability of five-year cardiovascular events and mortality were evaluated using Cox proportional hazard ratios (HR). The analyses were adjusted for demographics, baseline carotid atherosclerosis status, and CVD risk factors. The FI showed characteristic properties and was independently associated with the major carotid atherosclerosis symptoms, including carotid artery intima-media thickening (the most frail vs. the least frail: OR = 4.39: 1.98-7.82), carotid plaque (OR = 3.41: 1.28-6.54), and carotid plaque stability (OR = 1.19, 95 % CI: 1.01-3.59). Compared with the least frail, the most frail individuals were more likely to develop a cardiovascular event in five years, including myocardial infarction (HR = 3.38, 95 % CI = 1.84-6.19), stroke (HR = 1.26, 95 % CI = 1.00-5.87), CVD death (HR = 6.33, 95 % CI = 1.69-11.02), and all-cause death (HR = 5.95, 95 % CI = 2.74-8.95). Deficit accumulation was closely associated with carotid atherosclerosis risks and strongly predicted five-year CVD events. The frailty index can be used to help identify older adults at high risks of CVD for improved preventive healthcare.


An Open-Label, Uncontrolled, Single-Arm Clinical Trial of Tofacitinib, an Oral JAK1 and JAK3 Kinase Inhibitor, in Chinese Patients with Keloid.
The keloid treatment is still a thorny and complicated clinical problem, especially in multiple keloids induced by wound, severe burn, ethnic background or cultural behaviors, or unexplained skin healing. Mainstream treatments have limited efficacy in treating multiple keloids. As no oral treatment with painlessness and convenience is available, oral treatment strategies should be formulated. This study aimed to investigate the efficacy and therapeutic mechanism of oral tofacitinib in keloid patients. We recruited the 7 patients with keloid scars and prescribed 5 mg of tofacitinib twice a day orally with a maximum follow-up of 12 weeks. The Patient and Observer Scar Assessment Scale (POSAS), the Vancouver scar scale (VSS), ANTERA 3D camera, and the DUB Skin Scanner 75 were used to assess the characteristics of the lesion. Immunohistochemistry was performed to evaluate collagen synthesis, proliferation, and relative molecular pathways. Moreover, the effects of tofacitinib were assessed on keloid fibroblast in vitro. After 12 weeks of oral tofacitinib, significant improvement in POSAS, VSS, and Dermatology Life Quality Index (DLQI) scores was observed (p < 0.05). The volume, lesion height, and dermis thickness of the keloid decreased (p < 0.05). Moreover, significant decreases in the expression of collagen I, Ki67, p-STAT 3, and p-SMAD2 were observed after 12 weeks of administration. In vitro experiments suggested that tofacitinib treatment inhibits fibroblast proliferation and collagen I synthesis via suppression of STAT3 and SMAD2 pathway. Tofacitinib, a new candidate oral drug for keloid, could reduce keloid lesion volume by inhibiting collagen synthesis and inhibiting fibroblast proliferation, and alleviate itch and pain to obtain a better life quality.


[Anesthesia for craniotomy in the conscious patient].
Craniotomy in the conscious patient (CPC) enables the neurological changes to be assessed during the mapping in epilepsy surgery, the location of the electrodes during deep brain stimulation surgery, and tumor resection in eloquent areas of the brain. CPC is a useful technique for radical surgery in order to minimize the damage to the functional areas of the brain. The anesthesiologist must ensure, adequate patient comfort, analgesia and ensure optimal collaboration. The appropriate selection of potential candidates for CPC should be made jointly with all professionals involved in the case. Knowledge of the different phases of CPC, coordination and communication among specialists, the right management of the pharmacology, and anesthetic techniques specific to CPC, along with the ability of psycho-emotional communication with the patient, determine the success of the procedure to be performed in the culture of patient safety. The aim of this review was to describe the anesthetic management, comprehensive considerations, and intraoperative neurophysiological tests for CPC.


Acquired Holmes Tremor in a Human Immunodeficiency Virus Immune Reconstitution Inflammatory Syndrome Patient Treated with Deep Brain Stimulation.
The authors present a case of a 66-year-old male who was diagnosed with human immunodeficiency virus, and his medical course of highly active antiretroviral therapy was complicated with the development of immune reconstitution inflammatory syndrome, which led to development of movement disorder consisting of right-sided resting tremor, neck dystonia, and jaw clenching. The patient's symptoms resembled that of rubral tremor, and he underwent placement of a deep brain stimulation electrode into the left ventral intermediate nucleus of the thalamus with significant improvement of symptoms. This is the first reported case in the literature of a human immunodeficiency virus-positive patient's treatment course complicated with immune reconstitution inflammatory syndrome with neurologic manifestation, which was refractory to medical therapy and thus treated with deep brain stimulation.


