Reduced coronary dilatory capacity and ultrastructural changes of the myocardium in patients with angina pectoris but normal coronary arteriograms.
Hemodynamic and metabolic studies were performed in 15 patients without heart disease (controls, group A), in 21 patients with typical stress-induced anginal pain but normal coronary and left ventricular angiograms (angina pectoris with normal arteriogram, group B), and in 10 patients with angiographically proved coronary artery disease (CAD, group C). Coronary dilatory capacity, determined by measuring total myocardial blood flow at rest and during maximal coronary vasodilatation (dipyridamole, 0.5 mg/kg i.v.), was markedly reduced in group B and C patients. In group B patients, left ventricular catheter biopsy specimens revealed no evidence of small-vessel disease, but did show histologic alterations of mitochondria. During atrial pacing, the control subjects showed no changes in myocardial lactate uptake, whereas in group B patients, myocardial lactate production occurred. In contrast to controls, patients in group B showed a significant decline in ejection fraction and circumferential fiber shortening during isometric exercise. These findings suggest that myocardial ischemia is the cause of angina pectoris in patients who have angina but normal coronary arteriograms.


Dopa-responsive dystonia: long-term treatment response and prognosis.
We report observations on the treatment of 66 patients with presumed dopa-responsive dystonia (DRD). Forty-seven of these patients had hereditary disease; 19 had disease of sporadic occurrence. Initial diagnostic confusion with "cerebral palsy" or "spastic diplegia" existed in 16 patients. Several patients benefited from anticholinergic medications and a few from carbamazepine. Levodopa was the most effective treatment in all cases. In the majority, there was an excellent response, with continued long-term clinical stability on levodopa therapy for as long as 10 to 22 years. Four men with sporadic disease and 1 woman with a sister affected with adolescent-onset parkinsonism had similar initial treatment response, but developed "wearing-off" and a less satisfactory response to levodopa within the first few years of treatment. This indicates that some patients with clinical syndromes suggestive of DRD may not have an excellent prognosis on long-term levodopa treatment and may represent misclassified cases of childhood-onset parkinsonism.


Power-Tool Use in Orthopaedic Surgery: Iatrogenic Injury, Its Detection, and Technological Advances: A Systematic Review.
Power tools are an integral part of orthopaedic surgery but have the capacity to cause iatrogenic injury. With this systematic review, we aimed to investigate the prevalence of iatrogenic injury due to the use of power tools in orthopaedic surgery and to discuss the current methods that can be used to reduce injury. We performed a systematic review of English-language studies related to power tools and iatrogenic injuries using a keyword search in MEDLINE, Embase, PubMed, and Scopus databases. Exclusion criteria included injuries related to cast-saw use, temperature-induced damage, and complications not clearly related to power-tool use. A total of 3,694 abstracts were retrieved, and 88 studies were included in the final analysis. Few studies and individual case reports looked directly at the prevalence of injury due to power tools. These included 2 studies looking at the frequency of vascular injury during femoral fracture fixation (0.49% and 0.2%), 2 studies investigating the frequency of vertebral artery injury during spinal surgery (0.5% and 0.08%), and 4 studies investigating vascular injury during total joint arthroplasty (1 study involving 138 vascular injuries in 124 patients, 2 studies noting 0.13% and 0.1% incidence, and 1 questionnaire sent electronically to surgeons). There are multiple methods for preventing damage during power-tool use. These include the use of robotics and simulation, specific drill settings, and real-time feedback techniques such as spectroscopy and electromyography. Power tools have the potential to cause iatrogenic injury to surrounding structures during orthopaedic surgery. Fortunately, the published literature suggests that the frequency of iatrogenic injury using orthopaedic power tools is low. There are multiple technologies available to reduce damage using power tools. In high-risk operations, the use of advanced technologies to reduce the chance of iatrogenic injury should be considered. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Risk factors for depressive symptoms among older Chinese adults: A meta-analysis.
The study aims to explore the risk factors for depressive symptoms among older Chinese adults. PubMed, PsycINFO, Cochrane Library, EMbase, Google Scholar, Chinese National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database, and Wanfang data were searched for potentially relevant articles published before September 1st, 2019. Stata/IC 15 was used to perform a meta-analysis and subgroup analysis to compute the pooled odds ratio. The retrieve strategy yielded 11 studies that met the inclusion criteria. The total sample size was 31528 across seven districts, including Mainland China, Hong Kong, and Taiwan. Patients with depression were included in the sample size. Fourteen risk factors were extracted for at least having two or more relative studies. The combined odds ratio ranged from 0.70 to 4.75. Female, poor self-perceived financial condition, single, average and poor self-perceived health status, diabetes, adverse life events, poor social support, two or more numbers of cardiovascular diseases, and functional disability are risk factors of depressive symptoms among older Chinese adults. Fair or good social support is a protective factor. These findings may be somewhat limited by (i) quality of studies included, (ii) a finite number of studies met inclusion criteria. Despite the methodological limitations of the studies and this meta-analysis, average or poor self-perceived health status, functional disability, poor social support, poor self-perceived financial condition, negative life events, and diabetes appear to be significant risk factors for depressive symptoms among the aged population in China. Social support can mitigate depressive symptoms.


A Novel Technique to Reconstruct Tricuspid Valve Anterior Leaflet in Massive Endocarditis.
Tricuspid valve (TV) endocarditis is a common complication in intravenous drug addicts. In case of TV replacement, the main issue is the high risk of new endocarditis on TV prosthesis. On November 2014, a 44 year-old male patient with a history of intravenous drug addiction was referred for TV endocarditis owing to Staphylococcus aureus and severe regurgitation complicated by pulmonary embolism and heart failure. Preoperative echocardiography showed a large vegetation of the anterior leaflet (1.95 × 0.92 cm) covering a huge hole in the leaflet itself. Herein, a novel technique for the treatment of massive endocarditis of the TV is described. Complete anterior leaflet reconstruction was achieved with a huge equine pericardium patch along with native chordae tendinae reimplantation onto the free edge of the patch. Finally, a ring annuloplasty was performed to stabilize the valve reconstruction. The postoperative course was uneventful with evidence of trivial tricuspid regurgitation and no signs of IE recurrence. Complete reconstruction of the anterior leaflet with a patch of xenopericardium and native chordae tendinae reimplantation might be an alternative technique to TV replacement.


Effects of a course in neonatal resuscitation--evaluation of an educational intervention on the standard of neonatal resuscitation.
Appropriate assessment and resuscitation is an important part of neonatal care provided during the first minutes of life. Midwifery and junior medical staff are often in the frontline of neonatal resuscitation. Appropriate education and training of midwifery staff is therefore essential if the standard of care delivered to babies in the delivery suite is to be improved and maintained. Evaluation of any such educational interventions is necessary to assess their effectiveness. To assess the effect of a course in neonatal resuscitation introduced in 1995 aimed at midwifery staff, on the standard of care provided to babies immediately after birth. Prior to this, training in neonatal resuscitation was largely theoretical. Naturalistic design observational study conducted in a maternity unit with a tertiary neonatal intensive care unit in the North of England. We compared two groups of babies born before and after the course was introduced. Use of naloxone in the delivery suite and appropriateness of its use, and temperature on admission to neonatal intensive care unit were used as proxy markers for standard of care and compared in the two groups. We also looked at the use of mask intermittent positive pressure ventilation (IPPV) and tracheal intubation in the delivery suite. Use of naloxone fell dramatically from 13.2% of all babies born in 1994 to 0.5% in 2003. Inappropriate use of naloxone before other resuscitation measures were initiated declined from 75% of babies given naloxone in 1994 to 10% in 2003. The incidence of hypothermia (<35 degrees C) on admission to neonatal unit declined from 9% of all admissions to 2.3% in 2003. There was a trend towards increased use of mask ventilation in the delivery suite with a corresponding trend towards less tracheal intubation. We have shown that the intervention has been related temporally to an improvement in the quality of care delivered by midwifery staff to newborn babies. Practical courses in neonatal resuscitation can contribute to improvements in the quality of care provided to babies immediately after birth. These courses are more effective than theoretical teaching alone.


Effect of chlorhexidine gluconate mouth wash on the plaque microflora in children using intra oral appliances.
The effect of 0.2% chlorhexidine mouth wash (Hexidine) on the plaque microflora was evaluated on children wearing intra oral removable appliances. Plaque samples were collected from the enamel sections, both primary and permanent, mounted on the removable appliances. These appliances were worn by 12 children for one week. Plaque was allowed to accumulate on the in situ test sites and on the adjacent natural dentition. At the end of the experimental period the plaque microflora associated with the enamel sections were compared with that obtained from lingual and interproximal areas of the lower molar teeth. It was also compared with a control group of 12 children without an appliance. In addition, the effect of 0.2% chlorhexidine mouth wash on the plaque microflora for the next 14 days was also determined on both the groups. Although some quantitative difference was found between the proportion of isolates obtained from the different enamel surfaces, it was not statistically significant. There was a statistically significant increase in the isolates of plaque microflora after the insertion of removable appliance in children which decreased significantly with the use of 10 ml of 0.2% chlorhexidine gluconate mouth wash twice a day. The study indicates that the primary and permanent tooth specimens mounted on the intra-oral device collected plaque microflora similar to that present on the adjacent natural dentition and that chlorhexidine gluconate mouth wash therapy is effective in reducing plaque microflora in children with removable appliances.


Template-Free Hierarchical Self-Assembly of Iron Diselenide Nanoparticles into Mesoscale Hedgehogs.
The ability of semiconductor nanoparticles (NPs) to self-assemble has been known for several decades. However, the limits of the geometrical and functional complexity for the self-assembled nanostructures made from simple often polydispersed NPs are still continuing to amaze researchers. We report here the self-assembly of primary ∼2-4 nm FeSe2 NPs with puck-like shapes into either (a) monocrystalline nanosheets ∼5.5 nm thick and ∼1000 nm in lateral dimensions or (b) mesoscale hedgehogs ∼550 nm in diameter with spikes of ∼250 nm in length, and ∼10-15 nm in diameter, the path of the assembly is determined by the concentration of dodecanethiol (DT) in the reaction media. The nanosheets represent the constitutive part of hedgehogs. They are rolled into scrolls and assembled around a single core with distinct radial orientation forming nanoscale "needles" approximately doubling its fractal dimension of these objects. The core is assembled from primary NPs and nanoribbons. The size distribution of the mesoscale hedgehogs can be as low as 3.8%, indicating a self-limited mechanism of the assembly. Molecular dynamics simulation indicates that the primary FeSe2 particles have mobile edge atoms and asymmetric basal surfaces. The top-bottom asymmetry of the puck-like NPs originates from the Fe-rich/Se-rich stripes on the (011) surface of the orthorhombic FeSe2 crystal lattice, displaying 2.7 nm periodicity that is comparable to the lateral size of the primary NPs. As the concentration of DT increases, the NPs bind to additional metal sites, which increases the chemical and topographic asymmetry and switches the assembly pathways from nanosheets to hedgehogs. These results demonstrate that the self-assembly of NPs with non-biological surface ligands and without any biological templates results in morphogenesis of inorganic superstructures with complexity comparable to that of biological assemblies, for instance mimivirus. The semiconductor nature of FeSe2 hedgehogs enables their utilizations in catalysis, drug delivery, optics, and energy storage.


