Effect of delta-V errors in NASS on frontal crash risk calculations.
The most important factor in predicting the risk of injury or death in a frontal crash is the crash severity, which is expressed as the velocity change, or delta-V, experienced by the vehicle during the crash. The National Automotive Sampling System (NASS) is the largest database in the world linking injury outcomes with delta-Vs, which are obtained from field reconstructions. The accuracy of these reconstructions was assessed by analyzing 228 NASS cases involving single event frontal crashes in which the vehicle's frontal delta-V was also measured directly by an onboard event data recorder (EDR). Compared to the EDR measurements, the delta-V values in NASS averaged 19% lower with a standard deviation of 8.6 kph. The effect of this error on injury and fatality risk calculations was investigated using NASS data from 1997 - 2006 for frontal crashes with a known delta-V. Injury and fatality risk functions were calculated by curve fitting the distributions of the delta-V values associated with injury and fatality incidence normalized by the fitted crash exposure distribution. Individual delta-V values were linearly scaled to correct for the bias error, and the delta-V distributions were corrected for scatter error using a numerical deconvolution technique. Correcting for delta-V bias error shifted the calculated risk curves to the right and correcting for delta-V scatter error shifted the curves back to the left, but to a lesser extent. The effects of occupant age, gender, and belt use on injury and fatality risk were substantial.


Creation of Tissue-Engineered Urethras for Large Urethral Defect Repair in a Rabbit Experimental Model.
Introduction: Tissue engineering is a potential source of urethral substitutes to treat severe urethral defects. Our aim was to create tissue-engineered urethras by harvesting autologous cells obtained by bladder washes and then using these cells to create a neourethra in a chronic large urethral defect in a rabbit model. Methods: A large urethral defect was first created in male New Zealand rabbits by resecting an elliptic defect (70 mm2) in the ventral penile urethra and then letting it settle down as a chronic defect for 5-6 weeks. Urothelial cells were harvested noninvasively by washing the bladder with saline and isolating urothelial cells. Neourethras were created by seeding urothelial cells on a commercially available decellularized intestinal submucosa matrix (Biodesign® Cook-Biotech®). Twenty-two rabbits were divided into three groups. Group-A (n = 2) is a control group (urethral defect unrepaired). Group-B (n = 10) and group-C (n = 10) underwent on-lay urethroplasty, with unseeded matrix (group-B) and urothelial cell-seeded matrix (group-C). Macroscopic appearance, radiology, and histology were assessed. Results: The chronic large urethral defect model was successfully created. Stratified urothelial cultures attached to the matrix were obtained. All group-A rabbits kept the urethral defect size unchanged (70 ± 2.5 mm2). All group-B rabbits presented urethroplasty dehiscence, with a median defect of 61 mm2 (range 34-70). In group-C, five presented complete correction and five almost total correction with fistula, with a median defect of 0.3 mm2 (range 0-12.5), demonstrating a significant better result (p = 7.85 × 10-5). Urethrography showed more fistulas in group-B (10/10, versus 5/10 in group-C) (p = 0.04). No strictures were found in any of the groups. Group-B histology identified the absence of ventral urethra in unrepaired areas, with squamous cell metaplasia in the edges toward the defect. In group-C repaired areas, ventral multilayer urothelium was identified with cells staining for urothelial cell marker cytokeratin-7. Conclusions: The importance of this study is that we used a chronic large urethral defect animal model and clearly found that cell-seeded transplants were superior to nonseeded. In addition, bladder washing was a feasible method for harvesting viable autologous cells in a noninvasive way. There is a place for considering tissue-engineered transplants in the surgical armamentarium for treating complex urethral defects and hypospadias cases.


Sharing specialist skills for diabetes in an inner city: a comparison of two primary care organisations over 4 years.
To evaluate the effects of organizational change and sharing of specialist skills and information technology for diabetes in two primary care groups (PCGs) over 4 years. In PCG-A, an intervention comprised dedicated specialist sessions in primary care, clinical guidelines, educational meetings for professionals and a shared diabetes electronic patient record (EPR). Comparison was made with the neighbouring PCG-B as control. In intervention and control PCGs, practice development work was undertaken for a new contract for family doctors. Data were collected for clinical measures, practice organizational characteristics and professional and patient views. Data were analysed for 26 general practices including 17 in PCG-A and nine in PCG-B. The median practice-specific proportions of patients with HbA1c recorded annually increased in both areas: PCG-A from median 65% to 77%, while PCG-B from 53% to 84%. For cholesterol recording, PCG-A increased from 50% to 76%, and PCG-B from 56% to 80%. Organizational changes in both PCGs included the establishment of recall systems, dedicated clinics and educational sessions for patients. In both PCGs, practices performing poorly at baseline showed the greatest improvements in organization and clinical practice. Primary care professionals' satisfaction with access and communication with diabetes specialist doctors and nurses increased, more so in the intervention PCG. Only 16% of primary care professional respondents used the diabetes EPR at least monthly. Patient satisfaction and knowledge did not change. Improvements in practices' organizational arrangements were associated with improvements in clinical care in both PCGs. Sharing specialist skills in one PCG was associated with increased professional satisfaction but no net improvement in clinical measures. A shared diabetes EPR is unlikely to be used, unless integrated with practice information systems.


What's new in enteric infectious diseases at home and abroad.
This review was designed to focus on the important research in the area of acute infectious diarrhea published within the past year. PubMed was reviewed for articles published in 2004 and 2005 relating to pathogen-specific diarrhea and for travelers' diarrhea to identify the newly published articles. New studies continue to show the importance of the diarrheagenic Escherichia coli as causes of acute and persistent diarrhea. Enteroaggregative E. coli has recently been shown to be an unrecognized cause of community-acquired diarrhea in infants in the USA. Genetic factors explain an increased susceptibility to travelers' diarrhea among international travelers. Also, poorly non-absorbed rifaximin (< 0.4%) was shown to be an effective drug when used prophylactically to prevent bacterial diarrhea during high risk travel. Studies will continue to define the etiology of diarrhea and to better understand the epidemiology and prevention of infectious diarrhea. Antibacterial resistance among enteric bacterial pathogens is a growing problem, leading to the search for newer antibacterial drugs. Diarrhea due to bacterial agents in international travelers can be prevented and treated successfully by antibacterial drugs. The nonabsorbed rifamycin drug, rifaximin, appears to be ideally suited to become the important new drug in prevention and treatment of travelers' diarrhea. Studies are underway to determine the value of the drug in preventing invasive forms of diarrhea during travel to Asia and in the prevention of the commonly occurring post-infectious irritable bowel syndrome.


Intragraft Th17 infiltrate promotes lymphoid neogenesis and hastens clinical chronic rejection.
To evaluate the influence of intragraft inflammatory infiltrate on the course of chronic rejection, 11 human renal grafts, detransplanted for terminal failure, were analyzed. Samples were divided into two groups according to their graft survival (> or < or = 8 y). In both groups, the main cell population infiltrating the graft interstitia was T lymphocytes. The extent of the lymphocytic infiltration and the distribution of naive and memory, CD4(+) and CD8(+) T cells, were similar in both groups. Although all types of Th polarization profiles can lead to terminal chronic rejection, a correlation between shorter graft survival and the presence of Th17 cells that produce IL-17 and IL-21 was observed. In contrast, grafts infiltrated by regulatory T cells survived significantly longer. The correlation between the expressions of activation-induced cytidine deaminase (the key enzyme of the germinal center reaction) and IL-21 suggests that Th17 could exert their deleterious effect by promoting lymphoid neogenesis, namely, the organization of inflammatory effectors into ectopic germinal centers in which a local humoral immune response is elicited. Further studies will determine whether Th17 infiltration can be used as a prognosis tool and whether the Th17 subset constitutes a therapeutic target for slowing down chronic rejection.


Shoulder assessment according to the international classification of functioning by means of inertial sensor technologies: A systematic review.
This review investigates current protocols using Inertial Measurement Units (IMUs) in shoulder research, and outlines future paths regarding IMU use for shoulder research. Different databases were searched for relevant articles. Criteria for study selection were (1) research in healthy persons or persons with shoulder problems, (2) IMUs applied as assessment tool for the shoulder (in healthy subjects and shoulder patients) or upper limb (in shoulder patients), (3) peer-reviewed, full-text papers in English or Dutch. Studies with less than five participants and without ethical approval were excluded. Data extraction included (1) study design, (2) participant characteristics, (3) type/brand of IMU, (4) tasks included in the assessment protocol, and (5) outcomes. Risk of bias was assessed using the Downs and Black checklist. Scapulothoracic/glenohumeral and humerothoracic kinematics were reported in respectively 10 and 27 of the 37 included papers. Only one paper in healthy persons assessed, next to scapulothoracic/glenohumeral kinematics, other upper limb joints. IMUs' validity and reliability to capture shoulder function was limited. Considering applied protocols, 39% of the protocols was located on the International-Classification-of-Functioning (ICF) function level, while 38% and 23% were on the 'capacity' and 'actual performance'-sublevel, of the ICF-activity level. Most available IMU-research regarding the shoulder is clinically less relevant, given the widely reported humerothoracic kinematics which do not add to clinical-decision-making, and the absence of protocols assessing the complete upper limb chain. Apart from knowledge on methodological pitfalls and opportunities regarding the use of IMUs, this review provides future research paths.


Spinal Cord Injury Due to Cervical Disc Herniation without Bony Involvement Caused by Wrestling - A Case Report.
Many cases of cervical spinal disc herniation caused by sporting injury have been reported. Those cases generally accompanied high-energy trauma such as fractures and/or dislocations. The purpose is to present the case of spinal cord injury (SCI) due to cervical disc herniation without bony involvement caused by wrestling. We report a case of a 23-year-old man who sustained a cervical SCI during the wrestling competition. He was quadriplegic with no sensory or motor function preserved in sacral segments S4-S5. Conventional radiographs and computed tomography did not reveal bony abnormalities. Magnetic resonance imaging (MRI) showed a free herniated cervical disc severely compressing the spinal cord from central at C3/4 level. He underwent anterior cervical discectomy and interbody fusion using autologous iliac crest bone graft and fixation with the cervical plate. He made an eventful recovery, and 5 years later, he was playing at high competitive level. Competitive wrestling-related injuries are quite high. Fortunately, the incidence of SCI among wrestlers is extremely low. Although rare, SCI due to cervical disc herniation without bony involvement is a serious debilitating injury that exerts a devastating effect on a wrestler from a physical, psychological, and socioeconomic point of view, and places an immense burden on society from a public health perspective. The MRI is the golden examination in diagnosing such lesion. The management comprises surgical decompression of neural elements, stabilization, and fusion to provide a higher recovery rate from cord damage to return to play. Wrestler who is completely pain free with full range of motion and strength may be eligible for return to play.


