Dyslipoproteinemia in systemic lupus erythematosus. Effect of corticosteroids.
The increased incidence of atherosclerotic coronary artery disease in patients with systemic lupus erythematosus (SLE) may be due to a dyslipoproteinemia caused by corticosteroid administration. To determine whether lipoprotein lipid levels are abnormal in SLE and the relation of lipoprotein levels to corticosteroid use, lipid and apolipoprotein levels were measured in 46 female patients with SLE and 30 matched control subjects. The patients with SLE had higher levels of plasma triglyceride (134 versus 73 mg/dl; p less than 0.001), cholesterol (201 versus 168 mg/dl; p less than 0.001), and low-density lipoprotein cholesterol (121 versus 94 mg/dl; p less than 0.001) than control subjects. The levels of high-density lipoprotein cholesterol, high-density lipoprotein subfraction 3 cholesterol, and apolipoprotein Al were similar in the two groups, but high-density lipoprotein subfraction 2 cholesterol was lower in the patients with SLE (10.2 versus 18.2 mg/dl; p less than 0.001). When patients with SLE treated with prednisone (n = 32) were compared to patients with SLE not treated with prednisone (n = 14), the former had higher triglyceride (158 versus 87 mg/dl; p less than 0.001), cholesterol (214 versus 170 mg/dl; p less than 0.001), and low-density lipoprotein cholesterol (130 versus 103 mg/dl; p less than 0.001) levels. The patients with SLE not treated with prednisone had lipid levels similar to those in control subjects except that high-density lipoprotein cholesterol was lower (49.7 versus 59.0 mg/dl; p less than 0.05). The daily prednisone dosage in the treated patients with SLE correlated with levels of cholesterol (r = 0.38, p less than 0.02), high-density lipoprotein cholesterol (r = 0.40, p less than 0.02), and high-density lipoprotein subfraction 3 cholesterol (r = 0.47, p less than 0.01). Thus, female patients with SLE have a dyslipoproteinemia of the type that would place them at an increased risk for coronary artery disease. Corticosteroids, used in the treatment of SLE, seem to play a role in the pathogenesis of the observed lipoprotein abnormalities.


Integrated identification/confirmatory and targeted analysis of epoxyeicosatrienosic acids in human serum by LC-TOF MS and automated on-line SPE-LC-QqQ MS/MS.
A combined strategy is here proposed for qualitative/quantitative targeted analysis of epoxyeicosatrienoic acids (EETs) in human serum. Identification of EET regioisomers was initially carried out by LC-TOF MS in high accuracy mode under optimum conditions for chromatographic separation of the four isomers with an isocratic method using 40:40:20 (v/v/v) methanol-acetonitrile-water containing 0.02% acetic acid. Confirmatory analysis was supported on MS/MS experiments using the hybrid QqTOF mass analyzer by targeted fragmentation of the precursor ion fitting with the molecular formula C₂₀H₃₂O₃ (319.2279 m/z). Identification of selective fragment ions in high accuracy mode enabled the localization of the epoxy functional group and, therefore, the assignation of chromatographic peaks to each EET isomer. After qualitative analysis, an automated method was developed for analysis of EETs in human serum by direct analysis using an on-line platform based on SPE-LC-QqQ MS/MS in selected reaction monitoring. Recovery factors estimated with a dual-cartridge configuration were above 87% for all metabolites either using non-spiked and spiked serum at three different concentrations. Precision, calculated as within-laboratory repeatability and expressed as relative standard deviation, ranged from 2.5 to 9.9% with detection limits below 0.15 ng mL(-1). The optimization of the method was completed with a stability study under different conditions to assess the suited conditions for analysis of EET intermediate metabolites. Finally, concentration ranges of EETs were measured in nine healthy individuals.