ARHGAP25 expression in colorectal cancer as a biomarker associated with favorable prognosis.
Although progress has been made in the early diagnosis of colorectal cancer (CRC) and in the systemic therapy of patients with CRC, the prognosis for advanced CRC remains poor. Our previous study demonstrated that ARHGAP25 overexpression significantly inhibits CRC cell growth, invasion and migration. However, it was not possible to evaluate and analyze the overall survival (OS) rate of patients with CRC. Thus, the discovery of relevant factors and their expression on the basis of existing research is necessary to predict the OS rate of patients with advanced CRC. Therefore, the aim of the present study was to define the value of Rho GTPase-activating protein 25 (ARHGAP25) expression in predicting the OS rate in patients with CRC. The clinical data of 153 patients with CRC who underwent colorectal resection were retrospectively analyzed. In order to explore the expression of ARHGAP25, immunohistochemical analysis of the tumor tissues of these patients, was performed. Univariate Cox regression analysis was used to assess the prognostic value of ARHGAP25 expression for OS. Multivariate analysis was used to evaluate the effect of ARHGAP25 expression in the presence of other variables. Confounding factors and interaction were assessed by a stratified analysis using ARHGAP25 expression and other variables associated with survival. The univariate analysis revealed that, ARHGAP25 expression was associated with an improved OS in patients with CRC (P<0.05). The multivariate analysis revealed that ARHGAP25 expression was still correlated with an improved OS after adjusting for sex, age, invasion degree, lymph node metastasis, distant metastasis, TNM stage, tumor location, histological type, histological grade, tumor deposits, and postoperative treatment (P<0.05). The stratified analysis demonstrated that the predictive value of ARHGAP25 for the OS of patients with CRC was stronger in males, elderly patients (>70 years old), patients with T3 stage tumor, lymph node metastasis, TNM stage III, right hemicolon location and patients with a poorly differentiated tumor (P<0.05). Overall, our results demonstrated that ARHGAP25 may have an important potential value for improving the prognosis of patients with CRC.


The Transformation of Conflicts into Relational Well-Being in Physical Education: GIAM Model.
To educate the relational well-being in order to learn to live together in society is one of the main needs of modern physical education (PE). Teachers are in need of pedagogical models to instruct peaceful coexistence and transform possible conflicts into PE. The goal of this study was to determine the effect of a pedagogical model (GIAM model) designed for conflict transformation on the relational well-being of students in obligatory secondary school (ESO in Spain). This study was an empirical research (associative strategy, comparative study using mixed methods). A number of 287 valid students (M = 14.90; SD = 0.66) participated in this study from 4 different secondary schools (SSs): third ESO (SS1 (n = 75); SS3 (n = 45); SS4 (n = 86)) and fourth ESO (SS2 (n = 81)). A sequence of seven learning sessions was conducted, the intervention of the teachers on the GIAM model and the student's motivational climate perception caused by this learning sequence was analyzed. The teachers who best adapted their intervention to the GIAM model obtained greater significant changes (p < 0.005) in favor of the relational well-being of their students. This research provides scientific evidence and intervention strategies for students to learn how to transform the conflicts, adopting a collaborating style based on reflection-for, -in- and on-motor action.


Medical and surgical management of sinusitis in adults.
Sinusitis may be caused by bacteria, viruses, or trauma and may appear in immunosuppressive settings. Acute sinusitis is most commonly diagnosed on the basis of pain and discharge; endoscopic or fiberoptic examination may be helpful in less obvious cases. Radiography can identify maxillary, frontal, and sphenoid sinusitis; transillumination can be used if radiography is undesirable. Culture and Gram stains may help determine the appropriate antibiotic therapy. Surgery may be necessary if the frontal or sphenoid sinus is involved, or if ethmoiditis is progressing to orbital cellulitis. In chronic sinusitis, endoscopic examination and computed tomographic scanning are useful for diagnosis. Chronic sinusitis may be associated with airway disease, aspirin allergy, and such diseases as cystic fibrosis. Antibiotic therapy that acts against anaerobes and beta-lactamase-producing organisms should be chosen. Surgical treatment includes intranasal and external ethmoidectomy, antrostomy, and, on occasion, obliteration of the involved cavity.


Importance of the alternative NF-κB activation pathway in inflammation-associated gastrointestinal carcinogenesis.
Chronic inflammation is a common factor in the development of many gastrointestinal malignancies. Examples include inflammatory bowel disease predisposing to colorectal cancer, Barrett's esophagus as a precursor of esophageal adenocarcinoma, and Helicobacter pylori-induced gastric cancer. The classical activation pathway of NF-κB signaling has been identified as regulating several sporadic and inflammation-associated gastrointestinal tract malignancies. Emerging evidence suggests that the alternative NF-κB signaling pathway also exerts a distinct influence on these processes. This review brings together current knowledge of the role of the alternative NF-κB signaling pathway in the gastrointestinal tract, with a particular emphasis on inflammation-associated cancer development.


Identification of national trends in nursing education through the use of an online survey.
Increased access and familiarity with computer technology has enhanced research data collection and analysis processes. Use of the Internet in these processes is rapidly becoming an alternative to traditional paper and pencil methods and can be a useful tool in conducting nursing education research. The purpose of this article is to discuss the use of online survey methodologies to identify nursing education trends and disseminate information nationwide. Advantages, disadvantages and pitfalls of using e-mail in conducting a Web-based survey are presented. The authors describe relevant aspects of developing and implementing an online survey; relate their experience in using this survey method with regard to its strengths and limitations; and, comment regarding efficacy of electronic collection and analysis of research data. The authors' experience in conducting a previously published national study of the integration of holistic nursing practices and complementary and alternative modalities in curricula of baccalaureate and higher degree schools of nursing is used as an exemplar. The authors conclude that, regardless of the current status of technology and lack of computer support in some schools of nursing, an online national survey is a valuable tool in conducting research in nursing education and increasingly will be the method of choice for gathering survey data.


[New nocturnal penile tumescence recorder].
Records of nocturnal penile tumescence are still important test and necessary to distinguish organic impotence from psycogenic impotence. We developed the nocturnal penile tumescence recorder with a disposab indiumgallium straingauge, and we examined its clinical usefulness for volunteers with normal erectile function. The results were that the indium-gallium straingauge had almost the same resistance change with extension, and that it showed almost the same resistance value at respective circumferences with consecutively ten times measurements. Only two of thirty-nine volunteers experienced the snapping of the indium-gallium strain-gauge. None of the volunteers complained of discomfort during measurements. The nocturnal penile tumescence of five volunteers were recorded with a conventional mercuric straingauge and a newly developed indium-gallium straingauge simultaneously, and there were no significant differences between the results of the two materials. This recorder is very simple to manage, and the softwares for preservation of data and making graph are also simple. This new straingauge is clean and dose not require maintenance because of the disposable use. We concluded that this recorder system was clinically useful for t examination of nocturnal penile tumescence.


Switching to Doravirine/Lamivudine/Tenofovir Disoproxil Fumarate (DOR/3TC/TDF) Maintains HIV-1 Virologic Suppression Through 48 Weeks: Results of the DRIVE-SHIFT Trial.
Doravirine is a novel, nonnucleoside reverse transcriptase inhibitor with demonstrated efficacy in treatment-naive adults with HIV-1. In this open-label, active-controlled, noninferiority trial, adults with HIV-1 virologically suppressed for ≥6 months on 2 nucleoside reverse transcriptase inhibitors plus a boosted protease inhibitor, boosted elvitegravir, or a non-nucleoside reverse transcriptase inhibitor were randomized (2:1) to switch to once-daily, single-tablet doravirine 100 mg with lamivudine 300 mg and tenofovir disoproxil fumarate 300 mg (DOR/3TC/TDF) or to continue their current therapy (Baseline Regimen) for 24 weeks. The primary endpoint was the proportion of participants with HIV-1 RNA <50 copies/mL (defined by the FDA Snapshot approach), with the primary comparison between DOR/3TC/TDF at week 48 and Baseline Regimen at week 24 and a secondary comparison between the groups at week 24 (noninferiority margin, -8%). Six hundred seventy participants (447 DOR/3TC/TDF, 223 Baseline Regimen) were treated and included in the analyses. At week 24, 93.7% on DOR/3TC/TDF vs 94.6% on Baseline Regimen had HIV-1 RNA <50 copies/mL [difference -0.9 (-4.7 to 3.0)]. At week 48, 90.8% on DOR/3TC/TDF had HIV-1 RNA <50 copies/mL, demonstrating noninferiority vs Baseline Regimen at week 24 [difference -3.8 (-7.9 to 0.3)]. In participants on ritonavir-boosted protease inhibitor at entry, mean reductions in fasting LDL-C and non-HDL-C at week 24 were significantly greater for DOR/3TC/TDF vs Baseline Regimen (P < 0.0001). Adverse events occurred in 68.9% on DOR/3TC/TDF and 52.5% on Baseline Regimen by week 24, leading to treatment discontinuation in 2.5% and 0.4%, respectively. Switching to once-daily DOR/3TC/TDF is a generally well-tolerated option for maintaining viral suppression in patients considering a change in therapy. ClinicalTrials.gov NCT02397096.