Inhibitory effects of potassium channel blockers on carbachol-induced contraction in rat detrusor muscle.
We present accidental findings that potassium channel blockers, such as tetraethyl-ammonium (TEA) or 4-aminopyridine (4-AP), inhibit the sustained tonic contraction induced by carbachol in rat detrusor muscle strips. The relatively lower concentrations (<2 mM) of TEA and 4-AP inhibited phasic and tonic contractions induced by 5 micro M carbachol, whilst the relatively higher concentrations of TEA and 4-AP (>5 mM) potentiated phasic contractions. The potentiation of phasic contraction was not observed in nicardipine pretreated condition. In nicardipine pretreated condition, the concentration-response curves for the negative inotropic effect of potassium channel blockers were shifted to the right by the increasing concentration of carbachol from 0.5 microM to 5 microM. IC50 was changed significantly from 0.19 to 0.64 mM (TEA) and from 0.21 to 0.96 (4-AP). Such inhibitory effects were also observed in Ca2+ depleted condition, where 0.1 mM EGTA and 1 microM thapsigargin were added into Ca2+ free solution. In conclusion, inhibitory effects of potassium channel blockers on carbachol-induced contraction may be ascribed to the direct inhibition of receptor-agonist binding.


Causes and consequences of the DNA damage response.
A prerequisite for maintaining genome stability in all cell types is the accurate repair and efficient signaling of DNA double strand breaks (DSBs). It is believed that DSBs are initially detected by damage sensors that trigger the activation of transducing kinases. These transducers amplify the damage signal, which is then relayed to effector proteins, which regulate the progression of the cell cycle, DNA repair and apoptosis. Errors in the execution of the repair and/or signaling of DSBs can give rise to multi-systemic disorders characterized by tissue degeneration, infertility, immune system dysfunction, age-related pathologies and cancer. This special Spotlight issue of Cell Cycle highlights recent advances in our understanding of the biology and significance of the DNA damage response. A range of issues are addressed including mechanistic ones: What is the aberrant DNA structure that triggers the activation of the checkpoint? How does chromatin structure influence the recruitment of repair and checkpoint proteins? How does chromosomal instability contribute to the evolution of cancer? In addition, questions related to the physiology of the DNA damage response in normal and abnormal cells is explored: What is the in vivo consequence of altering specific amino acids in a DNA damage sensor? Does DNA damage accumulation in stem cells cause aging? How is neurodegeneration linked to deficiencies in specific DNA repair pathways? And finally, what is the biological basis for selection of aberrant DNA damage responses in cancer cells?


Value of different ultrasound elastography techniques in patients with venous malformations prior to and after sclerotherapy.
Comparison of different ultrasound elastography techniques for detection of changes after sclerotherapy within venous malformations. In patients with venous malformations sonography was executed at exactly the same position prior to and after ethanol-gel sclerotherapy. Both examinations included B-Mode, vascular sonography with Color-Coded Duplex Sonography, and additional sonography with different elastography techniques (strain, qualitative and quantitative Acoustic Radiation Force Impulse (ARFI) elastography) with a linear transducer (6-9 MHz). Qualitative elastograms were read in consensus and scored. Differences of elasticity scores were statistically analyzed, p-values <0.05 were regarded significant. Elasticity scores of strain and qualitative ARFI elastography in 25 patients (21 females, averagely 24.4 years old) were comparable before treatment (p = 0.69). After therapy qualitative ARFI scores changed significantly compared to pre-treatment scores (p = 0.0017), whereas strain elastography scores revealed no significant changes (p = 0.13). Quantitative ARFI values obtained after sclerotherapy within the venous malformations were significantly higher compared to pre-treatment values (p = 0.049), and significantly higher to values obtained in surrounding tissue (p = 0.030). Comparison of pre- and post-treatment ARFI values of the surrounding tissue was not significant (p = 0.67). Elasticity scores of qualitative ARFI elastography reliably detect ethanol-gel induced changes in venous malformations. Quantitative ARFI may be a tool for therapy planning, and for monitoring sclerotherapy outcome as well as the effect of sclerosing agents on malformation and surrounding tissue in patients with venous malformations.


Use of topical rapamycin in acral pseudolymphomatous angiokeratoma of children (APACHE): A report of two cases and review of the literature.
Acral pseudolymphomatous angiokeratoma of children (APACHE) is a rare, benign disease characterized clinically by multiple, asymptomatic, erythematous papules in the acral regions. We report APACHE in a 12-year-old girl with erythematous-violaceous papules on the lateral dorsum of her foot and toes, and a 3-year-old girl with erythematous papules on the plantar aspect of her foot. Topical rapamycin ointment improved the lesions and both patients tolerated the medication well. Topical rapamycin appears to be a potentially efficacious, well-tolerated, non-invasive therapy in APACHE, although further studies are needed.


Activity of cell-wall degradation associated with differentiation of isolated mesophyll cells of Zinnia elegans into tracheary elements.
Cell walls were prepared from cultured mesophyll cells of Zinnia elegans L. that were transdifferentiating into tracheary elements and incubated in a buffer to undergo autolysis. The rate of autolysis of cell walls was determined by measuring the amount of carbohydrate released from the cell walls into the buffer during incubation. During the course of culture of mesophyll cells, the autolysis rate increased markedly at the time when thickenings of secondary cell walls characteristic of tracheary elements became visible (after 48-72 h of culture), and thereafter the rate remained at a high level. Comparative studies on the autolysis rate of cell walls using various control cultures, in which tracheary element differentiation did not take place, revealed a close relationship between the autolysis rate around the 60th hour of culture and differentiation. Sugar analysis by colorimetric assays and gas chromatography of carbohydrates released from the cell walls detected uronic acid, arabinose, galactose, glucose, xylose, rhamnose, fucose, and mannose. Among these sugars, uronic acid was the most abundant, and accounted for approximately half of the total released sugars. The decrease of acidic polysaccharides in the primary cell walls during tracheary element differentiation was visualized by staining cultured cells with alcian blue at pH 2.5. These results suggest that active degradation of components of primary cell walls, including pectin, is integrated into the program of tracheary element differentiation.


Synthesis, Thermodynamic Properties, and Crystal Structure of RNA Oligonucleotides Containing 5-Hydroxymethylcytosine.
5-Hydroxymethylcytosine (hm5C) is an RNA modification that has attracted significant interest because of the finding that RNA hydroxymethylation can favor mRNA translation. For insight into the mechanistic details of hm5C function to be obtained, the availability of RNAs containing this modification at defined positions that can be used for in vitro studies is highly desirable. In this work, we present an eight-step route to 5-hydroxymethylcytidine (hm5rC) phosphoramidite for solid-phase synthesis of modified RNA oligonucleotides. Furthermore, we examined the effects of hm5rC on RNA duplex stability and its impact on structure formation using the sarcin-ricin loop (SRL) motif. Thermal denaturation experiments revealed that hm5rC increases RNA duplex stability. By contrast, when cytosine within an UNCG tetraloop motif was replaced by hm5rC, the thermodynamic stability of the corresponding hairpin fold was attenuated. Importantly, incorporation of hm5rC into the SRL motif resulted in an RNA crystal structure at 0.85 Å resolution. Besides changes in the hydration pattern at the site of modification, a slight opening of the hm5rC-G pair compared to the unmodified C-G in the native structure was revealed.


A Multidimensional Analytical Comparison of Remicade and the Biosimilar Remsima.
In April 2016, the Food and Drug Administration approved the first biosimilar monoclonal antibody (mAb), Inflectra/Remsima (Celltrion), based off the original product Remicade (infliximab, Janssen). Biosimilars promise significant cost savings for patients, but the unavoidable differences between innovator and copycat biologics raise questions regarding product interchangeability. In this study, Remicade and Remsima were examined by native mass spectrometry, ion mobility, and quantitative peptide mapping. The levels of oxidation, deamidation, and mutation of individual amino acids were remarkably similar. We found different levels of C-terminal truncation, soluble protein aggregates, and glycation that all likely have a limited clinical impact. Importantly, we identified more than 25 glycoforms for each product and observed glycoform population differences, with afucosylated glycans accounting for 19.7% of Remicade and 13.2% of Remsima glycoforms, which translated into a 2-fold reduction in the level of FcγIIIa receptor binding for Remsima. While this difference was acknowledged in Remsima regulatory filings, our glycoform analysis and receptor binding results appear to be somewhat different from the published values, likely because of methodological differences between laboratories and improved glycoform identification by our laboratory using a peptide map-based method. Our mass spectrometry-based analysis provides rapid and robust analytical information vital for biosimilar development. We have demonstrated the utility of our multiple-attribute monitoring workflow using the model mAbs Remicade and Remsima and have provided a template for analysis of future mAb biosimilars.


Paul Klee's illness (systemic sclerosis) and artistic transfiguration.
Klee's symptoms, and the rapid progression of the illness, ending with his death after only 5 years, in all probability indicate the rarest but most serious form of scleroderma, known as diffuse systemic sclerosis. Although his skin and internal organs were heavily stricken by the illness, the artist's hands were fortunately spared. Thus he was able to draw and paint without hindrance to the end. Classified amongst diseases of the autoimmunity system, this form of sclerosis often has inexplicable causes. I believe, however, that the defamations suffered by Klee, his dismissal as professor of the Art Academy in Düsseldorf by the National Socialists, and the unintended isolation after his return to Berne were causative factors in the outbreak of the illness. Mentally and spiritually, the artist rose above his heavy bodily suffering. Constantly, his creativity remained vigorous. Although the greater part of Klee's works in his last years cannot be linked directly with his illness, careful viewing reveals a significant preoccupation with fate and illness. It is above all in his drawings, that were created like a diary, that the sorrows and troubles of the ill artist emerge: his fears, but also his hopes and finally his resignation to the illness, and his readiness for death. In undesired isolation, and in his own spiritual world, Paul Klee created with exemplary concentration, discipline and diligence a considerable number of late works, which differ from his early work and which deserve our full admiration. Reserved, quiet and kind, Paul Klee was nevertheless charismatic. And his art is poetic. Possessing a special aura, it can enchant those who surrender to it without any prejudice. Paul Klee has created an oeuvre that is unique, reflecting his character closely: a body of work that moves and stirs us by its deep humanity.