An investigation on the respiratory mechanics of mechanically ventilated patients during spontaneous breathing trials with enhanced low-level pressure support ventilation.
Low-level pressure support ventilation (PSV) is most commonly adopted in spontaneous breathing trials (SBTs), and some have proposed setting the positive end-expiratory pressure (PEEP) to 0 cmH2 O in order to shorten the observation time of SBTs. This study aims to investigate the effects of two PSV protocols on the patients' respiratory mechanics. A prospective randomized self-controlled crossover design was adopted in this study, which involved enrolling 30 difficult-to-wean patients who were admitted to the intensive care unit of the First Affiliated Hospital of Guangzhou Medical University between July 2019 and September 2021. Patients were subjected to the S group (pressure support: 8 cmH2 O, PEEP: 5 cmH2 O) and S1 group (PS: 8 cmH2 O, PEEP: 0 cmH2 O) for 30 min in a random order, and respiratory mechanics indices were dynamically monitored via a four-lumen multi-functional catheter with an integrated gastric tube. Among the 30 enrolled patients, 27 were successfully weaned. The S group showed higher airway pressure (Paw), intragastric pressure (Pga) and airway pressure-time product (PTP) than the S1 group. The S group also showed a shorter inspiratory trigger delay, (93.80 ± 47.85) versus (137.33 ± 85.66) ms (P = 0.004); and fewer abnormal triggers, (0.97 ± 2.65) versus (2.67 ± 4.48) (P = 0.042) compared with the S1 group. Stratification based on the causes of mechanical ventilation revealed that under the S1 protocol, patients with chronic obstructive pulmonary disease (COPD) had a longer inspiratory trigger delay compared to both post-thoracic surgery (PTS) patients and patients with acute respiratory distress syndrome. Despite providing greater respiratory support, S group led to significant reductions in inspiratory trigger delay and less abnormal triggers compared to S1 group, especially among patients with chronic obstructive pulmonary disease. These findings suggest that the zero PEEP group was more likely to induce a higher number of patient-ventilator asynchronies in difficult-to-wean patients.


Candida tropicalis infection in a term neonate with gall bladder masses and infective endocarditis.
Candida endocarditis is extremely rare in term neonates, and gall bladder involvement due to candidemia has never been reported amongst neonates and infants. A term, appropriate for gestational age neonate developed Candida tropicalis blood stream infection in second week of life. He was started on conventional amphotericin B. However, he failed to show any clinical improvement, and candidemia keep on persisting. Repeat sanctuary sites screening revealed multiple echogenic masses in heart (vegetations) and gall bladder. On changing the treatment to liposomal amphotericin B and fluconazole, he recovered clinically, echogenic masses in gall bladder disappeared, and intracardiac vegetations decreased in size.


High-performance liquid chromatography-fluorometry for the determination of thiols in biological samples using N-[4-(6-dimethylamino-2-benzofuranyl) phenyl]-maleimide.
The selective determination of thiols in biological samples was investigated by high-performance liquid chromatography using N-[4-(6-dimethylamino-2-benzofuranyl)phenyl] maleimide, which was found to give fluorescent products when treated with certain thiols. Six kinds of thiol (reduced glutathione, cysteine, N-acetylcysteine, cysteamine, homocysteine and coenzyme A) could be separated simultaneously within ca. 12 min and determined at final level of sensitivity. The method was successfully applied to the determination of thiols in rat tissues and plasma and in human normal serum.


Carboplatin and irinotecan (CI) vs. carboplatin and etoposide (CE) for the treatment of extended-stage small-cell lung cancer in an elderly population: A phase II/III randomized control trial.
Cisplatin plus irinotecan has been considered as the standard therapy in younger (<70 years old) patients for extensive-disease small-cell lung cancer (ED-SCLC) in Japan. However, there is a lack of high-quality evidence for the use of irinotecan in elderly patients with ED-SCLC. This study aimed to demonstrate that carboplatin plus irinotecan (CI) improves overall survival (OS) in elderly patients with ED-SCLC. This was a randomized Phase II/III trial which enrolled elderly patients with ED-SCLC. Patients were randomized to the CI or carboplatin plus etoposide (CE) arm in a 1:1 ratio. The CE group intravenously received carboplatin (AUC 5 mg/ml/min on day 1) and etoposide (80 mg/m2 on days 1-3) every 3 weeks for four cycles. The CI group received carboplatin (AUC 4 mg/ml/min on day 1) and irinotecan (50 mg/m2 on days 1 and 8) intravenously every 3 weeks for 4 cycles. In total, 258 patients were enrolled and randomized (CE arm, 129 patients; CI arm, 129 patients). The median overall survival, progression-free survival, and objective response rate of the CE vs. CI arms were 12.0 (95% CI, 9.3-13.7) vs. 13.2 (95% CI, 11.1-14.6) months (HR, 0.85 (95% CI, 0.65-1.11)) (one-sided P = 0.11), 4.4 (95% CI, 4.0-4.7) vs. 4.9 (95% CI, 4.5-5.2) months (HR, 0.85 (95% CI, 0.66-1.09)), and 59.5% vs. 63.2%, respectively. A higher incidence of myelosuppression was observed in the CE group, whereas a higher incidence of gastrointestinal toxicity was observed in the CI group. Three treatment-related deaths occurred (one due to lung infection in the CE arm, and one due to lung infection and sepsis each in the CI arm). The CI treatment showed favorable efficacy; however, the difference was not statistically significant. These results suggest that CE should remain as the standard chemotherapy regimen for elderly patients with ED-SCLC.