Hip arthroplasty by matching cups.
A total hip surface arthroplasty consisting of matching cups and uncemented prosthetic components is a noteworthy operation. The femoral cup obtains cylindrical support from the femoral head which is reamed in the shape of a cylinder. The acetabular cup is metallic with a polyethylene liner. It is mobile over the bone but its position is constrained by contact with the femoral cup and therefore "self-centering." On the femoral side, the cup must be placed strictly in the axis of the femoral neck. The main consideration in femoral head surface replacement is the vitality of the underlying bone. Necrosis was observed in the earliest clinical trials but there have been no cases of necrosis in the past 3 1/2 years. This is attributed to a more limited surgical approach in which only the anterior part of the gluteus medius is divided and all the posterior elements of the hip are preserved. The acetabulum is sufficiently reamed to receive the cup, which protrudes beyond the external margins of the acetabulum in all positions. Errors have been committed while perfecting the prosthetic material, but the results as determined by a 6 1/2 year follow-up on purely metallic cups are encouraging. Metal-polyethylene cups presently under investigation have almost a 2 year follow-up. The reaction of the acetabulum to an uncemented cup is not yet known. However, the existence of 2 sliding surfaces and the fact that the acetabular cup moves only during the extremes of hip movement, is reason to assume that if the acetabulum is not reamed to expose cancellous bone, the risks of protrusion are minimal or delayed. Total surface arthroplasty by concentric cups has been performed in 335 hips to date. The operation is especially recommended when osteotomy is no longer possible and disabling coxarthrosis is present in relatively young patients.


Bone turnover markers to assess jawbone quality prior to dental implant treatment: a case-control study.
Bone quality is as important as bone mineral density in terms of bone strength. Bone turnover markers (BTMs) are clinical indicators of bone quality. In implant dentistry, bone quality is considered equivalent to bone density on radiographic assessments. The purpose of this study was to determine whether the BTM values are reflected in jawbone condition by evaluating the relationship at baseline and during follow-up in patients with prosthodontic implants. Computed tomography (CT) scans were obtained and BTM (osteocalcin, bone-specific alkaline phosphatase, pyridinoline cross-linked carboxyterminal telopeptide of type I collagen, and crosslinked N-telopeptide of type I collagen) levels in blood samples were measured in partially edentulous eighteen patients before implant surgery. During the follow-up observation after implant surgery, marginal bone loss (MBL) was measured on dental radiography. We investigated the relationship between the presence of BTM abnormalities and radiographic bone density. More women than men had abnormal BTM values. Bone turnover was accelerated in the group of women with abnormal BTM values. The density of cancellous bone at the implant placement site was significantly lower in the patients with abnormally high BTM values than in their counterparts with BTM values in the normal range. Female patients who undergo implant treatments may have reduced bone quality; evaluations of bone strength will require assessments of both BTMs and the density of cancellous bone.


Australia to fund HIV / AIDS projects in Southeast Asia.
Australia will fund 23 new HIV-AIDS projects in Southeast Asian countries, the government announced. "Asia is predicted to be the major growth area for human immunodeficiency virus (HIV) infections over the next decade, " Minister for Development Cooperation Gordon Bilney said. "These projects, worth some $4.35 million over three years, will help meet the challenge of preventing the spread of the disease in the region." The projects--in Thailand, Vietnam, the Philippines, Indonesia, Malaysia and Cambodia--emphasize education and prevention activities as well as programs which focus on the care and support of people living with HIV, Bilney said. He also said a variety of Australian and overseas organizations will implement the projects, many of which will feature the significant involvement of communities at risk and people with HIV. "It is in keeping with the fundamental spirit of the aid program that we should seek to share this expertise with our neighbors in the region." Bilney said one Australian success story--the creative "Streetwize comics" (publications in Australia which help street kids and under privileged kids understand HIV/AIDS problems)--will be piloted in Vietnam in conjunction with the Vietnam Youth Federation. He said Vietnamese staff will be trained in the production of a series of bilingual mini-comics on HIV-AIDS prevention for youth. "This project will receive funding of $187,500 over three years," Bilney said. Bilney said the projects would help minimize the individual and social impact of the epidemic in the targeted countries.


Solvent viscosity mismatch between the solute plug and the mobile phase: considerations in the applications of two-dimensional HPLC.
Understanding the nature of viscosity contrast induced flow instabilities is an important aspect in the design of two-dimensional HPLC separations. When the viscosity contrast between the sample plug and the mobile phase is sufficiently large, the phenomenon known as viscous fingering can be induced. Viscous fingering is a flow instability phenomenon that occurs at the interface between two fluids with different viscosities. In liquid chromatography, viscous fingering results in the solute band undergoing a change in form as it enters into the chromatography column. Moreover, even in the absence of viscous fingering, band shapes change shape at low viscosity contrasts. These changes can result in a noticeable change in separation performance, with the result depending on whether the solvent pushing the solute plug has a higher or lower viscosity than the solute plug. These viscosity induced changes become more important as the solute injection volume increases and hence understanding the process becomes critical in the implementation of multidimensional HPLC techniques, since in these techniques the sample injection plug into the second dimension is an order of magnitude greater than in one-dimensional HPLC. This review article assesses the current understanding of the viscosity contrast induced processes as they relate to liquid chromatographic separation behaviour.


Molecular cloning and expression of a 58-kDa cis-Golgi and intermediate compartment protein.
An abundant 58-kDa (p58) homodimeric and hexameric microsomal membrane protein has been biochemically characterized and localized to tubulo-vesicular elements at the endoplasmic reticulum-Golgi interface and the cis-Golgi cisternae in pancreatic acinar cells (Lahtinen, U., Dahllöf, B., and Saraste, J. (1992) J. Cell Sci. 103, 321-333). Here we report the purification of p58 by two-dimensional gel electrophoresis, and the cloning and sequencing of the rat and part of the Xenopus laevis cDNAs. The rat cDNA encodes a 517-amino acid protein having a putative signal sequence, a transmembrane domain close to the C terminus and a short cytoplasmic tail. The C-terminal tail contains a double-lysine motif (KKFF), known to mediate retrieval of proteins from the Golgi back to the endoplasmic reticulum. The rat p58 sequence was found to be 89% identical with those of ERGIC-53 and MR60, two previously identified human membrane proteins. Strong homology with the frog sequence was also observed indicating high evolutionary conservation. Overexpression of c-Myc-tagged p58 resulted in accumulation of the protein both in the endoplasmic reticulum and in an apparently enlarged Golgi complex, as well as its leakage to the plasma membrane. Immunolocalization using antibodies raised against a lumenal peptide stained the total cellular pool of p58, while anti-tail peptide antibodies detected p58 only in a restricted Golgi region. This suggests that the C-terminal tail of p58 located in the endoplasmic reticulum and transport intermediates is hidden, but becomes exposed when the protein reaches the Golgi complex.


The mouth and palliative care.
Oral complications are common among patients with advanced cancer, though relatively little research has been undertaken in this field. This review article discusses the common problem of xerostomia among the terminally ill, together with an overview of oral candidosis, oral viral infections, chemotherapy- and radiotherapy-associated mucositis, and alterations in taste sensation among those with advanced cancer. Suggested management regimes, based on the limited clinical trial data available, are provided where appropriate.


Prognostic value of ambulatory blood pressure : current evidence and clinical implications.
This article is a critical review of the available evidence on the prognostic value of ambulatory blood pressure (ABP). Several event-based cohort studies have shown that ABP improves cardiovascular risk stratification over and beyond traditional risk factors, including office BP. Most of these studies have been conducted in subjects with essential hypertension who were untreated at the time of execution of ABP monitoring; other studies have been conducted in subjects who were poorly controlled with treatment or in the general population. In these studies, ABP was examined as a continuous variable or with operational risk categories. Cardiovascular risk showed a direct and independent association with the observed ABP (systolic, diastolic, and pulse) and an inverse association with the degree of BP reduction from day to night. Cardiovascular risk was also directly associated with the difference between the observed value of ABP and that predicted from the office BP. White-coat hypertension versus ambulatory hypertension and dippers versus nondippers are 2 classifications based on arbitrary operational risk categories. A blunted or absent BP reduction from day to night, defined with ABP as a continuous variable or with operational thresholds, was also associated with a worse outcome regardless of the average value of ABP during the 24 hours. Overall, these studies indicate that ABP monitoring is particularly valuable to refine cardiovascular risk stratification in untreated subjects with office hypertension and in those with resistant hypertension. Intervention studies targeted at ABP are now needed.


Blood Pressure and Vascular Cognitive Impairment.
High blood pressure (BP) is detrimental to brain health. High BP contributes to cognitive impairment and dementia through pathways independent of clinical stroke. Emerging evidence shows that the deleterious effect of high BP on cognition occurs across the life span, increasing the risk for early-onset and late-life dementia. The term vascular cognitive impairment includes cognitive disorders associated with cerebrovascular disease, regardless of the pathogenesis. This focused report is a narrative review that aims to summarize the epidemiology of BP and vascular cognitive impairment, including differences by sex, race, and ethnicity, as well as the management and reversibility of BP and vascular cognitive impairment. It also discusses knowledge gaps and future directions.


Catheter ablation of ventriculoatrial conduction in the treatment of pacemaker-mediated tachycardia.
Pacemaker generator reprogramming does not always present an adequate solution to the problem of pacemaker-mediated tachycardia. A case is described where direct current shock catheter ablation of ventriculoatrial conduction prevented pacemaker-mediated tachycardia and allowed optimal dual chamber pacemaker programming.


[A case of rheumatoid arthritis with malignant lymphoma taking methotrexate].
We describe one case with rheumatoid arthritis who developed non-Hodgkin's lymphoma during treatment with low dose weekly methotrexate. A 73 year-old man had seropositive RA since 1974. He had been treated with several medications, including nonsteroidal antiinflammatory drugs, gold sodium thiomalate (from January, 1987), and bucillamine (from January, 1988). He presented to this hospital in April 1988, at a time when his rheumatoid arthritis worsened. Methotrexate was administered at a weekly dose of 7.5 mg orally, together with a daily dose of 5 mg of prednisone. He had had no joint-related pain and no side effects until December 1991 (total dose 1290 mg) when severe abdominal pain was started abruptly. The chest X-ray showed an abdominal free air and a diagnosis of acute panperitonitis was made. An emergency operation was carried out. There was a soft-tissue mass in the terminal of ileum which was ruptured with massive ascites. Histologic examination of the mass revealed a diffuse large cell lymphoma. The oncogenic potential of MTX and rheumatoid arthritis is reviewed.