Phase-shift anomaly caused by subwavelength-scale metal slit or aperture diffraction.
Terahertz time-domain spectroscopy probes anomalous phase-shift caused by wave diffraction from a subwavelength-scale metal slit or aperture. Carrier frequency phase measurements in the far-field region reveals that nearly 30° phase advance is induced from a subwavelength slit diffraction and that 180° phase-advance from a subwavelength aperture. These results indicate that the conventional 90° phase advance of diffracted waves in the far-field region, known as the Gouy phase shift, is not valid for subwavelength diffraction phenomena. The physical origin of these phase-shift anomalies is attributed to induced electric currents or magnetic dipole radiation, and theoretical analyses based on these factors are in good agreement with the experimental results.


Improvement of osseointegration of Ti-6Al-4V ELI alloy orthodontic mini-screws through anodization, cyclic pre-calcification, and heat treatments.
Mini-screws are widely used as temporary anchorages in orthodontic treatment, but have the disadvantage of showing a high failure rate of about 10%. Therefore, orthodontic mini-screws should have high biocompatibility and retention. Previous studies have demonstrated that the retention of mini-screws can be improved by imparting bioactivity to the surface. The method for imparting bioactivity proposed in this paper is to sequentially perform anodization, periodic pre-calcification, and heat treatments with a Ti-6Al-4V ELI alloy mini-screw. A TiO2 nanotube-structured layer was formed on the surface of the Ti-6Al-4V ELI alloy mini-screw through anodization in which a voltage of 20 V was applied to a glycerol solution containing 20 wt% H2O and 1.4 wt% NH4F for 60 min. Fine granular calcium phosphate precipitates of HA and octacalcium phosphate were generated as clusters on the surface through the cyclic pre-calcification and heat treatments. The cyclic pre-calcification treatment is a process of immersion in a 0.05 M NaH2PO4 solution and a saturated Ca(OH)2 solution at 90 °C for 1 min each. It was confirmed that the densely structured protrusions were precipitated, and Ca and P concentrations, which bind and concentrate endogenous bone morphogenetic proteins, increased on the surface after simulated body fluid (SBF) immersion test. In addition, the removal torque of the mini-screw fixed into rabbit tibias for 4 weeks was measured to be 8.70 ± 2.60 N cm. A noteworthy point in this paper is that the Ca and P concentrations, which provide a scaffold suitable for endogenous bone formation, further increased over time after SBF immersion of the APH group specimens. The other point is that our mini-screws have a significantly higher removal torque compared to untreated mini-screws. These results represent that the mini-screw proposed in this paper can be used as a mini-screw for orthodontics.


Service utilization patterns and characteristics among clients of integrated supervised consumption sites in Toronto, Canada.
Supervised consumption services (SCS), intended to reduce morbidity and mortality among people who inject drugs, have been implemented in a variety of delivery models. We describe and compare access to and uptake of co-located and external services among clients accessing harm reduction-embedded (HR-embedded) and community health center-embedded (CHC-embedded) SCS models. Cross-sectional baseline data were collected between November 2018 and March 2020 as part of a cohort of people who inject drugs in Toronto, Canada designed to evaluate one HR-embedded and two CHC-embedded SCS. This analysis was restricted to clients who reported accessing these SCS more than once in the previous 6 months. Participants were classified as HR-embedded or CHC-embedded SCS clients based on self-reported usage patterns. Client characteristics, as well as access to onsite services and referral and uptake of external services, were compared by SCS model. Among 469 SCS clients, 305 (65.0%) primarily used HR-embedded SCS and 164 (35.0%) primarily used CHC-embedded SCS. Compared to clients accessing CHC-embedded SCS, clients accessing HR-embedded SCS were somewhat younger (37.6 vs. 41.4, p < 0.001), more likely to report fentanyl as their primary injected drug (62.6% vs. 42.7%, p < 0.001), and visited SCS more often (49.5% vs. 25.6% ≥ daily, p < 0.001). HR-embedded SCS clients were more likely to access harm reduction services onsite compared to CHC-embedded SCS clients (94.8% vs. 89.6%, p = 0.04), while CHC-embedded SCS clients were more likely to access non-harm reduction services onsite (57.3% vs. 26.6%, p < 0.001). For external services, HR-embedded SCS clients were more likely to receive a referral (p = 0.03) but less likely to report referral uptake (p = 0.009). Clients accessing HR-embedded and CHC-embedded SCS were largely demographically similar but had different drug and SCS use patterns, with CHC-embedded SCS clients using the site less frequently. While clients of CHC-embedded SCS reported greater access to ancillary health services onsite, external service use remained moderate overall, underscoring the importance of co-location and support for clients with system navigation. Importantly, lack of capacity in services across the system may impact ability of staff to make referrals and/or the ability of clients to take up a referral.


[How to continue after an error in family practice?].
Not just malfunctioning doctors make mistakes and errors, all doctors do. Patients suffer through errors, while the doctor is burdened by feelings of guilt and self-reproach. Furthermore the taboo on errors in medicine impedes doctors from learning from mistakes. Adequate management of these situations is of great importance. In order to minimise emotional damage to the patient and his relatives and to improve the quality of medical practice, acknowledgement of having made a mistake comes first; the general practitioner should be aware of personal defence mechanisms such as projection, denial or rationalisation. He should share his experience with some colleagues; in an atmosphere of trust the emotions of regret, shame and anger can be aired. Next the peer group assists in analysing the incident step by step. This analysis makes it possible to learn from the error and perhaps to take measures to prevent recurrence. Thereafter management with respect to the patient or his relatives should be established with aid of the group. Guidelines are: make an appointment with the patient without delay; take ample time and avoid disturbance; listen to the patient and respect his feelings; express regret with regard to the consequences for the patient; contact the patient again after an interval to check if new questions have arisen. This approach is helpful in restoring the patient-doctor relation after a mistake.


The role of growth hormone in ovulation induction.
During the last few years the potential importance of intraovarian regulators of follicular development has been recognized, and the effects of various growth factors on granulosa cell responses to gonadotrophins have been extensively investigated. Ovarian responses to exogenous gonadotrophins were improved by adjuvant growth hormone (GH) treatment of GH-deficient patients, and responses to hMG were apparently predicted by estimated GH reserve. However, the results of different studies of GH/hMG cotreatment were equivocal. Therefore, a randomized, prospective, cross-over study protocol between GH/hMG/hCG versus hMG/hCG was undertaken. Whereas 16 pregnancies were achieved in the 26 Clonidine-negative patients (61.5%) either in the GH/hMG cycle (11) or in the succeeding one (5), no benefit was detected in 8 Clonidine-positive patients from the GH/hMG combination. The recently described GH-binding protein (BP) may reflect the GH-receptor. GH-BP levels were evaluated in the sera and follicular fluids (FF) of patients undergoing ovulation induction with either hMG/hCG or GH/hMG/hCG. GH-BP increase in serum correlated with E2, and progesterone (P4) concentrations. The FF GH-BP correlated with serum GH-BP levels. Lower FF GH-BP levels were measured in older compared to younger women, while increased values were obtained both in patients with elevated E2 concentrations in serum and in FF, or when more than five oocytes were retrieved. Primary increased GH-BP in unexplained infertility may suggest a new mechanism whereby excessive GH-BP levels may deprive GH from its receptor and thus decrease the introavarian IGF-I production.(ABSTRACT TRUNCATED AT 250 WORDS)


Homochiral xanthine quintet networks self-assembled on Au(111) surfaces.
Xanthine molecule is an intermediate in nucleic acid degradation from the deamination of guanine and is also a compound present in the ancient solar system that is found in high concentrations in extraterrestrial meteorites. The self-assembly of xanthine molecules on inorganic surfaces is therefore of interest for the study of biochemical processes, and it may also be relevant to the fundamental understanding of prebiotic biosynthesis. Using a combination of high-resolution scanning tunneling microscopy (STM) and density functional theory (DFT) calculations, two new homochiral xanthine structures have been found on Au(111) under ultrahigh vacuum conditions. Xanthine molecules are found to be self-assembled into two extended homochiral networks tiled by two types of di-pentamer units and stabilized by intermolecular double hydrogen bonding. Our findings indicate that the deamination of guanine into xanthine leads to a very different base pairing potential and the chemical properties of the base which may be of relevance to the function of the cell and potential development of human diseases. Moreover, the adsorption of xanthine molecules on inorganic surfaces leading to homochiral assemblies may be of interest for the fundamental understanding of the emerged chirality at early stages of life.


Efficacy of endoscopic trans-papillary gallbladder stenting and drainage in acute calculous cholecystitis in high-risk patients: a systematic review and meta-analysis.
Acute calculous cholecystitis (ACC) represents about one-third of all surgical emergencies. The gold standard management of ACC is laparoscopic cholecystectomy. Although cholecystectomy is a safe procedure, it may be dangerous and contraindicated in patients with complex comorbidities. Endoscopic transpapillary gallbladder stenting (ETGBS) and drainage had been widely used to manage patients suffering from ACC with comorbidities. We searched PubMed, SCOPUS, Web of Science, and Cochrane Library for relevant studies assessing the use of ETGBS in patients suffering from ACC with various comorbidities. Risk of bias assessment was performed using the National Institues of Health (NIH) tool. We included the following outcomes: clinical success, technical success, late complications, and pancreatitis. We included seven studies that met our inclusion criteria. We found that the pooled proportion of clinical success, technical success, late complications, and pancreatitis was [91.3%, 95% confidence interval (CI) (86.8%, 95.9%)], [92.8%, 95% CI (89%, 96.5%)], [5.4%, 95% CI (2.9%, 7.9%)], and [3.5%, 95% CI (1.2%, 5.8%)], respectively. We found that an ETGBS was an effective and well-tolerated method for the treatment of cholecystitis, especially in high-risk individuals.