Persistence of subsyndromal residual symptoms after remission of major depression in patients without cardiovascular disease may condition maintenance of elevated platelet factor 4 and β-thromboglobulin plasma levels.
Depressive patients show a state dependent platelet activation that may heighten their cardiovascular risk, specially when comorbid with Coronary Artery Disease (CAD). We still have little information however on the possibility that residual symptoms that often persist after recovery from a major depressive episode may contribute to drive forward platelet activation, thus extending the exposure to the associated cardiovascular risk. Nineteen major depressed inpatients treated with electroconvulsive therapy (ECT) were enrolled and tested for platelet aggregation by measuring platelet factor-4 (PF4) and β-thromboglobulin (β-TG) plasma levels, and for psychometric evaluation by using the 20-item Hamilton Depression Rating Scale (HDRS) and the Symptom Checklist 90 Revised (SCL-90R). Subjects were tested at the beginning of treatment (baseline) and after clinical remission (endpoint). At baseline the patients showed high HDRS (31±6) and total SCL-90R (200±38) scores, followed by a significant decrease at endpoint. However, even if all patients showed full syndromal recovery, SCL-90R "Hostility" and "Psychoticism" subscores showed no significant reduction from baseline, indicating the persistence of subtle residual symptoms. Baseline PF4 and β-TG plasma levels were found remarkably higher and no significant reduction was observed at the endpoint. Small study population. No follow-up evaluation. Despite of clinical remission obtained with ECT in patients with major depression, persistence of subsyndromal residual symptoms may contribute to maintain a condition of platelet hyperactivation at the endpoint, increasing their cardiovascular risk and making them more vulnerable to develop cardiovascular disease.


Interactions of salicylic acid derivatives with calcite crystals.
Investigation of basic interactions between the active pharmaceutical compounds and calcium carbonates is of great importance because of the possibility to use the carbonates as a mineral carrier in drug delivery systems. In this study the mode and extent of interactions of salicylic acid and its amino acid derivates, chosen as pharmaceutically relevant model compounds, with calcite crystals are described. Therefore, the crystal growth kinetics of well defined rhombohedral calcite seed crystals in the systems containing salicylic acid (SA), 5-amino salicylic acid (5-ASA), N-salicyloil-l-aspartic acid (N-Sal-Asp) or N-salicyloil-l-glutamic acid (N-Sal-Glu), were investigated. The precipitation systems were of relatively low initial supersaturation and of apparently neutral pH. The data on the crystal growth rate reductions in the presence of the applied salicylate molecules were analyzed by means of Cabrera & Vermileya's, and Kubota & Mullin's models of interactions of the dissolved additives and crystal surfaces. The crystal growth kinetic experiments were additionally supported with the appropriate electrokinetic, spectroscopic and adsorption measurements. The Langmuir adsorption constants were determined and they were found to be in a good correlation with values obtained from crystal growth kinetic analyses. The results indicated that salicylate molecules preferentially adsorb along the steps on the growing calcite surfaces. The values of average spacing between the adjacent salicylate adsorption active sites and the average distance between the neighboring adsorbed salicylate molecules were also estimated.


Can solid phase assays be better utilized to measure efficacy of antibody removal therapies?
Antibody removal therapies are used for patients with antibody-mediated-rejection or those requiring desensitization to become transplantable. Accurate measurement of antibody levels prior to, and during treatment, are required to choose the best therapeutic approach, and to provide measure of treatment efficacy. Currently, the FDA does not regard solid-phase assays for HLA-antibody identification as a reliable surrogate-marker for treatment efficacy. Serum samples from 40 patients (58 assays; >2200 positive data points) undergoing antibody-removal-therapies were tested as sample-pairs, pre- and post-treatment. MFI values of IgG and C1q single-antigen-bead assays were compared with antibody titer values (serial dilutions). Antibody reduction was tracked and the differences in pre-to-post-treatment values were calculated as delta-reduction of antibody levels. Dynamic patterns of titration studies reduced effects of serum-inherent inhibitory factors (prozone-like); eliminated over-saturation limitations, and provided better estimation of antibody-binding strength compared with the other methods. Moreover, delta-reduction of antibody values using titration studies was significantly more uniform compared with either IgG or C1q tests. Analyzing antibody results using only C1q positive or only higher MFI values did not change the overall magnitude of results. Overall, titration studies provided better estimate of responsiveness to treatment and thus can serve as companion to monitoring efficacy of antibody-removal therapies.