RAD51AP1 and RAD54L Can Underpin Two Distinct RAD51-Dependent Routes of DNA Damage Repair via Homologous Recombination.
Homologous recombination DNA repair (HR) is a complex DNA damage repair pathway and an attractive target of inhibition in anti-cancer therapy. To help guide the development of efficient HR inhibitors, it is critical to identify compensatory HR sub-pathways. In this study, we describe a novel synthetic interaction between RAD51AP1 and RAD54L, two structurally unrelated proteins that function downstream of the RAD51 recombinase in HR. We show that concomitant deletion of RAD51AP1 and RAD54L further sensitizes human cancer cell lines to treatment with olaparib, a Poly (adenosine 5'-diphosphate-ribose) polymerase inhibitor, to the DNA inter-strand crosslinking agent mitomycin C, and to hydroxyurea, which induces DNA replication stress. We also show that the RAD54L paralog RAD54B compensates for RAD54L deficiency, although, surprisingly, less extensively than RAD51AP1. These results, for the first time, delineate RAD51AP1- and RAD54L-dependent sub-pathways and will guide the development of inhibitors that target HR stimulators of strand invasion.


Chemiluminescence optosensing implemented with multicommutation: determination of salicylic acid.
In this paper we have coupled, for the first time, chemiluminescent detection with multicommuted optosensing principles. This approach has been implemented with the use of a commercial flow cell of 1mm optical path length filled with an appropriate anionic exchanger gel as chemiluminescence sensing phase. The cell was placed in front of the window of the photosensor module of a home-made luminometer developed in our laboratory and a flat mirror was stuck on the back of the cell. The suitability of using chemiluminescence as detection technique in multicommuted flow-through optosensors has been demonstrated: the determination of salicylic acid by simple oxidation with permanganate on the sensing solid phase was chosen as model reaction. The proposed system allows the determination of salicylic acid in pharmaceuticals, with a sample frequency as high as even 60 samples h(-1) and showing a detection limit of 0.30 microg mL(-1), the linear response range is 1-30 microg mL(-1) and the R.S.D. is 3.1%. Satisfactory results have been obtained when applying the sensor to pharmaceuticals. The accuracy of the proposed methodology has been tested by using a reference method.


ANKYLOGLOSSIA AND ITS INFLUENCE ON GROWTH AND DEVELOPMENT OF THE STOMATOGNATHIC SYSTEM.
To critically examine the existing Brazilian and International scientific literature regarding the influence of short lingual frenulum over growth and development of the stomatognathic system, as well as how it impacts the achievement of the shape-function balance. An electronic literature search was conducted in databases, including MEDLINE/PubMed, Google Scholar, LILACS, SciELO, and ScienceDirect, using the key words "lingual frenum" and "development", as well as their equivalents in Brazilian Portuguese. The literature search yielded 51 papers published between January 1997 and the present date; 14 articles of clinical trials were selected for meeting the inclusion criteria and were read in full. The integrated literature review supported the proposition that some malocclusions are closely related to the presence of ankyloglossia and, although very few clinical trials on this topic have been published so far, there is a consensus among authors concerning the negative effects of functional imbalances over the stomatognathic system's proper growth and development. Half of the studies found state that surgical interventions for releasing the lingual frenum are both safe and effective, concerning improvement in breastfeeding scores. Moreover, 4 out of the 14 studies included in this integrated review, report a negative influence of ankyloglossia over the orofacial muscular system. There is a consensus among the authors concerning the negative effects of lingual frenulum's anatomic and functional alterations over craniofacial growth and development. The opinion about the early surgical intervention, however, is not unanimous.