The alpha 2-agonist clonidine suppresses seizures, whereas the alpha 2-antagonist idazoxan promotes seizures--a microinfusion study in amygdala-kindled kittens.
This is the first report showing that local, in vivo microinfusion of alpha 2-adrenoreceptor agonists and antagonists have contrasting effects on amygdala-kindled seizure susceptibility. Microinfusions (1 microliter) of the alpha 2-agonist clonidine (CLON) and of the alpha 2-antagonist idazoxan (IDA) were made over 1 min through cannulae adjacent to stimulating electrodes in five amygdala-kindled kittens. Order of administered drugs (CLON vs. IDA) and dosages (n = 3 each) was partly counterbalanced. Focal and convulsive seizure thresholds were evaluated 10-12 min post-infusion and compared to thresholds obtained during two, interspersed control conditions (vehicle control: 1 microliter microinfusion of sterile saline; sham control: needle insertion only). CLON significantly elevated focal and generalized seizure thresholds, whereas IDA significantly reduced seizure thresholds when compared to controls. Magnitude of effects was dose-dependent. Results confirm and extend previous findings which employed unlocalized, in vivo manipulations to show that norepinephrine is a potent antiepileptic agent in the amygdala kindling preparation.


Metal-Phosphate Bilayers for Anatase Surface Modification.
Compared to many other metal oxides, anatase TiO2 shows relatively lower reactivity toward carboxylic acid anchor groups. The latter is crucial for applications, for example, in dye-sensitized solar cells (DSSCs), where the most used dyes bind to the metal oxide surface through carboxylic acid terminations. To improve the surface reactivity, metal-phosphate bilayers of Ni or Co were synthesized on anatase TiO2 compact oxide and nanotubes. In both cases, time-of-flight secondary ion mass spectrometry (ToF-SIMS) and X-ray photoelectron spectroscopy (XPS) results showed that the bilayers were successfully formed and that the phosphate layer works as an intermediate between TiO2 and the other species. ToF-SIMS depth profiles of modified nanotubes showed that Ni and Co are present through the whole tube length and reduce in content after heat treatment, in agreement with XPS results. Phosphate groups, on the other hand, are more present in the tubes' depth, and their content on the surface is reduced upon exposure to temperature. The reactivity of the modified surfaces toward carboxylic acid-terminated molecules, as stearic acid and Ru-based N719 dye, was evaluated. Contact angle measurements together with dye desorption experiments demonstrated that the Co-phosphate bilayers heat-treated at 300 °C resulted in the largest enhancement compared to the reference. Bilayer-modified compact anatase TiO2 and anatase TiO2 nanotubes were utilized as photoanodes in DSSCs. An increase in efficiency was observed for all modified electrodes with phosphate-Co treatment, leading to the highest JSC values and an efficiency improvement of 48%.


Inflammation and oxidative stress as mediators of the impacts of environmental exposures on human pregnancy: Evidence from oxylipins.
Inflammation and oxidative stress play major roles in healthy and pathological pregnancy. Environmental exposure to chemical pollutants may adversely affect maternal and fetal health in pregnancy by dysregulating these critical underlying processes of inflammation and oxidative stress. Oxylipins are bioactive lipids that play a major role in regulating inflammation and increasing lines of evidence point towards an importance in pregnancy. The biosynthetic production of oxylipins requires oxygenation of polyunsaturated fatty acids, which can occur through several well-characterized enzymatic and nonenzymatic pathways. This review describes the state of the science of epidemiologic evidence on oxylipin production in pregnancy and its association with 1) key pregnancy outcomes and 2) environmental exposures. We searched PubMed for studies of pregnancy that measured one or more oxylipin analytes during pregnancy or delivery. We evaluated oxylipin associations with three categories of adverse pregnancy outcomes, including preeclampsia, preterm birth, and fetal growth restriction, along with several categories of environmental pollutants. The majority of studies evaluated one to two oxylipins, most of which focused on oxylipins produced from nonenzymatic processes of oxidative stress. However, an increasing number of recent studies have leveraged technological advancements to profile a large number of oxylipins produced from distinct biosynthetic pathways. Although the literature indicated robust evidence that oxylipins produced via nonenzymatic pathways are associated with pregnancy outcomes and environmental exposures, evidence for enzymatically produced oxylipins showed that associations may differ between biosynthetic pathways. Along with summarizing this evidence, we review promising therapeutic options to regulate oxylipin production and provide a set of recommendations for future epidemiologic studies in these research areas. Further evidence is needed to improve our understanding of how oxylipins may act as key biological mediators for the adverse effects of environmental pollutants on pregnancy outcomes.


Cardiac outflow morphogenesis depends on effects of retinoic acid signaling on multiple cell lineages.
Retinoic acid (RA), the bioactive derivative of vitamin A, is essential for vertebrate heart development. Both excess and reduced RA signaling lead to cardiovascular malformations affecting the outflow tract (OFT). To address the cellular mechanisms underlying the effects of RA signaling during OFT morphogenesis, we used transient maternal RA supplementation to rescue the early lethality resulting from inactivation of the murine retinaldehyde dehydrogenase 2 (Raldh2) gene. By embryonic day 13.5, all rescued Raldh2(-/-) hearts exhibit severe, reproducible OFT septation defects, although wild-type and Raldh2(+/-) littermates have normal hearts. Cardiac neural crest cells (cNCC) were present in OFT cushions of Raldh2(-/-) mutant embryos but ectopically located in the periphery of the endocardial cushions, rather than immediately underlying the endocardium. Excess mesenchyme was generated by Raldh2(-/-) mutant endocardium, which displaced cNCC derivatives from their subendocardial, medial position. RA signaling affects not only cNCC numbers but also their position relative to endocardial mesenchyme during the septation process. Our study shows that inappropriate coordination between the different cell types of the OFT perturbs its morphogenesis and leads to a severe congenital heart defect, persistent truncus arteriosus.


A Visuospatial Planning Task Coupled with Eye-Tracker and Electroencephalogram Systems.
The planning process, characterized by the capability to formulate an organized plan to reach a goal, is essential for human goal-directed behavior. Since planning is compromised in several neuropsychiatric disorders, the implementation of proper clinical and experimental tests to examine planning is critical. Due to the nature of the deployment of planning, in which several cognitive domains participate, the assessment of planning and the design of behavioral paradigms coupled with neuroimaging methods are current challenges in cognitive neuroscience. A planning task was evaluated in combination with an electroencephalogram (EEG) system and eye movement recordings in 27 healthy adult participants. Planning can be separated into two stages: a mental planning stage in which a sequence of steps is internally represented and an execution stage in which motor action is used to achieve a previously planned goal. Our protocol included a planning task and a control task. The planning task involved solving 36 maze trials, each representing a zoo map. The task had four periods: i) planning, where the subjects were instructed to plan a path to visit the locations of four animals according to a set of rules; ii) maintenance, where the subjects had to retain the planned path in their working memory; iii) execution, where the subjects used eye movements to trace the previously planned path as indicated by the eye-tracker system; and iv) response, where the subjects reported the order of the visited animals. The control task had a similar structure, but the cognitive planning component was removed by modifying the task goal. The spatial and temporal patterns of the EEG revealed that planning induces a gradual and lasting rise in frontal-midline theta activity (FMθ) over time. The source of this activity was identified within the prefrontal cortex by source analyses. Our results suggested that the experimental paradigm combining EEG and eye-tracker systems was optimal for evaluating cognitive planning.


The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma.
Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are used as the first-line treatment for patients with metastatic clear cell renal cell carcinoma (mCCRCC). Recently, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) blockade emerged as promising therapy for renal cell carcinoma. However, the expression pattern and prognostic implication of programmed death-ligands (PD-Ls) in mCCRCC patients receiving VEGF-TKI remain unclear. PD-L1 and PD-L2 expression in tumor cells and the quantities of PD-1+ tumor-infiltrating lymphocytes were immunohistochemically evaluated in 91 mCCRCC patients treated with VEGF-TKI, and their associations with VEGF-TKI responsiveness and clinical outcome were analyzed. PD-L1 immunopositivity was observed in 17.6% and significantly associated with a high International Society of Urological Pathology grade (p = .031) and sarcomatoid features (p = .014). PD-L2 immunopositivity was observed in 39.6% and was not associated with any of the assessed clinicopathological variables. PD-L1-positive cases showed poor VEGF-TKI responsiveness (p = .012) compared with PD-L1-negative cases. In univariate survival analysis, PD-L1 immunopositivity was significantly associated with shorter overall survival (OS) (p = .037) and progression-free survival (PFS) (p = .043). Multivariate survival analysis revealed that PD-L1 expression was independently associated with poor OS (p = .038) and PFS (p = .013) in addition to tumor necrosis (p = .006; p = .029, respectively) and Memorial Sloan Kettering Cancer Center score (p = .018; p = .032, respectively). PD-L2 expression was neither associated with VEGF-TKI responsiveness nor patients' outcome. PD-L1 expression was significantly related to lack of VEGF-TKI responsiveness and independently associated with shorter survival in mCCRCC patients after VEGF-TKI treatment. PD-L1 may have a predictive and prognostic value for determining the value of VEGF-TKI treatment in patients with mCCRCC. Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are essential for the treatment of metastatic renal cell carcinoma patients, but the treatment suffers from a lack of predictive markers. This study demonstrates that PD-L1 expression is a predictor for unfavorable response to VEGF-TKI and a prognostic indicator for poor overall survival and progression-free survival in patients with metastatic clear cell renal cell carcinoma receiving VEGF-TKI.


Kill curve analysis and response of first generation Capsicum annuum L. B12 cultivar to ethyl methane sulfonate.
Pepper seeds (Capsicum annuum L.) var. B12 were mutagenized by four presoaking treatments in ten concentrations of ethyl methane sulfonate (EMS) to determine the sensitivity of the first generation (M1) to mutagens. The spectrum of mutations and induced variability for various quantitative traits, including germination, percent plant height, injury occurrence, survival ratio, first three fruits weight, and number of seeds per first fruit, were observed in the M1 generation. Our results indicated that all of the test parameters decreased with increasing EMS concentration, except for seedling injury. There were significant differences in germination ratio, LD50, plant height, percent injury, and survival ratio among the tested presoaking treatment. The LD50 was 1% EMS in seeds that were not presoaked (T1) and seeds presoaked for 12 h before treating with EMS (T3). In contrast, the LD50 was 0.5% EMS in seeds presoaked for 6 h (T2) and seeds presoaked in water for 6 h then incubated at 28°C for 12 h before EMS treatment (T4). Five dwarf plants were observed in mutagenized seeds without presoaking as compared to control seeds (at the maturity stage of the control plant).