Quality of life of asthmatic adolescents: assessment of asthma severity, comorbidity, and life style.
To assess the quality of life (QoL) of asthmatic adolescents and its association with asthma severity, chronic diseases, and life style. Cross-sectional study involving 210 female and male asthmatic adolescents between 12 and 21 years old. The Paediatric Asthma Quality of Life Questionnaire, a self-administered instrument, was used. Explanatory variables were: allergic diseases, use of medication, passive smoking, occupational status, asthma severity, and life style. The analyses considered the dichotomous outcome (good/poor QoL) based on the mean scores. Generalized linear models (log-binomial) were used to calculate the crude and adjusted prevalence ratios (PR). Forty-six per cent of the girls and 57% of the boys had poor QoL. There was no correlation between chronic diseases and poor QoL. Low educational level, use of medication, passive smoking, and occupational factors had a statistically significant association (p < 0.05) with poor QoL. The adjusted analysis showed that severe asthma (PR = 1.53; 95%CI 1.12-2.11), use of medication (PR = 1.58; 95%CI 1.09-2.28), having asthma diagnosis established less than 5 years ago (PR = 1.30; 95%CI 0.97-1.86), passive smoking (PR = 1.38; 95%CI 1.35-2.00), and being employed (PR = 1.30; 95%CI 0.96-1.74) were associated with poor QoL. A multidisciplinary team needs to face the challenge of providing good QoL with the purpose of making these patients better adapted to society and to their own needs.


Mechanical compression drives cancer cells toward invasive phenotype.
Uncontrolled growth in a confined space generates mechanical compressive stress within tumors, but little is known about how such stress affects tumor cell behavior. Here we show that compressive stress stimulates migration of mammary carcinoma cells. The enhanced migration is accomplished by a subset of "leader cells" that extend filopodia at the leading edge of the cell sheet. Formation of these leader cells is dependent on cell microorganization and is enhanced by compressive stress. Accompanied by fibronectin deposition and stronger cell-matrix adhesion, the transition to leader-cell phenotype results in stabilization of persistent actomyosin-independent cell extensions and coordinated migration. Our results suggest that compressive stress accumulated during tumor growth can enable coordinated migration of cancer cells by stimulating formation of leader cells and enhancing cell-substrate adhesion. This novel mechanism represents a potential target for the prevention of cancer cell migration and invasion.


A Total Economic Valuation of Wetland Ecosystem Services: An Evidence from Jagadishpur Ramsar Site, Nepal.
Wetlands are the most productive ecosystem and provide wide arrays of wetland ecosystems (goods and services) to the local communities in particular and global communities in general. However, management of the wetland often does not remain priority and recognized as the unproductive waste land mainly due to poor realization of the economic value of the wetlands. Taking this into account, the study estimated the total economic value of the Jagadishpur Reservoir taking into account direct, indirect, and nonuse value. The study prioritized six major values of the reservoir which include wetland goods consumption, tourism, irrigation, carbon sequestration, biodiversity conservation, and conservation for future use (existence and option value). The study used market and nonmarket based valuation techniques to estimate total economic value of the reservoir. Household survey, focus group discussions, and interaction with the tourism entrepreneurs and district stakeholders were carried out to collect information. The study estimated the total annual economic value of the reservoir as NRs 94.5 million, where option/existence value remains main contributor followed by direct use value such as wetland goods and tourism and indirect use value, for example, carbon sequestration, biodiversity conservation, and irrigation. The study reveals that the local communities gave high importance to the future use value and are willing to make investment for conservation and restoration of reservoir given its conservation significance.


Campylobacter fetus subspecies fetus spondylodiscitis.
Campylobacter spp. are common causes of gastrointestinal infections. Campylobacter fetus is a much rarer pathogen in humans, and usually causes bacteraemia and systemic complications in patients with predisposing conditions. We report a case of spondylodiscitis caused by C. fetus subsp. fetus as revealed by vertebral biopsy culture. This identification was confirmed by sequencing the 16S rRNA gene and by phylogenetic analysis. Treatment consisted of 6 weeks antimicrobial therapy combined with a strict initial immobilization, followed by a re-education program. The patient's recovery was uneventful.


[Effects of ginkgolide B on lipopolysaccharide-induced TNFalpha production in mouse peritoneal macrophages and NF-kappaB activation in rat pleural polymorphonuclear leukocytes].
To study the effects of ginkgolide B on lipopolysaccharide (LPS)--induced TNFalpha production in mouse peritoneal macrophages and NF-kappaB activation in rat pleural polymorphonuclear leukocytes. L929 crystal violet staining assay was used to show the level of TNFalpha released from mouse peritoneal macrophages induced by LPS. Electrophoretic mobility shift assay (EMSA) was used to determine NF-kappaB binding activities. Ginkgolide B (1, 10 micromol x L(-1)) was shown to significantly inhibit LPS (10 mg x L(-1))-induced TNFalpha production in mouse peritoneal macrophages, the IC50 was 0.26 micromol x L(-1); LPS (1 mg x L(-1)) and PAF (1 nmol , L(-1)) were shown to increase the NF-kappaB binding activities in rat pleural polymorphonuclear leukocytes; ginkgolide B (10 micromol x L(-1)) was found to inhibit LPS (1 mg x L(-1))-induced NF-kappaB activation in rat pleural polymorphonuclear leukocytes; ginkgolide B (1, 10 micromol x L(-1)) was shown to inhibit PAF (1 nmol x L(-1))-induced NF-kappaB activation in rat pleural polymorphonuclear leukocytes. The inhibition of NF-kappaB activation and TNFalpha production might be considered to be part of the mechanisms underlying the antiinflammatory action of ginkgolide B; PAF is involved in activation of the NF-kappaB pathway stimulated with LPS.


A Scoping Review on the Epidemiology of Chronic Low Back Pain among Adults in Sub-Saharan Africa.
The global burden of chronic low back pain (CLBP) is a major concern in public health. Several CLBP epidemiological studies have been conducted in high-income-countries (HICs) with little known in low-and-middle-income-countries (LMICs) due to other competing priorities of communicable diseases. The extrapolation of results of studies from HICs for use in LMICs is difficult due to differences in social norms, healthcare systems, and legislations, yet there is urgent need to address this growing burden. It is against this backdrop that we conducted this review to map the current evidence on the distribution of CLBP in Sub-Saharan Africa (SSA). A comprehensive literature search was conducted from the following databases: PubMed, Google Scholar, Science Direct databases, World Health Organizations library databases, EMBASE, EBSCOhost by searching the following databases within the platform; academic search complete, CINAHL with full text, health sources: nursing/academic and MEDLINE. The title, abstract and the full text screening phases were performed by two independent reviewers with the third reviewer employed to adjudicate discrepancies. The reference list of all included articles was also searched for eligible articles. This scoping review was reported in accordance with the PRISMA extension for scoping reviews (PRISMA-ScR): checklist and explanation, as well as guided by Arksey and O'Malley's scoping review framework. A thematic content analysis was used to give a narrative account of the review. The electronic search strategy retrieved 21,189 articles. Title/abstract and full text screening only identified 11 articles, which were included in this review. The prevalence of CLBP among the general population ranged from 18.1% to 28.2% and from 22.2% to 59.1% among LBP patients. The prevalence of occupation based CLBP ranged from 30.1% to 55.5%. Identified risk factors for CLBP are multifactorial and included biomechanical, psychological, socioeconomic and lifestyle factors, with psychosocial factors playing a significant role. Hypertension, diabetes mellitus, peptic ulcer disease were the most common comorbidities identified. CLBP disability was significantly associated with psychosocial factors. The management of CLBP in primary care follows the traditional biomedical paradigm and primarily involves pain medication and inconsistent with guidelines. There are limited epidemiological data on CLBP in SSA, however, this study concluded that the prevalence and risk factors of CLBP in SSA are comparable to reports in HICs. Considering the projected increase in the burden of CLBP in LMICs extensive research effort is needed to close this knowledge gap.


A limited-sampling strategy to estimate individual pharmacokinetic parameters of vinorelbine in elderly patients with advanced metastatic cancer.
The aim of this study was to characterize the population pharmacokinetic of vinorelbine in elderly patients and to propose a limited-sampling strategy to estimate individual pharmacokinetic parameters. Vinorelbine was administered by a 10-min continuous infusion at a dose of 20-30 mg/m2. The population parameters were computed, using a three-compartment model, from an initial group of 27 patients. Twelve additional courses were used for model validation and evaluation of eight different limited-sampling strategies. The inter-individual variability of CL was explained by a linear dependency with age. The population average parameters and the interindividual variabilities (CV%) were: CL=47.1 l/h (31.7%), V=16.6 l (64%), k21=0.776 h-1 (20%), k31=0.0346 h-1 (15.2%), alpha=0.431 h-1 (6.84%) and beta=0.0167 h-1 (25%). Bayesian estimation with three measured levels (end of infusion, and 6 and 48 h) can be selected, because it allows adequate estimation of CL, elimination half-life and vinorelbine concentrations with a non-significant bias. Moreover, the choice of these three sampling times presents practicality advantages for the patient's comfort. Vinorelbine clearance decreasing with age and AUC being a good predictor of several toxicity end points during vinorelbine treatment, the limited-sampling strategy developed in this paper may be clinically relevant.


Gut Microbiota as Early Predictor of Infectious Complications before Cardiac Surgery: A Prospective Pilot Study.
Cardiac surgery remains a field of medicine with a high percentage of postoperative complications, including infectious ones. Modern data indicate a close relationship of infectious disorders with pathological changes in the composition of the gut microbiome; however, the extent of such changes in cardiac surgery patients is not fully clarified. In this prospective, observational, single center, pilot study, 72 patients were included, 12 among them with the infectious complications. We analyzed the features of the fecal microbiota before and in the early postoperative period, as one of the markers for predicting the occurrence of bacterial infection. We also discovered the significant change in microbial composition in the group of patients with infectious complications compared to the non-infectious group before and after cardiac surgery, despite the intra-individual variation in composition of gut microbiome. Our study demonstrated that the group of patients that had a bacterial infection in the early postoperative period already had an altered microbial composition even before the surgery. Further studies will evaluate the clinical significance of the identified proportions of individual taxa of the intestinal microbiota and consider the microbiota as a novel target for reducing the risk of infectious complications.