[The value of allergy survey in a retrospective series of 40 patients with burning-mouth syndrome (stomatodynia)].
By definition, stomatodynia or burning-mouth syndrome involves oral pain with no causes being found on history taking or examination. An allergic origin is often suspected by doctors and patients alike. In this study, we attempted to assess the value of epicutaneous tests in demonstrating allergic causes for patients presenting stomatodynia. This was a single-centre retrospective study of patients undergoing epicutaneous tests between 1996 and 2003 to screen for allergic causes of mouth pain not accounted for by any abnormalities seen during examination performed at consultations for mouth disease. Forty patients were included (11 male, 29 female; mean age: 58 years), and 39 were excluded. Sixteen patients presented at least one positive test, with a total of 35 positive tests in all. In decreasing order of frequency, the causes were metals, mercury derivatives (nickel salts: n=5; chrome salts: n=3; palladium salts: n=2; phenylmercuric acetate: n=2; thiomersal: n=2; cobalt salts: n=1; gold salts: n=1; mercury: n=1) and resins (acrylates: n=4). The relevance of these test results was considered probable in three cases and possible in five cases, associated with the existence of metals or resins in patients' mouths. The Peru balm test was positive in four cases but was not relevant. Tests for personal products were negative in all cases, with the exception of one case of resin from a prosthesis and one case of tixocortol pivalate. Type I stomatodynia (daily occurrence with gradually increase in discomfort throughout the day) and type II stomatodynia (permanent) are not normally attributable to allergies. However, for type III stomatodynia (non-permanent, with acute episodes followed by remission), an allergy survey guided by questioning may be undertaken to determine the cause, primarily prostheses or diet. The relevance of positive test results must be interpreted with caution in view of the incidence of positive epicutaneous tests for metals and Peru balm among the general population studied.


Concordance between a neuroradiologist, a consultant radiologist and trained reporting radiographers interpreting MRI head examinations: An empirical study.
This study assessed agreement between MRI reporting radiographers and a consultant radiologist compared with an index neuroradiologist when reporting MRI head (brain/internal auditory meati [IAMs]) examinations. The effect on patient management of any discordant reports was also examined. Two trained MRI reporting radiographers (RRs), a consultant radiologist (CR) and an index neuroradiologist (INR) reported on a random sample of 210 MRI examinations. The radiographers reported during clinical practice and the radiologists in clinical practice conditions. Two independent consultant physicians (neuro-rehabilitation and neuropsychiatry) compared these reports with the index neuroradiologist report for agreement and the clinical importance of discrepant reports. Overall observer agreement between the RRs and CR was comparable in relation to agreement with the INR: RR; 93/210 (44.3%); and the CR; 83/210 (39.4%) for all head MRI examinations (p = 0.32). For brain examinations the difference was similar: RR; 64/180 (35.6%); and CR; 54/190 (30.0%), p = 0.26. Agreement rates for the IAMs examinations were identical, 29/30 (97.7%). For all head MRI examinations (n = 210) there was a very small observed difference of <0.5% in mean agreement between the reporting radiographers and the consultant radiologist (p = 0.92) for examinations where a major disagreement would have been likely to have led to a change in patient management. MRI reporting radiographers reported during clinical practice on MRI head examinations to a level of agreement comparable with a consultant radiologist. This is an area in which radiographers could provide additional reporting roles to the reporting service to increase capacity. Wider potential benefits include cost-effectiveness and role development/retention of radiographers.


Modified vertical lid split orbitotomy: a case series and literature review.
To describe the modified vertical lid split (VLS) technique for anterior orbitotomy and report surgical outcomes in patients with intraconal lesion removal using this surgical technique. Retrospective review of medical records and orbital images. A total of four (female = 3) patients with intraconal orbital lesions underwent modified VLS orbitotomy from January 1, 2019 to June 30, 2021 in Hong Kong East Cluster. The average age was 49.3 years old (range: 35-65). Complete excision of intraconal orbital lesion was performed in all four cases. All cases were cavernous haemangioma histologically. All patients were satisfied with their cosmesis postoperatively and most had satisfactory postoperative extraocular movement. Modified VLS approach is simple and provides good intraoperative surgical exposure for intraconal lesions, giving the additional advantage of better scar camouflage.


TNF-mediated IL6 gene expression and cytotoxicity are co-inducible in TNF-resistant L929 cells.
Interleukin (IL)-6 gene induction was studied in the murine cell line, L929r2, which is resistant to the cytotoxic action of tumor necrosis factor (TNF). Increasing concentrations of TNF slightly elevated the background levels of IL6 expression as compared to non-induced cells. Under conditions where the resistant cells are sensitive to TNF by combined TNF/IFN-gamma treatment, the IL6 levels were strongly induced. This induction could be further enhanced by the addition of lithium chloride, or reduced by inhibitors of cytotoxicity, such as dexamethasone. These results confirm our earlier conclusions regarding the close relationship between TNF-mediated IL6 gene expression and the pathway leading to cytotoxicity.