Efficacy and safety of indacaterol and tiotropium in COPD patients according to dyspnoea severity.
Guidelines for chronic obstructive pulmonary disease (COPD) recommend that treatment choices be based partly on symptoms. A post-hoc analysis of pooled data from clinical studies compared the efficacy and safety of once-daily inhaled bronchodilators indacaterol (150 and 300 μg) and open-label tiotropium (18 μg) according to baseline dyspnoea severity on the modified Medical Research Council (mMRC) scale in patients with COPD (mMRC scores <2 = 'less dyspnoea'; scores ≥2 = 'more dyspnoea'). Outcomes were assessed after 26 weeks. The analysis included 3177 patients. In patients with less dyspnoea: indacaterol (both doses) improved 24-h post-dose ('trough') forced expiratory volume in 1 s (FEV1), transition dyspnoea index (TDI) and St George's Respiratory Questionnaire (SGRQ) total scores at week 26 and reduced the risk of COPD exacerbations vs placebo; and open-label tiotropium improved trough FEV1 and TDI total score vs placebo at week 26. In patients with more dyspnoea: indacaterol (both doses) improved trough FEV1, TDI and SGRQ total scores at week 26; indacaterol 300 μg was the only treatment to improve the TDI total score by more than the minimum clinically important difference (≥1 point) vs placebo; and open-label tiotropium improved trough FEV1, TDI total score at week 26 and decreased the risk of COPD exacerbations vs placebo. In both subgroups, all treatments were well tolerated. In patients with less dyspnoea, all treatments had similar effects. Indacaterol 300 μg may be a useful treatment option for patients with COPD who experience more severe breathlessness.


Unexpected Clinical Outcome for Myxoinflammatory Fibroblastic Sarcoma, When Should They Be Considered High Grade?
Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare tumor of soft tissue. It typically presents as a low-grade sarcoma with myxoid stroma, has a predilection for distal extremities, and displays a high propensity for local recurrence, but low metastatic potential. The risk factors associated with high-risk lesions metastasizing are poorly defined. In cases where the tumor metastasizes, therapeutic options are few, and death is rare. Our case discusses an aggressive MIFS that progressed from a painless lesion on a patient's calf, to her death from a malignant pleural effusion within 21 months. The 58-year-old woman presented with a mass on her left calf. It was excised and was originally thought to be a benign process. It re-grew quickly after the initial resection, and she underwent re-excision of the mass. The pathologic examination was consistent with an MIFS. Despite negative margins on her second resection and an attempt at local control with radiotherapy, it metastasized to her lungs within less than 2 years. This resulted in a malignant pleural effusion that caused her death. An MIFS is typically benign but can metastasize in atypical cases. Even if the disease is metastatic, it is unlikely to be the cause of death. Treatment of metastatic MIFS is poorly defined, but there are suggested therapies beyond surgical resection and radiotherapy. Successful treatment of an MIFS should include a high index of suspicion in extremity lesions, screening for metastasis, and possible targeted therapies based on tumor genomics.


Ecology of Bats, Their Ectoparasites, and Associated Pathogens on Saint Kitts Island.
Ectoparasites of bats and bat-associated pathogens are poorly studied in the Lesser Antilles Islands. We report on an 11-mo field study on Saint Kitts Island of bat populations, their associated ectoparasites, and pathogens. We report on five ectoparasite species, including four Streblidae (Diptera) and a Spinturnicidae (Acari). Several genotypes of unnamed Bartonella were isolated from bats and ectoparasites. Microfilaria of an undetermined Litomosoides spp. were detected in blood from Artibeus jamaicensis Leach (Chiroptera: Phyllostomidae) (and associated ectoparasites: Trichobius intermedius Peterson and Hurka (Diptera: Streblidae) and Periglischrus iheringi Oudemans (Acari: Spinturnicidae)). In addition, an Ehrlichia sp. and Rickettsia africae were detected in the blood of several bat species. Our study is one of the first surveys of ectoparasite-borne pathogens in wild mammals from St. Kitts.


Small Cell-like Change in Central Zone Histology-A New Observation Mimicking Cribriform Intraductal Prostatic Adenocarcinoma.
A small cell-like change in prostate has been described in high-grade prostatic intraepithelial neoplasia (PIN), intraductal prostatic adenocarcinoma, and invasive prostate cancer. It occurs when these processes have a cribriform architecture. To date, small cell-like change has not been described in benign glands. Herein, I describe such a change in cribriform central zone histology from a radical prostatectomy with a spatially remote treatment naïve Grade Group 3 prostate cancer. The cancer did not have cribriform morphology or intraductal prostatic adenocarcinoma. The small cell-like change was positive for racemase in PIN-4 cocktail and no nuclei were highlighted by Ki-67. This is the first report of a small cell-like change in benign prostate tissue. Although rare, such finding in cribriform architecture of central zone histology can potentially be misinterpreted as a neoplastic process.


Luminol- and lucigenin-dependent chemiluminescence of neutrophils: role of degranulation.
The role of myeloperoxidase in luminol- and lucigenin-dependent chemiluminescence of stimulated human neutrophils has been investigated using purified myeloperoxidase and anti-(human myeloperoxidase) antiserum. This antiserum has been used as a specific enzyme inhibitor to assess myeloperoxidase-dependent neutrophil functions in single preparations of cells, thus overcoming the limitations inherent in other approaches using non-specific haem-inhibitors or myeloperoxidase-deficient neutrophils. The results show that luminol-dependent chemiluminescence is largely dependent on both oxidase activity and degranulation (of myeloperoxidase), while lucigenin monitors oxidase activity independently of the extent of degranulation. Since oxidase activation can occur in the absence of degranulation, assays utilizing luminol-dependent chemiluminescence to measure oxidant generation by stimulated neutrophils should include saturating levels of exogenous myeloperoxidase to overcome this problem.


Tumor-targeted efficiency of shRNA vector harboring chimera hTERT/U6 promoter.
Telomerase is closely related to tumor, and hTERT is the rate-limiting factor for telomerase activity. The transcription and expression of hTERT is determined by hTERT promoter, which has the ability of anchoring telomerase positive cells. RNA interference (RNAi) has been potentially used in the functional genomics and gene therapy recently. However, the limitations of RNAi uncertain interference and safety hamper its wide applications. To overcome these limitations, we constructed shRNA vectors harboring either U6 promoter or chimera hTERT/U6 promoter aiming at EGFP and hTERT genes (shRNA-EGFP-U6, shRNA-EGFP-hTERT/U6, shRNA-hTERT-U6 and shRNA-hTERT-hTERT/U6), to suppress the expression of GFP and hTERT in telomerase negative human normal fibroblast HELF cells and telomerase positive human hepatocarcinoma SMMC-7721 and HepG2 cells, respectively. HELF-EGFP and SMMC-7721-EGFP cells stably expressing EGFP or hTERT were constructed. GFP expression was inhibited in both HELF-EGFP and SMMC-7721-EGFP cells expressing shRNA-EGFP-U6. Further results showed that GFP expression was suppressed only in telomerase positive SMMC-7721 cells and HepG2 cells, but not in telomerase negative HELF cells expressing shRNA-EGFP-hTERT/U6. Further results found that hTERT expression was effectively inhibited from liver cancer cells expressing shRNA-hTERT-U6 or shRNA-hTERT-hTERT/U6 both in vitro and in vivo. Our study illustrates the tumor-targeted efficiency of shRNA vectors harboring chimera hTERT/U6 promoter in telomerase positive cells, which will benefit tumor therapy.


Complete mitochondrial genome of the crocodile shark Pseudocarcharias kamoharai (Lamniformes: Pseudocarchariidae).
In this study, we determined the complete mitogenome sequence of Pseudocarcharias kamoharai. The complete mitogenome of P. kamoharai is 16,694 bp in length, which contains 13 protein-coding genes, 22 transfer RNAs, 2 ribosomal RNAs and 2 non-coding regions: control region (D-loop) and origin of light-strand replication (OL). Overall, base composition of mitogenome is estimated to be 32.06% for A, 23.63% for C, 13.21% for G and 31.10% for T. The complete mtDNA sequence of P. kamoharai provides a useful data for the studies on the molecular systematic phylogeography and population genetics.


New aspects in clinicopathologic and oncogene studies of 23 pulmonary lymphoepithelioma-like carcinomas.
Lymphoepithelioma-like carcinoma, an uncommon epithelial tumor, has been described as being closely associated with Epstein-Barr virus (EBV) infection in many organs, especially the nasopharynx. We experienced 23 cases of lymphoepithelioma-like carcinoma arising in the lung from 2498 lung cancer patients in the Cancer Registry of our hospital. Seven patients were male and 16 were female. All patients were Chinese. Their ages ranged from 42 to 80 years. Six patients were smokers and 17 were nonsmokers. The tumor sizes ranged from 1.2 to 11.0 cm. All tumors showed the typical syncytial growth pattern of undifferentiated epithelial cells with a significant CD8+ T-lymphocyte reaction. EBV serology revealed prior infection in all 15 serum-available patients, all of whom were also found by in situ hybridization to have the virus genome. In addition, the higher the EBV serology titer, the larger the tumor size and the higher the staging would be. EBV viral capsid antigen IgG level remained elevated despite response to therapy. Nearly all cases had bcl-2 oncoprotein expression, but the detection rate of latent membrane protein-1, p53, and c-erb B-2 expression was extremely low. The encouraging chemotherapy response for advanced stage disease is also discussed.


Clinical Usefulness of Therapeutic Neuromodulation for Major Depression: A Systematic Meta-Review of Recent Meta-Analyses.
The authors conducted a meta-review of meta-analyses published in the past decade on therapeutic neuromodulation (ie, repetitive transcranial magnetic stimulation, transcranial direct current stimulation, vagus nerve stimulation and deep brain stimulation) for major depression. Active repetitive transcranial magnetic stimulation and transcranial direct current stimulation have been generally associated with small to moderate effect sizes vis-à-vis their efficacy and with similar acceptability compared with sham. Vagus nerve stimulation and deep brain stimulation (although more challenging to investigate) have demonstrated preliminary effectiveness, particularly during longer-term follow-up.