Induction and regulation of ethylene biosynthesis by pectic oligomers in cultured pear cells.
Pectic oligomers induced a rapid, transient increase in ethylene biosynthesis when added to pear cells in suspension culture. The rate of ethylene biosynthesis increased within 30 to 40 minutes after oligomer addition, reached a maximum between 90 and 120 minutes after addition, and then decreased to basal rates of synthesis. Both the rapid increase and decrease in biosynthesis appear to be precisely regulated components of the ethylene response to oligomers. Induction of ethylene biosynthesis by pectic oligomers resulted in a reduced sensitivity of cells to further ethylene induction. This reduction in sensitivity occurred within 90 minutes after an oligomer treatment, slightly preceding the decline in ethylene synthesis. The degree of insensitivity induced was proportional to the concentration of oligomer in the first treatment. Induced insensitivity to elicitors appears to represent a novel mechanism which may limit continued ethylene biosynthesis after ethylene induction. Ethylene was produced by pear cells throughout the cell growth cycle, as cells increased in density over a 6 day period. Endogenous ethylene biosynthesis was at a maximum during the first 4 days of rapid cell growth, then declined to half the peak rate through day 10. Pectic oligomers could induce an increase in ethylene biosynthesis above this background rate only after day 5, as endogenous biosynthesis declined. Changes in sensitivity to added oligomer during the growth cycle may result from insensitivity to elicitors induced by growth processes.


Western diet increases cardiac ceramide content in healthy and hypertrophied hearts.
Obesity and cardiac left ventricular hypertrophy (LVH) are recognised independent risk factors in the development of heart failure (HF). However, the combination of these factors may exacerbate the onset of cardiovascular disease by mechanisms as yet unclear. LVH leads to significant cellular remodelling, including alterations in metabolism which may result in an inappropriate accumulation of lipids and eventual lipotoxicity and apoptosis. The aim of the study was to determine the impact of dietary manipulation on cardiac metabolism in the obese and hypertrophied heart. LVH was induced via aortic constriction (AC) in an experimental model of cardiac hypertrophy and animals subjected to 9 weeks of dietary manipulation with either a standard, high fat, or a sucrose containing Western-style diet (SD, HFD and WD, respectively). This latter diet resulted in accelerated weight gain in both LVH/AC and control animals. LVH was greater in AC animals fed a WD, and both control and AC animals from this diet showed a significant reduction in cardiac fatty acid oxidation and increased triacylglycerol content. Ceramide content was significantly increased in the WD groups, with no additional effect of LVH. Comparison with a model of HF induced by exposure to Doxorubicin and WD showed exacerbated remodelling of cardiac ceramide species leading to increased C16 and C18 content. These findings highlight the inappropriate accumulation and re-distribution of cardiac ceramide species in a diet-induced model of obesity and LVH, potentially increasing susceptibility to cell death. The combination of increased fat and sugar leads to greater pathological remodelling and may explain why this diet pattern is consistently linked with poor cardiovascular outcomes.


Early cholecystectomy safely decreases hospital stay in patients with mild gallstone pancreatitis: a randomized prospective study.
We hypothesized that laparoscopic cholecystectomy performed within 48 hours of admission for mild gallstone pancreatitis, regardless of resolution of abdominal pain or abnormal laboratory values, would result in a shorter hospital stay. Although there is consensus among surgeons that patients with gallstone pancreatitis should undergo cholecystectomy to prevent recurrence, the precise timing of laparoscopic cholecystectomy for mild disease remains controversial. Consecutive patients with mild pancreatitis (Ranson score <or=3) were prospectively randomized to either an early laparoscopic cholecystectomy group (within 48 hours of admission) versus a control laparoscopic cholecystectomy group (performed after resolution of abdominal pain and normalizing trend of laboratory enzymes). The primary end point was hospital length of stay. Secondary end point was a composite of rates of conversion to an open procedure, perioperative complications, and need for endoscopic retrograde cholangiography. The study was designed to enroll 100 patients with an interim analysis after 50 patients. At interim analysis, 50 patients were enrolled at a single university-affiliated public hospital. Of them, 25 patients were randomized to the early group and 25 patients to the control group. Patient age ranged from 18 to 74 years with a median duration of symptoms of 2 days upon presentation and a median Ranson score of 1. There were no baseline differences between the groups with regards to demographics, clinical presentation, or the presence of comorbidities. The hospital length of stay was shorter for the early cholecystectomy group (mean: 3.5 [95% CI, 2.7-4.3], median: 3 [IQR, 2-4]) compared with the control group (mean: 5.8 [95% CI, 3.8-7.9], median: 4 [IQR, 4-6] [P = 0.0016]). Six patients from the early group required endoscopic retrograde cholangiography, compared with 4 in the control group (P = 0.72). There was no statistically significant difference in the need for conversion to an open procedure or in perioperative complication rates between the 2 groups. In mild gallstone pancreatitis, laparoscopic cholecystectomy performed within 48 hours of admission, regardless of the resolution of abdominal pain or laboratory abnormalities, results in a shorter hospital length of stay with no apparent impact on the technical difficulty of the procedure or perioperative complication rate.


Myr+-Gi2 alpha and Go alpha subunits restore the efficacy of opioids, clonidine and neurotensin giving rise to antinociception in G-protein knock-down mice.
In mice whose Gi/o-protein function had been impaired by antisense 'knock-down' or pertussis toxin treatment, i.c.v. injection of myr+-Gi/o alpha subunits restored the effectiveness of beta-endorphin, morphine, DPDPE, clonidine and neurotensin to produce antinociception. Myr+-G alpha subunits of the class of G-proteins actually impaired were more effective than unlike but related myr+-G alpha subunits. Selectivity was noted in that only exogenous myr+-G alpha subunits affected (enhanced) the activity of agonists in G alpha-deficient signalling systems. This treatment had little effect on agonist potency when the impairment resided at the receptor level. The potential of the opioids, clonidine and R-PIA to increase G alpha-related in vitro hydrolysis of GTP was also re-established after injecting myr+-Gi2 alpha subunits into Gi2-knocked-down mice. Myr+-Gi2 alpha subunits pre-incubated with GTPgammaS or GDPbetaS before i.c.v. injection did not improve the activity of agonists in vivo (antinociception) or in vitro (regulation of low Km GTPase). After impairing the function of PKCbeta1 by antisense treatment or with the inhibitor H7, the effect of myr+-G alpha subunits on agonist potency was prevented. Electron microscope analysis showed the entry of gold-conjugated myr+-G alpha subunits into neural cells. These particles were found in the cytoplasm, associated with the plasma membranes of different neuronal processes and also in synaptic junctions. In cultured neurons and astrocytes myr+-Gi2 alpha-associated fluorescence was internalised in a dose-dependent manner and distributed in the plasma membrane and cytosol, as well as in nuclei of dividing astrocytes. Thus, G alpha subunits in CSF enter into neurons and functionally couple to the receptor-triggered signalling cascade. As G-proteins have been implicated in the pathophysiology of several neural disorders, this finding may be valuable in the therapy of such dysfunctions.


Multicentre point-prevalence survey of antibiotic use and healthcare-associated infections in Ethiopian hospitals.
Effective antimicrobial containment strategies such as Antimicrobial Stewardship Programs (ASPs) require comprehensive data on antibiotics use which are scarce in Ethiopia. This study sought to assess antibiotics use and healthcare-associated infections (HCAIs) in Ethiopian public hospitals. We conducted a cross-sectional study using the WHO point-prevalence survey protocol for systemic antibiotics use and HCAIs for low/middle-income countries. The study was conducted among 10 public hospitals in 2021. All patients admitted to adult and paediatric inpatient and emergency wards before or at 08:00 on the survey date were enrolled. The primary outcome measures were the prevalence of antibiotic use, HCAIs and the hospitals' readiness to implement ASP. Data were collected from 1820 patient records. None of the surveyed hospitals had functional ASP. The common indication for antibiotics was for HCAIs (40.3%). Pneumonia was the most common bacterial infection (28.6%) followed by clinical sepsis (17.8%). Most treatments were empiric (96.7%) and the overall prevalence of antibiotic use was 63.8% with antibiotics prescription per patient ratio of 1.77. Ceftriaxone was the most commonly prescribed antibiotic (30.4%) followed by metronidazole (15.4%). Age, having HIV infection, ward type, type of hospital, catheterisation and intubation history had significant association with antibiotic use. Patients who were treated in paediatric surgical wards were about four times more likely to be on antibiotics compared with patients treated at an adult emergency ward. Patients on urinary catheter (adjusted OR (AOR)=2.74, 95% CI: 2.04 to 3.68) and intubation device (AOR=2.62, 95% CI: 1.02 to 6.76) were more likely to be on antibiotics than their non-intubated/non-catheterised counterparts. Patients treated at secondary-level hospitals had 0.34 times lower odds of being on antibiotics compared with those in tertiary hospitals. Antibiotic use across the surveyed hospitals was common and most were empiric which has both practical and policy implications for strengthening ASP and promoting rational antibiotics use.


Acquisition and carriage of multidrug-resistant organisms in dogs and cats presented to small animal practices and clinics in Switzerland.
The emergence and spread of multidrug-resistant organisms (MDRO) present a threat to human and animal health. To assess acquisition, prevalence of and risk factors for MDRO carriage in dogs and cats presented to veterinary clinics or practices in Switzerland. Privately owned dogs (n = 183) and cats (n = 88) presented to 4 veterinary hospitals and 1 practice. Prospective, longitudinal, observational study. Oronasal and rectal swabs were collected at presentation and 69% of animals were sampled again at discharge. Methicillin-resistant (MR) staphylococci and macrococci, cephalosporinase-, and carbapenemase-producing (CP) Enterobacterales were isolated. Genetic relatedness of isolates was assessed by repetitive sequence-based polymerase chain reaction and multilocus sequence typing. Risk factors for MDRO acquisition and carriage were analyzed based on questionnaire-derived and hospitalization data. Admission prevalence of MDRO carriage in pets was 15.5% (95% confidence interval [CI], 11.4-20.4). The discharge prevalence and acquisition rates were 32.1% (95% CI, 25.5-39.3) and 28.3% (95% CI, 22-35.4), respectively. Predominant hospital-acquired isolates were extended spectrum β-lactamase-producing Escherichia coli (ESBL-E coli; 17.3%) and β-lactamase-producing Klebsiella pneumoniae (13.7%). At 1 institution, a cluster of 24 highly genetically related CP (blaoxa181 and blaoxa48 ) was identified. Multivariate analysis identified hospitalization at clinic 1 (odds ratio [OR], 5.1; 95% CI, 1.6-16.8) and days of hospitalization (OR 3-5 days, 4.4; 95% CI, 1.8-10.9; OR > 5 days, 6.2; 95% CI, 1.3-28.8) as risk factors for MDRO acquisition in dogs. Veterinary hospitals play an important role in the selection and transmission of MDRO among veterinary patients.