Amphiphilic detergent-soluble acetylcholinesterase from Torpedo marmorata: characterization and conversion by proteolysis to a hydrophilic form.
The membrane-bound acetylcholinesterase (AChE) from the electric organ of Torpedo marmorata was solubilized by Triton X-100 or by treatment with proteinase K and purified to apparent homogeneity by affinity chromatography. Although the two forms differed only slightly in their subunit molecular weight (66,000 and 65,000 daltons, respectively), considerable differences existed between native and digested detergent-soluble AChE. The native enzyme sedimented at 6.5 S in the presence of Triton X-100 and formed aggregates in the absence of detergent. The digested enzyme sedimented at 7.5 S in the absence and in the presence of detergent. In contrast to the detergent-solubilized AChE, the proteolytically derived form neither bound detergent nor required amphiphilic molecules for the expression of catalytic activity. This led to the conclusion that limited digestion of detergent-soluble AChE results in the removal of a small hydrophobic peptide which in vivo is responsible for anchoring the protein to the lipid bilayer.


The high-risk bleeding category of different scores in patients with venous thromboembolism: Systematic review and meta-analysis.
In patients with venous thromboembolism (VTE), bleeding risk should be carefully assessed but none of the available risk scores is currently recommended. The aim of this study was to systematically evaluate the performance of bleeding scores in patients with VTE focusing on high-risk patients. Longitudinal studies were searched in Medline and Cochrane Library, as well as reviews and references of retrieved articles. Studies were identified, data were extracted, and reporting quality was evaluated. We determined the sensitivity, specificity, positive likelihood ratio (LR+), and diagnostic odds ratio (DOR) of the 'high risk' category of each bleeding score. Random effects meta-analysis was performed in order to derive the central estimates and 95% confidence intervals (95% CI). Twenty-one studies and ten bleeding scores fulfilled the inclusion criteria. VTE-BLEED showed the highest sensitivity but the second-lowest specificity (Se 76%; Sp 61%), followed by ACCP (Se 59%; Sp 57%). The remaining scores had high specificity (> 80%) but a low sensitivity (< 20%). HEMORR2HAGES and Niewenhuis score showed the best performance regarding LR+ that was 2.67 and 5.91, respectively. Regarding DOR, the Niewenhuis score and VTE-BLEED were the best performers with 9.04; 95% CI 3.87-21.09 and 4.94 95% CI 2.66-9.09, respectively. In a cohort with patients predominantly treated with direct oral anticoagulants (DOACs), VTE-BLEED had the highest sensitivity (Se 77%; Sp 60%). Overall, the majority of the risk scores showed a moderate ability to forecast major bleeding events, with the VTE-BLEED as the most sensitive in patients treated with DOACs.


Effect of transplant status in CD19-targeted CAR T-cell therapy: a systematic review and meta-analysis.
Chimeric antigen receptor (CAR) T-cell therapy has shown promise for relapsed/refractory malignancies. Many patients have undergone prior hematopoietic stem cell transplant (HSCT), yet effects of transplant status on CAR T-cell therapy efficacy and safety have not been reported. The purpose of the study is to systematically evaluate the likelihood of achieving optimum response, severe cytokine release syndrome (sCRS), and neurotoxicity in the context of CAR T-cell therapy for HSCT-naïve patients versus those with prior HSCT. Trials were identified in ClinicalTrials.gov, Cochrane Library, and PubMed, and through reference pearl growing. Included studies used CD19-directed CAR T-cells for relapsed/refractory B-lineage Acute Lymphoblastic Leukemia and B cell Chronic Lymphocytic Leukemia, enrolled both HSCT-naïve and prior-HSCT patients, and denoted transplant status with outcomes. Six studies were included for optimum response, five for sCRS incidence, and four for neurotoxicity incidence. The pooled odds ratio for optimum response was 1.57 favoring HSCT-naïve patients (95% CI 0.54-4.61), whereas the pooled odds ratios for sCRS and neurotoxicity were 1.41 (95% CI 0.51-3.94) and 1.37 (95% CI 0.28-6.77), respectively, toward HSCT-naïve patients. Odds ratios were non-statistically significant. Overall risk of bias was moderate. While pooled estimates showed an advantage among HSCT-naïve patients for achieving optimum response and increased likelihood for sCRS and neurotoxicity, findings were not statistically significant. Any differences in efficacy and safety of CAR T-cell therapy cannot be verifiably attributed to transplant status, and additional controlled trials with increased sample sizes are needed to determine whether suggestive patterns favoring HSCT-naïve patients are validated.