Distinct metabolic features in the plasma of patients with silicosis and dust-exposed workers in China: a case-control study.
Silicosis is a progressive pneumoconiosis characterized by interstitial fibrosis following exposure to silica dust. The role of metabolic dysregulation in the pathogenesis of silicosis has not been investigated in detail. This study aimed to identify different metabolic features in the plasma of patients with silicosis and dust-exposed workers without silicosis in metabolomics studies. Patients with silicosis, dust-exposed workers (DEWs) without silicosis and age-matched healthy controls were recruited in a case-control study. The metabolomics analyses by ultra-high performance liquid chromatography-mass spectrometry were conducted. Distinct metabolic features (DMFs) were identified in the pilot study and were validated in the validation study. The enriched signalling pathways of these DMFs were determined. The ability of DMFs to discriminate among the groups was analysed through receiver operating characteristic (ROC) curves. The correlations between DMFs and clinical features were also explored. Twenty-nine DMFs and 9 DMFs were detected and had the same trend in the pilot study and the validation study in the plasma of the DEW and silicosis groups, respectively. Sphingolipid metabolism was the major metabolic pathway in the DEWs, and arginine and proline metabolism was associated with silicosis. Twenty DMFs in the DEWs and 3 DMFs in the patients with silicosis showed a discriminatory ability with ROC curve analysis. The abundance of kynurenine was higher in Stage III silicosis than in Stage I or Stage II silicosis. L-arginine and kynurenine were both negatively correlated with the percentage of forced vital capacity predicted in silicosis. Distinct metabolic features in the plasma of DEWs and the patients with silicosis were found to be different. Sphingolipid metabolism and arginine and proline metabolism were identified as the major metabolic pathway in the DEW and silicosis groups, respectively. L-arginine and kynurenine were correlated with the severity of silicosis.


A comprehensive evaluation of progestin-primed ovarian stimulation protocol in patients with or without PCOS undergoing in vitro fertilization.
Progestin-primed ovarian stimulation (PPOS) regimen was established for assisted reproduction. However, its feasibility and outcomes in polycystic ovary syndrome (PCOS) patients need further evaluation. The outcomes of infertile patients with PCOS (study group) and normal ovaries (control group with unexplained infertility and tubal factor infertility) who underwent PPOS and IVF/ICSI protocol were retrospectively studied. The baseline information, primary, and secondary outcomes of patients were collected. The dynamic changes of hormones were closely monitored. 198 PCOS patients and 374 controls were included in this study. After controlled ovarian hyperstimulation (COH), 15 oocytes were retrieved from PCOS patients on average, which was more than those from the controls (p < 0.001). The oocytes and embryos obtained from the PCOS patients exhibited better developmental potential as the number of fertilized oocytes, cleaved embryos, top-quality embryos, viable embryos, cryopreserved embryos, the rate of fertilization, and viable embryo per oocyte retrieved in PCOS patients were significantly higher than those in the controls (all p < 0.001). No significant difference between the two groups was identified regarding the primary outcome, ongoing pregnancy, and other secondary outcomes. No moderate to severe ovarian hyperstimulation syndrome (OHSS) was diagnosed in either group. With the proposed PPOS protocol, the quantity, quality, developmental potential of oocytes, and embryos obtained from PCOS patients were superior to those from controls. The protocol was efficient and safe in terms of pregnancy, obstetric, and perinatal outcomes. OHSS was effectively mitigated in the patients, with or without PCOS, who underwent COH.


[Analysis of the safety and efficacy of percutaneous isolated hepatic perfusion after particle therapy for advanced hepatocellular carcinoma].
Here, we report the efficacy of dual treatment with hepatic resection and percutaneous isolated hepatic perfusion (PIHP) for advanced hepatocellular carcinoma( HCC). Recently, we introduced treatment with combined particle therapy and PIHP for unresectable HCC in cases of insufficient liver function. The purpose of this study was to evaluate the safety and efficacy of PIHP for local control in the liver after particle therapy. From 2006 to 2013, 6 patients underwent particle therapy for the main lesion and subsequent PIHP for remnant liver lesions. Their mean age was 64 years, and the mean size of the main lesion was 6.2 cm (range, 2.0-10.8 cm). All patients had liver cirrhosis. After particle therapy, PIHP was performed by hepatic arterial infusion of 100 mg/m2 of doxorubicin and 30 mg/m2 of mitomycin C. With regard to side effects, neutropenia occurred in all patients but no serious hepatobiliary injury was observed. The response rate for PIHP was 50% (partial response: 3 and stable disease: 3). The mean overall survival time was 26.9 months after particle therapy. In conclusion, even after particle therapy, PIHP is a safe treatment and is associated with a good local control rate for remnant HCCs. Further accumulation of data is needed to evaluate the efficacy of this treatment strategy in terms of prognosis.


[Peripheral arterial aneurysm of the brain occurring after brain abscess extirpation and healing spontaneously-report of a case and review of the literature (author's transl)].
In 33 year-old man an aneurysm of a pheripheral branch of the right middle cerebral artery was disclosed by angiography 8 days after extirpation of a parietotemporal brain abscess. The aneurysm was absent in the preoperative angiogram. Since the site of the aneutysm coincided with the operative field, it is sure that the etiology of the aneurysm was related to operative trauma and/or arteritis. Although inflammatory or mycotic factor could not be excluded from its etiology, it seems reasonable that traumatic factor was major one. The aneurysm was found to have disappeared eventually in the angiogram made on 372th postoperative day. Traumatic aneurysms arising from peripheral branches of the intracranial arteries are very rare. The first case was reported by Krauland in 1949. We collected 32 such cases from the literature. Of the 33 cases including the present one, 5 are iatrogenic. In more than half of the 33 cases, aneurysms were formed within 14 days following head injury. Posttraumatic delayed hemorrhage was found in 15 cases, the hemorrhage occurring within one month following injury in 12 cases. Of 31 cases with known prognosis, 11 died, 6 of them dying of delayed hemorrhage. Aneurysm operation was performed in 21 cases and 15 of them survived. In the present case, aneurysm luckily healed spontaneously. There are two cases including the present one, of spontaneous healing in the 33 cases. We believe surgical treatment is one of choice whenever possible.


Structure of bovine cytochrome c oxidase crystallized at a neutral pH using a fluorinated detergent.
Cytochrome c oxidase (CcO) couples proton pumping to O2 reduction. Its enzymatic activity depends sensitively on pH over a wide range. However, owing to difficulty in crystallizing this protein, X-ray structure analyses of bovine CcO aimed at understanding its reaction mechanism have been conducted using crystals prepared at pH 5.7, which is significantly lower than that in the cell. Here, oxidized CcO at pH 7.3 was crystallized using a fluorinated octyl-maltoside derivative, and the structure was determined at 1.77 Å resolution. No structural differences between crystals obtained at the neutral pH and the acidic pH were detected within the molecules. On the other hand, some differences in intermolecular interactions were detected between the two types of crystal. The influence of pH on the molecular surface is likely to contribute to the pH dependency of the aerobic oxidation of ferrocytochrome c.


Transcriptional profiling of hypothalamus during development of adiposity in genetically selected fat and lean chickens.
The hypothalamus integrates peripheral signals to regulate food intake, energy metabolism, and ultimately growth rate and body composition in vertebrates. Deviations in hypothalamic regulatory controls can lead to accumulation of excess body fat. Many regulatory genes involved in this process remain unidentified, and comparative studies may be helpful to unravel evolutionarily conserved mechanisms controlling body weight and food intake. In the present study, divergently selected fat (FL) and lean (LL) lines of chickens were used to characterize differences in hypothalamic gene expression in these unique genetic lines that develop differences in adiposity without differences in food intake or body weight. Hypothalamic transcriptional profiles were defined with cDNA microarrays before and during divergence of adiposity between the two lines. Six differentially expressed genes identified in chickens are related to genes associated with control of body fat in transgenic or knockout mice, supporting the importance of these genes across species. We identified differences in expression of nine genes involved in glucose metabolism, suggesting that alterations in hypothalamic glycolysis might contribute to differences in levels of body fat between genotypes. Expression of the sweet taste receptor (TAS1R1), which in mammals is involved in glucose sensing and energy uptake, was also higher in FL chickens, suggesting that early differences in glucose sensing might alter the set point for subsequent body composition. Differences in expression of genes associated with tumor necrosis factor (TNF) signaling were also noted. In summary, we identified alterations in transcriptional and metabolic processes within the hypothalamus that could contribute to excessive accumulation of body fat in FL chickens in the absence of differences in food intake, thereby contributing to the genetic basis for obesity in this avian model.


Neither heat pulse, nor multigenerational exposure to a modest increase in water temperature, alters the susceptibility of Guadeloupean Biomphalaria glabrata to Schistosoma mansoni infection.
There are increasing concerns regarding the role global climate change will have on many vector-borne diseases. Both mathematical models and laboratory experiments suggest that schistosomiasis risk may change as a result of the effects of increasing temperatures on the planorbid snails that host schistosomes. Heat pulse/heat shock of the BS90 strain of Biomphalaria glabrata was shown to increase the rate of infection by Schistosoma mansoni, but the result was not replicable in a follow up experiment by a different lab. We characterised the susceptibility and cercarial shedding of Guadeloupean B. glabrata after infection with S. mansoni under two temperature regimes: multigenerational exposure to small increases in temperature, and extreme heat pulse events. Neither long-term, multigenerational rearing at elevated temperatures, nor transient heat pulse modified the susceptibility of Guadeloupean B. glabrata to infection (prevalence) or shedding of schistosome cercaria (intensity of infection). These findings suggest that heat pulse-induced susceptibility in snail hosts may be dependent on the strain of the snail and/or schistosome, or on some as-yet unidentified environmental co-factor.


Non-invasive Fetal ECG Signal Quality Assessment for Multichannel Heart Rate Estimation.
The noninvasive fetal ECG (NI-FECG) from abdominal recordings offers novel prospects for prenatal monitoring. However, NI-FECG signals are corrupted by various nonstationary noise sources, making the processing of abdominal recordings a challenging task. In this paper, we present an online approach that dynamically assess the quality of NI-FECG to improve fetal heart rate (FHR) estimation. Using a naive Bayes classifier, state-of-the-art and novel signal quality indices (SQIs), and an existing adaptive Kalman filter, FHR estimation was improved. For the purpose of training and validating the proposed methods, a large annotated private clinical dataset was used. The suggested classification scheme demonstrated an accuracy of Krippendorff's alpha in determining the overall quality of NI-FECG signals. The proposed Kalman filter outperformed alternative methods for FHR estimation achieving accuracy. The proposed algorithm was able to reliably reflect changes of signal quality and can be used in improving FHR estimation. NI-ECG signal quality estimation and multichannel information fusion are largely unexplored topics. Based on previous works, multichannel FHR estimation is a field that could strongly benefit from such methods. The developed SQI algorithms as well as resulting classifier were made available under a GNU GPL open-source license and contributed to the FECGSYN toolbox.