Monitoring of irrigating fluid absorption during transurethral prostatectomy. A study in anaesthetised patients using a 1% ethanol tag solution.
A simple, reliable method to detect absorption of irrigating fluid during transurethral prostatectomy is to tag irrigating fluids with 1% ethanol and monitor expired breath ethanol concentrations. This method correlated well (n = 0.79) with other existing methods of absorption monitoring in 20 anaesthetised patients. Ethanol (1%) tagging does not alter the optical quality of the irrigating fluid and is harmless to the patient. The technique is non-invasive, repeatable, cheap and gives instant results. It can be used in anaesthetised or awake patients and can detect absorption of as little as 100-150 ml in any 10-minute period.


[A questionnaire on Satisfaction from psychiatric Training].
In the context of the psychiatric reform, as well as of the lifelong education, a Questionnaire for the evaluation of "Satisfaction from Psychiatric Training" has been constructed. It consists of 4 subscales (Satisfaction from Materials, Trainers, Program Organization, and General Satisfaction) and a total of 19 closed-ended items, evaluated in 5-point Likert scales, and an open-ended question for general remarks. One hundred and seventy six subjects, who participated in 8 consecutive training programs in psychiatry, organized by the Vocational Training Center of the Psychiatric Hospital of Petra Olympus, Greece, completed the questionnaire anonymously. The sample was divided into two groups: group A (N=112, from the first 5 programs), for the evaluation of the questionnaire's properties, and group B (N=65, from the next 3 programs) for the validation of the results. Principal component analysis in group A showed the existence of 4 factors corresponding to the 4 subscales and accounted for 67.4% of the questionnaire's variability, which were also confirmed in group B. Internal consistency was high in both groups for the overall questionnaire (Cronbach α>0.92) and for each subscale. Test-retest reliability of every subscale was also high (Pearson's r>0.90). The answers in the open-ended remark question were graded by two independent judges in a 5-point Likert scale, in relation to the satisfaction they revealed, which was highly correlated with all questionnaire subscales but one. For the total sample, the questionnaire subscales showed moderately high correlation with one another (r from 0.629 to 0.706) and even higher with the overall score (from 0.820 to 0.892). The questionnaire's sensitivity was demonstrated by the statistically significant differences observed in the satisfaction experienced from the various programs. None of the subscales was significantly correlated with age (r<0.134), with years in work (r<0.059) or was differentiated by gender. In general, this is a brief and easy to use satisfaction questionnaire for psychiatric training programs, with very satisfactory psychometric properties and relatively independent from demographic variables. It covers the four most important satisfaction components, independently from the specific characteristics of trainees or programs. Thus, it can be used as the main axis of satisfaction evaluation in a variety of programs.


The "in and out" of glucosamine 6-O-sulfation: the 6th sense of heparan sulfate.
The biological properties of Heparan sulfate (HS) polysaccharides essentially rely on their ability to bind and modulate a multitude of protein ligands. These interactions involve internal oligosaccharide sequences defined by their sulfation patterns. Amongst these, the 6-O-sulfation of HS contributes significantly to the polysaccharide structural diversity and is critically involved in the binding of many proteins. HS 6-O-sulfation is catalyzed by 6-O-sulfotransferases (6OSTs) during biosynthesis, and it is further modified by the post-synthetic action of 6-O-endosulfatases (Sulfs), two enzyme families that remain poorly characterized. The aim of the present review is to summarize the contribution of 6-O-sulfates in HS structure/function relationships and to discuss the present knowledge on the complex mechanisms regulating HS 6-O-sulfation.


Home care of the ventilator-dependent person.
Discharge of the ventilator-dependent person from a hospital requires careful advance planning by hospital personnel and rehabilitation of the patient to assure maximal functional ability in the home. The patient and family should be taught the techniques necessary for both routine and emergency care in the home. Respiratory equipment, including the type of mechanical ventilator best suited to the patient's needs and the home environment, and disposable supplies must be obtained, and payment from third-party payers must be assured. Equipment placement and the ability of the patient to perform self-care and activities of daily living following discharge can be facilitated by integrating results of a home care evaluation into the patient's rehabilitation program. Trips of gradually longer duration out of the hospital allow the patient to gain confidence in his ability to care for himself. Responsibilities for follow-up in the home can be shared by respiratory home care companies, visiting nurses, and pulmonary physicians.


Bacterial superglue generates a full-length circumsporozoite protein virus-like particle vaccine capable of inducing high and durable antibody responses.
Malaria, caused by Plasmodium falciparum, continues to have a devastating impact on global health, emphasizing the great need for a malaria vaccine. The circumsporozoite protein (CSP) is an attractive target for a malaria vaccine, and forms a major component of RTS,S, the most clinically advanced malaria vaccine. The clinical efficacy of RTS,S has been moderate, yet has demonstrated the viability of a CSP-based malaria vaccine. In this study, a vaccine comprised of the full-length CSP antigen presented on a virus-like particle (VLP) is produced using a split-intein conjugation system (SpyTag/SpyCatcher) and the immunogenicity is tested in mice. Full-length 3d7 CSP protein was genetically fused at the C-terminus to SpyCatcher. The CSP-SpyCatcher antigen was then covalently attached (via the SpyTag/SpyCatcher interaction) to Acinetobacter phage AP205 VLPs which were modified to display one SpyTag per VLP subunit. To evaluate the VLP-display effect, the immunogenicity of the VLP vaccine was tested in mice and compared to a control vaccine containing AP205 VLPs plus unconjugated CSP. Full-length CSP was conjugated at high density (an average of 112 CSP molecules per VLP) to AP205 SpyTag-VLPs. Vaccination of mice with the CSP Spy-VLP vaccine resulted in significantly increased antibody titres over a course of 7 months as compared to the control group (2.6-fold higher at 7 months after immunization). Furthermore, the CSP Spy-VLP vaccine appears to stimulate production of IgG2a antibodies, which has been linked with a more efficient clearing of intracellular parasite infection. This study demonstrates that the high-density display of CSP on SpyTag-VLPs, significantly increases the level and quality of the vaccine-induced humoral response, compared to a control vaccine consisting of soluble CSP plus AP205 VLPs. The SpyTag-VLP platform utilized in this study constitutes a versatile and rapid method to develop highly immunogenic vaccines. It might serve as a generic tool for the cost-effective development of effective VLP-vaccines, e.g., against malaria.


Treatment of hypertension: a clinical epidemiologist's view.
The majority of deaths attributable to hypertension are coronary artery disease (CAD) deaths and, consequently, the prevention of CAD should be the primary aim of hypertension management. Recent meta-analyses confirm the results of the individual hypertension intervention trials, which demonstrated a disappointing shortfall in the observed prevention of CAD events and mortality from lowering blood pressure compared with the expected benefits. These trial results, rather than challenging the validity of the causal nature of the association between hypertension and CAD may be interpreted to suggest that the management of hypertension in the trials was suboptimal. The drugs used in the trials were almost exclusively thiazide diuretics and to a lesser extent beta-blockers. Both of these drug groups have been shown to have adverse effects on lipid profiles--a pivotal risk factor for CAD. In addition to the effects on lipids, diuretics also adversely affect potassium, uric acid, glucose metabolism, and insulin resistance, all of which directly or indirectly affect the incidence of CAD. In the face of a major shortfall in the overall benefit from managing hypertension with diuretics and to a lesser extent beta-blockers, it therefore seems more logical to recommend for the management of hypertension the use of agents with a more metabolic-friendly profile.


Hemodynamic comparison of dopexamine and nitroprusside at high and low doses in patients with coronary artery disease and impaired left ventricular function.
Pure vasodilator drugs are currently the preferred agents for treatment of acute and chronic heart failure of all grades of severity. In contrast, the role of drugs that combine vasodilation with inotropic action remains highly controversial despite their several advantageous physiological actions and long therapeutic history in heart failure. We hypothesize that this uncertainty might be due first to subtle unfavorable hemodynamic effects not detectable by the relatively crude hemodynamic methods by which these agents are usually analyzed, particularly with regard to the quantification of afterload, and secondly to the narrow therapeutic range of these drugs, such that the dose administered is critical. We tested this hypothesis by comparing several refined hemodynamic measurements of dopexamine, an inotropic vasodilator, with a pure arteriovenous dilator (sodium nitroprusside, SNP) on left ventricular (LV) systolic and diastolic function, large arterial behavior, and coupling of the left ventricle to the arterial system at two dose levels in 35 patients with ischemic heart disease. The study protocol was a fixed order of 15-min infusions of saline, dopexamine 1 microg/kg/min, and dopexamine 3 + ++microg/kg/min, or saline, SNP 1 microg/kg/min, and SNP 3 microg/kg/min. Detailed hemodynamic observations were made at the end of each 15-min infusion period. Both drugs produced equivalent arterial vasodilation, as measured by the decrease in systemic vascular resistance index (SVRI), but dopexamine resulted in a significantly greater increase in cardiac index (CI). Myocardial contractility, assessed by several load-independent indexes, increased with dopexamine, as anticipated with an inotropic drug, but did not alter with SNP. Arterial compliance, a measure of the distensibility of large conduit arteries, was increased by SNP but not by dopexamine. Arterial wave reflection was increased by dopexamine, especially at high doses, but reduced by SNP. Increased arterial compliance and reduced wave reflection reduce LV afterload. SNP reduced preload, whereas dopexamine had no effect on this aspect of ventricular function. Vasodilator drugs and those which combine vasodilator and inotropy increase cardiac output (CO) and reduce SVR. Therapy with inotropic vasodilators has no effect on preload and does not reduce the dynamic components of ventricular afterload, although it does reduce its static components. These effects are dose dependent; there is less perturbation of afterload at lower doses. In contrast, vasodilator therapy reduces preload and both static and dynamic parts of afterload.