Clinical study to identify specific characteristics of cancer newly developed in the remnant stomach.
Cancer newly developed in the remnant stomach (CRS) after partial gastrectomy is worthy of attention not only because it is a typical model of carcinogenesis but also from the aspect of cancer diagnosis. We treated 47 patients with CRS in the 20 years from 1979 to 1998. Clinicopathological variables, as well as long-term survival results after the second surgery, were reviewed to clarify whether there were any differences in the characteristics of this disease entity compared with the usual primary gastric cancer. The mean time interval between the initial surgery and surgery for CRS was 25.8 years for patients with CRS with previous benign gastric lesions, and 10.6 years for those with previous gastric cancer. CRS was frequently detected at an early stage in the patients with previous cancer, and in the patients who had undergone reconstruction by the Billroth I method (regardless of the primary nature of the disease). Cancers with a differentiated histology developed more frequently in the patients who had undergone the initial surgery for cancer disease. Long-term survival results after the second surgery clearly demonstrated that surgical treatment for CRS was as effective as that for primary cancer in the upper stomach (PUC). In addition, it was confirmed that new lymphatic drainage into the lower mediastinum or the jejunal mesentery had developed after the initial gastric surgery. The findings suggested that patients with CRS and those with PUC should be treated similarly, although the findings of a high incidence of lymph node metastasis to the lower mediastinum and/or to the jejunal mesentery in the CRS patients should be taken into consideration.


[Effect of traditional Chinese medicine (dai-saiko-to) on experimental calcinosis].
To clarify the anti-calcinosis actions of traditional Chinese medicine (Dai: Dai-saiko-to) and estradiol benzoate (E2), 7-week or retired (about 6-months-old) female rats were treated with Vit. D2 (1.75 x 10(5) I.U./kg b.w./day) for 4 days, and then were fed a basal diet containing Dai (at ten times the medical dose in humans) or were injected i.p. with E2 (at the medical dose in humans) for 6 weeks. The following results were obtained: 1) Dai did not improve Ca and P metabolism in experimental calcinosis of 7-week female rats; 2) in retired female rats, Dai decreased both P in the heart and the ratio of Ca to P in bone, similar to the treatment with E2. Dai, as well as E2, seemed to nomalize Ca and P metabolism disturbed by Vit. D2 treatment.


Eligibility and Awareness Regarding Metabolic Surgery in Patients With Type 2 Diabetes Mellitus in the Real-World Clinical Setting; Estimate of Possible Diabetes Remission.
Despite high-quality evidence highlighting metabolic surgery as an effective treatment option for type 2 diabetes mellitus (T2DM), the number of patients receiving bariatric surgery (BS) remains low. Since the introduction of the Diabetes Surgery Summit II (DSS-II) eligibility criteria, data on eligibility rates for BS in T2DM cohorts remain scarce. The aims of the present study were to examine in a real-world clinical setting: (i) what is the percentage of T2DM patients visiting diabetes outpatient clinics who meet the DSS-II eligibility criteria, (ii) how many of these have been informed about the option of BS, and (iii) what are the characteristics associated with eligibility and awareness of BS. Demographic, anthropometric, clinical and socioeconomic data were obtained for all patients with T2DM who were consecutively examined in the outpatient clinics of three large-volume university hospitals (n = 1167). A medical registry form was completed to screen for BS eligibility. Patients were considered eligible if the recommendation by DSS-II criteria was either to "consider" or "recommend" BS. Eligible patients were further inquired whether they had ever been informed about the option of BS by their physicians. The advanced DiaRem score (ADRS) was applied to eligible patients to assess their probability of achieving postoperative T2DM remission. A significant percentage of T2DM patients who are routinely assessed in outpatient clinics meet the DSS-II eligibility criteria (15.3%). Eligible patients are younger and more obese, have a shorter T2DM duration, worse glycaemic control and better renal function, compared to non-eligible ones. Among eligible patients, only 39.3% have been medically informed about the option of BS. Informed patients are younger and more severely obese than non-informed ones. A significant percentage of non-informed patients (35%) have an ADRS ≤10, indicating a considerable probability for T2DM remission after BS, and are thus deprived of this opportunity due to lack of appropriate medical counseling. Screening and awareness of BS remain an unmet need in current T2DM management. Future research should focus on intensifying screening for BS eligibility at every medical visit and promoting evidence-based clinical recommendations for patients expected to benefit the most.


Leiomyoma: an unusual bladder neoplasm.
The authors present a case of a 42-year-old lady who visited her gynaecologist with dysuria and a sensation of incomplete voiding for 2 weeks. Urine culture grew Escherichia coli and blood studies were normal. Pelvic ultrasound revealed a smooth well-defined mass arising from the bladder wall. She was referred to the urologist who requested CT and MRI for further evaluation. These modalities confirmed an intramural bladder mass with normal overlying mucosa. The mass was deemed contributory to her symptoms and a decision was made to excise the mass surgically. Via a transurethral approach, cystoscopy revealed a smooth well-circumscribed intramural mass. This was partially excised. The mass was found to be a leiomyoma. Except for an uncomplicated urinary tract infection, her postoperative course has been uneventful.


Respiratory muscle function during emesis in awake canines.
Emesis requires a coordinated differential recruitment of gastrointestinal smooth muscle, upper airway muscles, and several muscles involved in respiration. In seven awake intact canines we measured the electrical activity (electromyogram) and shortening of costal and crural diaphragm segments, parasternal intercostal, and transversus abdominis during emesis that was induced by instillation of apomorphine into the lower conjunctival fornix. The process of emesis was tightly coordinated with ventilation and showed four respiratory phases: baseline ventilation (Base), initial preemetic hyperventilation (Hyperv), prodromal ventilation associated with salivation and probable nausea (Prodrome), and finally retching and expulsion (Expel) of gastric contents. Ventilation was suppressed during expulsive events, but a small inspiratory airflow was interjected between expulsions. Resting electromyogram of all four muscles increased during the process of emesis, with costal and crural segments showing a marked decrease in resting length through Prodrome and Expel. To produce an expulsive maneuver, both inspiratory and expiratory muscles were activated synchronously, unlike their usual sequential activation during ventilation, with costal and crural segments and transversus abdominis showing the most shortening. The crural segment showed a biphasic length change with initial shortening and then lengthening to assist esophageal sphincter function during Expel. These results indicate a strong coordinated interaction between brain stem centers responsible for control of respiration and of emesis.


Capsaicin pretreatment reversed pulmonary arterial hypertension by alleviating inflammation via p38MAPK pathway.
Purpose/Aim: Pulmonary arterial hypertension (PAH) is a lethal disease associated with pulmonary vascular remodeling as well as inflammation. As a kind of tachykinin secreted by nerves and inflammatory cells, substance P (SP) has been proved to be involved in the progression of PAH. Capsaicin can deplete substance P and provide benefits in PAH. However, the mechanism is still unclear. In this article, we aim to illustrate the possible mechanism involved in the process of capsaicin alleviating PAH. A single injection of monocrotaline (MCT) to male Sprague-Dawley (SD) rats was conducted to induce PAH. Capsaicin pretreatment was administered three days before MCT injection to deplete substance P. P38mitogen-activated protein kinase (p38MAPK) activator or inhibitor was given intraperitoneally after MCT injection. After 28 days, hemodynamic studies were carried out, and right ventricular systolic pressure (RVSP), right ventricular (RV)/left ventricle plus septum (LV+S), RV/body weight (BW), and lung weight (LW)/BW were recorded and calculated. In addition, the pulmonary vascular remodeling (pulmonary arterial medial wall thickness, area, perivascualr fibrosis), pro-inflammatory cytokines, the common signal pathways, such as peroxisome proliferator-activated receptor gamma (PPARγ), extracellular signal-regulated kinases (Erk), protein kinase B (Akt), and p38MAPK were also detected. Capsaicin pretreatment reversed PAH, including decreasing RVSP, RV/(LV+S), RV/BW, and LW/BW, and alleviating inflammation. Phosphorylated-p38 (p-p38) MAPK was up-regulated, which was partially reversed by capsaicin pretreatment. Interestingly, expression of Akt, Erk, and PPARγ was not altered by capsaicin pretreatment. Inhibition of p38MAPK provided the same benefits with capsaicin pretreatment, whereas it failed to provide additional improvement in the presence of capsaicin. Besides, p38MAPK activator abolished the effects of capsaicin pretreatment on PAH, suggesting a key role of p38MPAK pathway in the effects of capsaicin reversing PAH. Capsaicin pretreatment reversed PAH by alleviating inflammation via p38MAPK pathway.


Effect of isoprinosine on lymphocyte proliferation and natural killer cell activity following thermal injury.
The effect of in vivo administration of Isoprinosine (ISO) on, i) the proliferation of splenic lymphocytes in response to the T-cell mitogen, concanavalin-A (Con-A) and, ii) the natural killer (NK) cell cytotoxicity was studied following a full skin thickness burn injury in a rat model. Administration of ISO (100 mg/kg body wt/day) twice daily, resulted in significant augmentation of the proliferative responses of lymphocytes compared to non-treated burned animals, at 7 days post injury. However, it did not effect the lymphoproliferation at 14 days post injury, the time period at which a complete suppression of lymphocyte proliferation was observed in burned non-treated animals. Also, the proliferation of lymphocytes from normal nonburned animals was not affected by treatment with ISO. ISO treatment of the burned animals resulted in a significant increase in the NK cytotoxicity compared to non-treated burned animals. As with Con-A responses, ISO administered to control nonburned animals did not have any effect on NK cell cytotoxicity. Our studies thus indicate that ISO can be a potential immunomodulator of suppressed immune function following thermal injury, particularly in patients whose lymphocyte responses to T cell mitogen Con-A are not completely suppressed.


Immunohistochemical investigation of dermal capillaries in chronic venous insufficiency.
Skin biopsies from the area of the medial malleolus of 24 patients with chronic venous insufficiency, of 5 patients without signs or history of chronic venous insufficiency and of seven corpses without manifestation of chronic venous insufficiency, were sectioned and stained with hematoxylin and eosin and with Ki-67, a monoclonal antibody expressed in the nuclei of proliferating cells. Hematoxylin- and eosin-stained sections of all specimens were assessed blindly to determine the state of capillary increase in stasis dermatosis. Twenty-four patients were found to have different stages of stasis dermatosis. During the examination of the Ki-67 frozen sections, close attention was paid to the capillary bed of all sections for any Ki-67-positive nuclei in capillary cells. None of the three groups showed positive staining of nuclei in capillary cells. This finding proves that there is no capillary proliferation, but an elongation and distension of the capillaries.