Tobramycin exposure from active calcium sulfate bone graft substitute.
Bone graft substitute such as calcium sulfate are frequently used as carrier material for local antimicrobial therapy in orthopedic surgery. This study aimed to assess the systemic absorption and disposition of tobramycin in patients treated with a tobramycin-laden bone graft substitute (Osteoset® T). Nine blood samples were taken from 12 patients over 10 days after Osteoset® T surgical implantation. Tobramycin concentration was measured by fluorescence polarization. Population pharmacokinetic analysis was performed using NONMEM to assess the average value and variability (CV) of pharmacokinetic parameters. Bioavailability (F) was assessed by equating clearance (CL) with creatinine clearance (Cockcroft CLCr). Based on the final model, simulations with various doses and renal function levels were performed. (ClinicalTrials.gov number, NCT01938417). The patients were 52 +/- 20 years old, their mean body weight was 73 +/- 17 kg and their mean CLCr was 119 +/- 55 mL/min. Either 10 g or 20 g Osteoset® T with 4% tobramycin sulfate was implanted in various sites. Concentration profiles remained low and consistent with absorption rate-limited first-order release, while showing important variability. With CL equated to CLCr, mean absorption rate constant (ka) was 0.06 h-1, F was 63% or 32% (CV 74%) for 10 and 20 g Osteoset® T respectively, and volume of distribution (V) was 16.6 L (CV 89%). Simulations predicted sustained high, potentially toxic concentrations with 10 g, 30 g and 50 g Osteoset® T for CLCr values below 10, 20 and 30 mL/min, respectively. Osteoset® T does not raise toxicity concerns in subjects without significant renal failure. The risk/benefit ratio might turn unfavorable in case of severe renal failure, even after standard dose implantation.


Organic Waste Reduction at Hamilton Health Sciences.
Hamilton Health Sciences (HHS) cares for the community in many ways. This includes fulfilling responsibilities as an organization to reduce the environmental impact of healthcare waste that is generated on a daily basis. A significant amount of this is food waste generated by hospital kitchens and cafeterias, and has been identified as a waste stream that could be diverted from landfill. This article explores HHS' journey toward the implementation of a cost effective, environmentally sustainable waste stream management system.


Proprioceptive Neuromuscular Facilitation Kinesio Taping Improves Range of Motion of Ankle Dorsiflexion and Balance Ability in Chronic Stroke Patients.
This study aimed to determine the effect of a proprioceptive neuromuscular facilitation (PNF) pattern Kinesio taping (KT) application on the ankle dorsiflexion range of motion (DF-ROM) and balance ability in patients with chronic stroke. This crossover study included 18 patients with stroke. The subjects were randomly assigned to three interventions: barefoot, ankle KT (A-KT), and PNF-KT. The A-KT was applied to the gastrocnemius and tibialis anterior (TA) muscles, and subtalar eversion. The PNF-KT was applied on the extensor hallucis, extensor digitorum, and TA muscles. DR-ROM was measured using the iSen™, a wearable sensor. Balance ability was assessed based on static balance, measured by the Biodex Balance System (BBS), and dynamic balance, measured by the timed up and go (TUG) test and dynamic gait index (DGI). Compared with the barefoot and A-KT interventions, PNF-KT showed significant improvements in the ankle DF-ROM and BBS scores, TUG, and DGI. PNF-KT, for functional muscle synergy, improved the ankle DF-ROM and balance ability in patients with chronic stroke. Therefore, the application of PNF-KT may be a feasible therapeutic method for improving ankle movement and balance in patients with chronic stroke. Additional research is recommended to identify the long-term effects of the PNF-KT.


Investigation of gene expression profiles in a rat adjuvant arthritis model suggests an effective role of triptolide via PI3K-AKT signaling.
Rheumatoid arthritis (RA) is a common systemic autoimmune disease mainly involving the formation of a synovial pannus, for which no effective treatment is available. In order to study the molecular biological mechanisms underlying the inhibition of RA synovial pannus by triptolide, differentially expressed genes in synovial tissues from an adjuvant arthritis (AA) rat model with and without triptolide treatment were detected in an mRNA microarray profile produced by Agilent Technologies and verified by reverse transcription-quantitative polymerase chain reaction analysis (RT-qPCR). An AA model was established by subcutaneously injecting 0.1 ml Freund's complete adjuvant daily for 18 days and scored by arthritis index assessment. Subsequently, triptolide (0.4 mg/kg) or an equivalent amount of saline was administered daily for 14 days. At the end of the experiment, synovial tissues were obtained from the ankle joints of the rats' hind legs. Total RNA was extracted and purified, and microarray hybridization was used to obtain the gene expression profile for RA with and without triptolide treatment. A total of 48 genes were identified to be differentially expressed between the treatment and model groups, including 32 upregulated and 16 downregulated genes. The possible signaling pathways associated with the effect of triptolide were investigated by Gene Ontology and pathway analysis, revealing that the phosphoinositide-3 kinase (PI3K)/AKT signaling pathway has a key role in the proliferation and apoptosis of synovial cells in RA joints. Reverse transcription-quantitative polymerase chain reaction analysis was applied to confirm the aberrant expression of key mRNAs and revealed that vascular endothelial growth factor (VEGF) A and C1q and tumor necrosis factor related protein 3 (C1QTNF3) were downregulated in the treatment group compared with the model group (P<0.05). In conclusion, triptolide may exert its effects against RA via the PI3K/AKT pathway and has an inhibitory effect on the expression of VEGFA and C1QTNF3, thus are potentially associated with the occurrence and development of RA.


Predictors of increased left ventricular filling pressure in dialysis patients with preserved left ventricular ejection fraction.
To study the left and right ventricular function and to assess the predictors of increased left ventricular (LV) filling pressure in dialysis patients with preserved LV ejection fraction. This study included 63 consecutive patients (age 57+/-14 years, 57% women) with end-stage renal failure. Echocardiography, including tissue Doppler measurements, was performed in all patients. Based on the median value of the ratio of transmitral early diastolic velocity to early myocardial velocity (E/E' ratio), patients were divided into 2 groups: the group with high filling pressure (E/E'>10.16) and the group with low filling pressure (E/E'< or =10.16). Compared with patients with low filling pressure, the group of patients with high filling pressure included a higher proportion of diabetic patients (41% vs 13%, P=0.022) and had greater LV mass index (211+/-77 vs 172+/-71 g/m3, P=0.04), lower LV lateral long axis amplitude (1.4+/-0.3 vs 1.6+/-0.3 cm, P=0.01), lower E wave (84+/-19 vs 64+/-18cm/s, P<0.001), higher systolic myocardial velocity (S': 8.6+/-1. 5 vs 7.0+/-1.3 cm/s, P<0.001), and lower diastolic myocardial velocities (E': 6.3+/-1.9 vs 9.5+/-2.9 cm/s, P<0.001; A': 8.4+/-1.9 vs 9.7+/-2.5 cm/s, P=0.018). Multivariate analysis identified LV systolic myocardial velocity - S' wave (adjusted odds ratio, 1.909; 95% confidence interval, 1.060-3.439; P=0.031) and age (1.053; 1.001-1.108; P=0.048) as the only independent predictors of high LV filling pressure in dialysis patients. In dialysis patients with preserved left ventricular ejection fraction, reduced systolic myocardial velocity and elderly age are independent predictors of increased left ventricular filling pressure.


Comparative study of afterpulsing behavior and models in single photon counting avalanche photo diode detectors.
Single-photon avalanche diode (SPAD) detectors, have a great importance in fields like quantum key distribution, laser ranging, florescence microscopy, etc. Afterpulsing is a non-ideal behavior of SPADs that adversely affects any application that measures the number or timing of detection events. Several studies based on a few individual detectors, derived distinct mathematical models from semiconductor physics perspectives. With a consistent testing procedure and statistically large data sets, we show that different individual detectors - even if identical in type, make, brand, etc. - behave according to fundamentally different mathematical models. Thus, every detector must be characterized individually and it is wrong to draw universal conclusions about the physical meaning behind these models. We also report the presence of high-order afterpulses that are not accounted for in any of the standard models.


Real-time detection of DNA interactions with long-period fiber-grating-based biosensor.
Using an optical biosensor based on a dual-peak long-period fiber grating, we have demonstrated the detection of interactions between biomolecules in real time. Silanization of the grating surface was successfully realized for the covalent immobilization of probe DNA, which was subsequently hybridized with the complementary target DNA sequence. It is interesting to note that the DNA biosensor was reusable after being stripped off the hybridized target DNA from the grating surface, demonstrating a function of multiple usability.


A thymidine triphosphate shape analog lacking Watson-Crick pairing ability is replicated with high sequence selectivity.
Compound 1 (F), a nonpolar nucleoside analog that is isosteric with thymidine, has been proposed as a probe for the importance of hydrogen bonds in biological systems. Consistent with its lack of strong H-bond donors or acceptors, F is shown here by thermal denaturation studies to pair very poorly and with no significant selectivity among natural bases in DNA oligonucleotides. We report the synthesis of the 5'-triphosphate derivative of 1 and the study of its ability to be inserted into replicating DNA strands by the Klenow fragment (KF, exo- mutant) of Escherichia coli DNA polymerase I. We find that this nucleotide derivative (dFTP) is a surprisingly good substrate for KF; steady-state measurements indicate it is inserted into a template opposite adenine with efficiency (Vmax/Km) only 40-fold lower than dTTP. Moreover, it is inserted opposite A (relative to C, G, or T) with selectivity nearly as high as that observed for dTTP. Elongation of the strand past F in an F-A pair is associated with a brief pause, whereas that beyond A in the inverted A-F pair is not. Combined with data from studies with F in the template strand, the results show that KF can efficiently replicate a base pair (A-F/F-A) that is inherently very unstable, and the replication occurs with very high fidelity despite a lack of inherent base-pairing selectivity. The results suggest that hydrogen bonds may be less important in the fidelity of replication than commonly believed and that nucleotide/template shape complementarity may play a more important role than previously believed.