Leading into the 21st century: changing the vision and leading toward success.
This article depicts real challenges facing nursing leaders today. Today's health care climate is fraught with many conflicts necessitating nursing leaders to guide their staffs in more positive, productive models of care delivery. This article explores the experience in one organization of seeking an alternative model of care delivery. The needed leadership skills and expertise in leading the implementation of trained teams are highlighted for each phase of the implementation. The background for success is illustrated as well as the successful outcomes of this endeavor. The transdisciplinary model was a new concept to a nursing director who was seeking a better way to bring all health care disciplines on her unit together. It was her goal to expand and reinforce the team's definition of care integration and to define and operationalize a unique method of care delivery. The process and outcomes are outlined, focusing on successes and failures. It highlights the strengths of the transdisciplinary model, not only for the patient, but also for the staff.


Acupuncture Regulates Serum Differentially Expressed Proteins in Patients with Chronic Atrophic Gastritis: A Quantitative iTRAQ Proteomics Study.
To identify differentially expressed proteins (DEPs) in sera of patients with chronic atrophic gastritis (CAG) using isobaric tags for relative and absolute quantitation (iTRAQ) and to explore acupuncture's mechanism in CAG. Peripheral sera from 8 healthy volunteers (HC), 8 chronic nonatrophic gastritis (NAG) patients, 8 CAG patients, and 8 CAG patients who underwent acupuncture treatment (CAG + ACU) were collected followed by labeling with iTRAQ reagent for protein identification and quantification using two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/MS). Representative DEPs were selected through bioinformatics, and proteins were verified by enzyme-linked immunosorbent assay (ELISA). A total of 4,448 unique peptides were identified, corresponding to 816 nonredundant proteins. A 1.4-fold difference was used as the threshold. Compared with the HC group, 75 and 106 DEPs were identified from CAG and NAG groups, respectively. Compared with the CAG group, 110 and 66 DEPs were identified from the NAG and CAG + ACU groups, respectively. The DEPs were mainly involved in protein binding and the Notch signaling pathway-related proteins, and the upregulated proteins included actin-binding proteins (thymosin beta-4, tropomyosin-4, profilin-1, transgelin-2), while the downregulated proteins included Notch2 and Notch3. After acupuncture, the expression of these proteins in CAG patients was less differentiated from that in healthy people. The level of the above 6 proteins were verified by ELISA, and the results were similar to the results of iTRAQ analysis. Actin-binding proteins and Notch signaling pathway-related proteins were correlated with the development and progression of CAG and thus are potential diagnostic markers for CAG. Acupuncture may play a role in regulating actin-binding proteins and Notch signaling pathway-related proteins to play a therapeutic role in CAG.


Antiglioma via regulating oxidative stress and remodeling tumor-associated macrophage using lactoferrin-mediated biomimetic codelivery of simvastatin/fenretinide.
Effective treatment of malignant glioma still remains a formidable challenge due to lack of the effective BBB-permeable drugs and efficient brain delivery methods, and the pharmacotherapy options are very limited. Therefore, to develop an effective therapeutic strategy is a pressing need. In this work, a noncytotoxic drug combination (i.e., simvastatin and fenretinide) was revealed to be potent for treating glioma, which was co-encapsulated into a TPGS-TAT-embedded lactoferrin nanoparticle system for achieving brain-targeted biomimetic delivery via the LRP-1 receptor. It was shown that the lactoferrin nanoparticle repolarized the tumor-associated macrophages from the M2 phenotype to M1 via regulating the STAT6 pathway, as well as induced the ROS-mediated mitochondrial apoptosis by inhibiting the Ras/Raf/p-Erk pathway in the glioma cells. The antiglioma efficacy was further demonstrated in both the subcutaneous and orthotopic glioma models. The repolarization of tumor-associated macrophages not only prompted the ROS generation but also induced the innate immunity (e.g., antitumor cytokine release). This delivery and therapeutic strategy provides a novel modality for the glioma treatment.


Bulk-fill restorative composites under simulated carious and erosive conditions.
Acidic conditions can cause hydrolysis and accelerate degradation of resin composites (RCs). Since there are limited and controversial data on the effect of acids on bulk-fill RCs, this study assessed the surface roughness (SR) and flexural strength (FS) of these RCs under simulated carious and erosion conditions. Bars of Filtek Bulk Fill (FBF, 3M/ESPE), X-tra fil (XTF, Voco), Tetric N-Ceram Bulk Fill (TBF, Ivoclar/Vivadent), and Aura Bulk Fill (ABF, SDI) and a conventional RC [Filtek Z350XT (FZ, 3M/ESPE)] were allocated (n=15) to undergo caries or erosion conditions. The control group was kept in artificial saliva (AS). The bars were evaluated for SR change (final-baseline) and for three-point FS. Data were analyzed using ANOVA and Tukey's test. At the baseline (p <0.001), the SR of RCs ranked as follows: (TBF = XTF) < FBF (none differed from FZ) < ABF. The interplay between RCs and conditions affected SR change (p = 0.025). While after storage in AS, there was no difference among RCs, following carious and erosive conditions, ABF showed higher SR change. For FS (p <0.001), XTF > (FBF = FZ) > (TBF = FZ) > ABF, with no difference among control, carious and erosive conditions (p = 0.148). Depending on the restorative bulk-fill RCs, carious and erosive conditions roughen the surface but do not affect the FS of these materials.


Drug-eluting balloon catheters for lower limb peripheral arterial disease: the evidence to date.
A significant proportion of patients with severe lower limb peripheral arterial disease require revascularization. Over the past decade, an endovascular-first approach even for complex disease has gained widespread use among vascular specialists. An important limitation of percutaneous transluminal balloon angioplasty or stenting remains the occurrence of restenosis. Drug-coated balloons have emerged as an exciting technology developed to overcome the limitations of standard balloon angioplasty and stenting. Drug-eluting devices inhibit neointimal growth of vascular smooth muscle cells with the potential of preventing restenosis. This review provides a synopsis of the up-to-date evidence on the role of drug-coated balloons in the treatment of lower limb peripheral arterial disease. Bibliographic searches were conducted using MEDLINE, EMBASE, and the Cochrane Library electronic database. Eleven randomized clinical trials, two systematic reviews, and a published registry providing the best available evidence were identified. Current evidence suggests that angioplasty with drug-coated balloon is reliable, safe, and efficient in increasing patency rates and reducing target lesion revascularization and restenosis. However, it remains unknown whether these improved results can translate into beneficial clinical outcomes, as current randomized clinical trials have failed to demonstrate a significant benefit in limb salvage and mortality. Further randomized trials focusing on clinical and functional outcomes of drug-eluting balloons and on cost versus clinical benefit are required.


Mild, Redox-Neutral Alkylation of Imines Enabled by an Organic Photocatalyst.
An operationally simple, mild, redox-neutral method for the photoredox alkylation of imines is reported. Utilizing an inexpensive organic photoredox catalyst, alkyl radicals are readily generated from the single-electron oxidation of ammonium alkyl bis(catecholato)silicates and are subsequently engaged in a C-C bond-forming reaction with imines. The process is highly selective, metal-free, and does not require a large excess of the alkylating reagent or the use of acidic additives.


Bacteria Transport in a Soil-Based Wastewater Treatment System under Simulated Operational and Climate Change Conditions.
Bacteria removal efficiencies in a conventional soil-based wastewater treatment system (OWTS) have been modeled to elucidate the fate and transport of bacteria under environmental and operational conditions that might be expected under changing climatic conditions. The HYDRUS 2D/3D software was used to model the impact of changing precipitation patterns, bacteria concentrations, hydraulic loading rates (HLRs), and higher subsurface temperatures at different depths and soil textures. Modeled effects of bacteria concentration shows that greater depth of treatment was required in coarser soils than in fine-textured ones to remove . The initial removal percentage was higher when HLR was lower, but it was greater when HLR was higher. When a biomat layer was included in the transport model, the performance of the system improved by up to 12.0%. Lower bacteria removal (<5%) was observed at all depths under the influence of precipitation rates ranging from 5 to 35 cm, and 35-cm rainfall combined with a 70% increase in HLR. Increased subsurface temperature (23°C) increased bacteria removal relative to a lower temperature range (5-20°C). Our results show that the model is able to effectively simulate bacteria removal and the effect of precipitation and temperature in different soil textures. It appears that the performance of OWTS may be impacted by changing climate.


Modified melanocortin tetrapeptide Ac-His-dPhe-Arg-Trp-NH at the arginine side chain with ureas and thioureas.
The Ac-His-dPhe-Arg-Trp-NH2 tetrapeptide is a nonselective melanocortin agonist and replacement of Arg in the tetrapeptide with acidic, basic or neutral amino acids results in reduced potency at the melanocortin receptor (MCR) isoforms (MC1R and MC3-5R). To determine the importance of the positive charge and the guanidine moiety for melanocortin activity, a series of urea- and thiourea-substituted tetrapeptides were designed. Replacement of Arg with Lys or ornithine reduced agonist activity at the mouse mMC1 and mMC3-5 receptors, thus supporting the hypothesis that the guanidine moiety is important for receptor potency, particularly at the MC3-5 receptors. The Arg side chain-modified tetrapeptides examined in this study include substituted phenyl, naphthyl, and aliphatic urea and thiourea residues using a Lys side-chain template. These ligands elicit full-agonist pharmacology at the mouse MCRs examined in this study.


Traditional Tongan medicine and the role of traditional Tongan healers in New Zealand.
The aim of the study was to investigate the role of traditional Tongan healers in New Zealand. Qualitative interviews were carried out with twenty nine healers who were contacted through community networks. Every healer was unique in the kinds of ailments they treated which included fakamahaki (spirit related illnesses), lavea (physical injuries), hangatamaki (a wide group of traditional illnesses) and mahaki (non specific symptoms). Healing was seen as an act of love and service for the community for which it was inappropriate to charge. Healing skills and powers were passed on within families through the use of special rituals. The nature and attitude of the healer was regarded as being very important; the efficacy of the healing was seen to be more a function of the healer than the treatment used. Referrals to other healers and general practitioners were common. The healers expressed concern about the lack of understanding of their role by the western health system. There is a need for an increased understanding of the cultural basis of all systems of health care.