Knowledge on Stroke Warning Signs and Associated Factors Among Hypertensive Patients, Northwest Ethiopia: An Institution-Based Cross-Sectional Study.
Stroke is one of the leading causes of death globally and is a major cause of disability worldwide. It is a preventable and treatable disease by the prevention of modifiable risk factors and early recognition of warning signs, respectively. To assess knowledge on stroke warning signs and associated factors among hypertensive patients at South Gondar Zone Comprehensive Specialized Hospital, Northwest Ethiopia, 2020. An institution-based cross-sectional study was conducted in South Gondar Zone Comprehensive Specialized Hospital from June 1-30, 2020. A systematic random sampling technique was used and data were collected through face to face interviews. Data were entered into Epi data version 22.214.171.124 and exported to SPSS version 25 for cleaning and analysis. Bivariate and multivariable logistic regression analysis was used and variables with p <0.05 in the multivariable analysis were considered as statistically significant. Two hundred and fifty-three hypertensive patients completed the questionnaire with a response rate of 100%. Among the total respondents, 15% (95% CI: 10.7, 19.4) of participants had good knowledge of stroke warning signs. Younger age (AOR: 2.82; 95% CI: 1.18, 6.74), urban residence (AOR: 2.9; 95% CI: 1.04, 8.11), being educated (AOR: 2.6; 95% CI: 1.09, 6.23) and having long duration hypertension follow up (AOR: 2.7; 95% CI: 1.25, 5.81) were significantly associated with good knowledge of stroke warning signs. This study revealed that participants had poor knowledge of stroke warning signs. Younger age, urban residence, being educated and having long duration hypertension follow up were predictors of good stroke warning signs knowledge. Health information dissemination needs to be strengthened for hypertensive patients, particularly for older, rural residents, the non-educated and those having short duration of hypertension follow up.


Evaluation of Warpage and Residual Stress of Precision Glass Micro-Optics Heated by Carbide-Bonded Graphene Coating in Hot Embossing Process.
A newly developed hot embossing technique which uses the localized rapid heating of a thin carbide-bonded graphene (CBG) coating, greatly reduces the energy consumption and promotes the fabrication efficiency. However, because of the non-isothermal heat transfer process, significant geometric deviation and residual stress could be introduced. In this paper, we successfully facilitate the CBG-heating-based hot embossing into the fabrication of microlens array on inorganic glass N-BK7 substrate, where the forming temperature is as high as 800 °C. The embossed microlens array has high replication fidelity, but an obvious geometric warpage along the glass substrate also arises. Thermo-mechanical coupled finite element modelling of the embossing process is conducted and verified by the experimental results. Based on trial and error simulations, an appropriate compensation curvature is determined and adopted to modify the geometrical design of the silicon wafer mold. The warpage of the re-embossed microlens array is significantly decreased using the compensated mold, which demonstrates the feasibility of the simulation-oriented compensation scheme. Our work would contribute to improving the quality of optics embossed by this innovative CBG-heating-based hot embossing technique.


In Vivo Reprogramming Ameliorates Aging Features in Dentate Gyrus Cells and Improves Memory in Mice.
Post-translational epigenetic modifications take place in mouse neurons of the dentate gyrus (DG) with age. Here, we report that age-dependent reduction in H3K9 trimethylation (H3K9me3) is prevented by cyclic induction of the Yamanaka factors used for cell reprogramming. Interestingly, Yamanaka factors elevated the levels of migrating cells containing the neurogenic markers doublecortin and calretinin, and the levels of the NMDA receptor subunit GluN2B. These changes could result in an increase in the survival of newborn DG neurons during their maturation and higher synaptic plasticity in mature neurons. Importantly, these cellular changes were accompanied by an improvement in mouse performance in the object recognition test over long time. We conclude that transient cyclic reprogramming in vivo in the central nervous system could be an effective strategy to ameliorate aging of the central nervous system and neurodegenerative diseases.


Two uniquely arranged thyroid hormone response elements in the far upstream 5' flanking region confer direct thyroid hormone regulation to the murine cholesterol 7alpha hydroxylase gene.
Cholesterol 7alpha hydroxlyase (CYP7A1) is a key enzyme in cholesterol catabolism to bile acids and its activity is important for maintaining appropriate cholesterol levels. The murine CYP7A1 gene is highly inducible by thyroid hormone in vivo and there is an inverse relationship between thyroid hormone and serum cholesterol. Eventhough gene expression has been shown to be upregulated, whether the induction was mediated through a direct effect of thyroid hormone on the CYP7A1 promoter has never been established. Using gene targeted mice, we show that either of the two TR isoforms are sufficient to maintain normal hepatic CYP7A1 expression but a loss of both results in a significant decrease in expression. We also identified two new functional thyroid hormone receptor-binding sites in the CYP7A1 5' flanking sequence located 3 kb upstream from the transcription start site. One site is a DR-0, which is an unusual type of TR response element, and the other consists of only a single recognizable half site that is required for TR/retinoid X receptor (RXR) binding. These two independent TR-binding sites are closely spaced and both are required for full induction of the CYP7A1 promoter by thyroid hormone, although the DR-0 site was more crucial.


Identification of two T-cell epitopes on the candidate Epstein-Barr virus vaccine glycoprotein gp340 recognized by CD4+ T-cell clones.
Current efforts to develop an Epstein-Barr virus subunit vaccine are based on the major envelope glycoprotein gp340. Given the central role of CD4+ T cells in regulating immune responses to subunit vaccine antigens, the present study has begun the work of identifying linear epitopes which are recognized by human CD4+ T cells within the 907-amino-acid sequence of gp340. A panel of gp340-specific CD4+ T-cell clones from an Epstein-Barr virus-immune donor were first assayed for their proliferative responses to a series of truncated gp340 molecules expressed from recombinant DNA vectors in rat GH3 cells, by using an autologous B lymphoblastoid cell line as a source of antigen-presenting cells. The first four T-cell clones analyzed all responded to a truncated form of gp340 which contained only the first 260 N-terminal amino acids. These clones were subsequently screened for responses to each of a panel of overlapping synthetic peptides (15-mers) corresponding to the primary amino acid sequence of the first 260 N-terminal amino acids of gp340. One clone (CG2.7) responded specifically to peptides from the region spanning amino acids 61 to 81, while three other clones (CG5.15, CG5.24, and CG5.36) responded specifically to peptides from the region spanning amino acids 163 to 183. Work with individual peptides from these regions allowed finer mapping of the T-cell epitopes and also revealed the highly dose-dependent nature of peptide-induced responses, with inhibitory effects apparent when the most antigenic peptides were present at supraoptimal concentrations. Experiments using homozygous typing B lymphoblastoid cell lines as antigen-presenting cells showed that the T-cell clones with different epitope specificities were restricted through different HLA class II antigens; clone CG2.7 recognized epitope 61-81 in the context of HLA DRw15, whereas clones CG5.15, CG5.24, and CG5.36 recognized epitope 163-183 in the context of HLA DRw11. The present protocol therefore makes a systematic analysis of CD4+ T-cell epitopes within gp340 possible; it will be necessary to screen gp340-specific T-cell clones from a variety of donors to assess the wider influence of HLA class II polymorphism upon epitope choice.


Tumor necrosis factor induction of endothelial cell urokinase-type plasminogen activator mediated proteolysis of extracellular matrix and its antagonism by gamma-interferon.
Tumor necrosis factor (TNF) has a profound capacity to alter the endothelial cell phenotype that includes morphologic and functional changes that may be central for proinflammatory processes. Recent observations have indicated that TNF can promote the synthesis and secretion of urokinase plasminogen activator (uPA) in low passage human endothelial cells that normally release little uPA. In this report we have confirmed and expanded upon these initial observations in human endothelial cells and describe the ability of gamma-interferon (gamma-IFN) to inhibit TNF-induced uPA synthesis and secretion in a dose-dependent manner (0.025 to 25 ng/mL). Analysis of cell-free conditioned medium derived from gamma-IFN-treated cultures by micro-enzyme-linked immunosorbent assay (ELISA) methodologies using uPA- and plasminogen activator inhibitor type 1 (PAI-1)-specific monoclonal antibodies (MoAbs) indicate that the decrease in uPA activity observed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) zymography is a direct result of a decrease in extracellular uPA antigen and is not a consequence of increased PAI-1 antigen. These findings are supported by Northern blot analyses that indicate that gamma-IFN treatment of endothelial cells resulted in a decreased steady state level of uPA messenger RNA (mRNA) with no measurable change in PAI-1 mRNA. This inhibitory response is specific for gamma-IFN because alpha-IFN fails to elicit a similar inhibitory response. In addition, TNF augmented extracellular proteolysis of radiolabeled subendothelial extracellular matrix (ECM) in a dose-dependent manner. The observed increase in ECM degradation mediated by TNF treatment of endothelial cells was dependent on the presence of plasminogen and could be inhibited by an anticatalytic uPA MoAb implying the requirement of proteolytically active uPA in this process. gamma-IFN (25 ng/mL) treatment of endothelial cells antagonized TNF-promoted degradation of radiolabeled ECM at a concentration that completely inhibited TNF-mediated uPA expression and activity. In addition, endothelial cells treated with TNF (18 hours) displayed the ability to invade ECM and reorganize individual cells into tube-like structures that were not evident in untreated control cultures when grown on Matrigel-coated culture dishes. gamma-IFN treatment of endothelial cells propagated on Matrigel was observed to inhibit TNF-mediated ECM invasion and tube formation at concentrations that were analogous to those required for the inhibition of uPA expression and activity. In summary, these observations suggest a novel homeostatic control mechanism for endothelial cell regulation of subendothelial ECM degradation promoted by TNF and inhibited by gamma-IFN.(ABSTRACT TRUNCATED AT 400 WORDS)


Synthesis, characterization and antiproliferative effects of naphtho [2,3-b] thiophen-4,9-quinone on bladder tumor cells.
Naphthoquinones are natural plants products or synthesized compounds. They have α, β-cyclic aromatic dienones structure with a naphthalene skeleton. Little is known about naphthoquinone and nothing about naphtho [2,3-b] thiophen-4,9-quinone effects on bladder cancer. In this study, a naphthoquinone containing a hetero sulfur atom was synthesized using classical synthetic method. The molecular structure was elucidated by NMR techniques and the antitumor effects were evaluated on bladder tumor cell lines with different TP53 status using tripan blue and MTT cytotoxic method, quantification of reactive oxygen species (ROS), wound healing, cell morphology and cell cycle progression assays. The results showed selective cytotoxicity, colonies reduction, morphological change, inhibition of the cell migration process, induction of ROS production and cell cycle arrest. Naphtho [2,3-b] thiophen-4,9-quinone presents antiproliferative activity regardless TP53 status and may be a promising agent in the treatment of bladder cancer, as they have an oxidizing effect and interfere with cell cycle.