In vivo echo-planar imaging of rat spinal cord.
An integrated approach to echo-planar imaging of rat spinal cord in vivo with a small field of view (FOV) is presented. This protocol is based on a multishot interleaved echo-planar imaging (EPI) sequence and includes: 1) use of an inductively coupled implantable coil for improved signal-to-noise ratio (SNR); 2) three-dimensional (3D) automatic shimming of the magnetic field over the spinal cord; and 3) post-acquisition data processing using a multireference scan for minimizing image artifacts. Some of the practical issues in implementing this protocol are discussed. This imaging protocol will be useful in characterizing the spinal cord pathology using techniques that are otherwise time-consuming, such as diffusion tensor imaging.


Exome sequencing in adult neurology practice: Challenges and rewards in a mixed resource setting.
To share the experience of next-generation sequencing (NGS) in delineating molecular basis of neuro-genetic disorders in adults of Indian origin. Adults (aged ≥18 years) evaluated in a single neurology unit at a tertiary-care teaching hospital between August 2014 and September 2016, underwent NGS for (i) sporadic occurrence of neurological disorder where an extensive search did not reveal an acquired cause or (ii) familial or sporadic, uncommon, seemingly genetic disorder where single monogenic cause could not be ascertained based on phenotype. Presence of pathogenic/ likely-pathogenic variants, novel genetic variants, and novel phenotype associations were noted. Clinical phenotypes included: neuromuscular (n = 14), extrapyramidal (n = 8), ataxia (n = 7), leukoencephalopathy (n = 6), spastic paraplegia (n = 5), stroke (n = 4), progressive myoclonic epilepsy (n = 1) and epilepsy with developmental delay (n = 1). Fifty-eight variants were identified in 43 genes in 34 patients, that included 15 (25.9%) reported variants. Genetic diagnosis could be established in 14 (30.43%) subjects. Six probands (13%) harboured previously unreported variants in a clinically relevant gene. Nine probands harboured unreported variants in two or more different genes associated with the clinical phenotype. In three probands we noted novel associations between the phenotype and genetic variation. In all patients, genetic diagnosis impacted treatment and prognostication. We present data of NGS in adults with suspected neuro-genetic disorders from India and this is the first report of its kind. It sets a platform for further basic science research to validate 'novel' variants and those of 'uncertain significance' as pathogenic or otherwise with specific reference to Indian ethnicity.


The effectiveness of tools used to evaluate successful critical decision making skills for applicants to healthcare graduate educational programs: a systematic review.
Students leave healthcare academic programs for a variety of reasons. When they attrite, it is disappointing for the student as well as their faculty. Advanced practice nursing and other healthcare professions require not only extensive academic preparation, but also the ability to critically evaluate patient care situations. The ability to critically evaluate a situation is not innate. Critical decision making skills are high level skills that are difficult to assess. For the purpose of this review, critical decision making and critical thinking skills refer to the same constructs and will be referred to globally as critical decision making skills. The objective of this review was to identify the effectiveness of tools used to evaluate critical decision making skills for applicants to healthcare graduate educational programs. Adult (18 years of age or older) applicants, students enrolled and/or recent graduates (within one year from completion) of healthcare graduate educational programs. Types of interventions: This review considered studies that evaluated the utilization of unique tools as well as standard tools, such as the Graduate Record Exam or grade point average, to evaluate critical decision making skills in graduate healthcare program applicants. Types of studies: Experimental and non-experimental studies were considered for inclusion. Types of outcomes: Successful quantitative evaluations based on specific field of study standards. The search strategy aimed to find both published and unpublished studies. Studies published in English after 1969 were considered for inclusion in this review. Databases that included both published and unpublished (grey) literature were searched. Additionally, reference lists from all articles retrieved were examined for articles for inclusion. Selected papers were assessed by two independent reviewers using standardized critical appraisal instruments from Joanna Briggs Institute. Any disagreement between reviewers was resolved through discussion or with a third reviewer. Data was extracted independently by each reviewer from papers included in the review using a Microsoft Excel spreadsheet. Included data included study type, 'r' values, number of subjects and reported 'p' values. These were indexed by author, year and study title. The meta-analysis was performed using the method for effect size analysis from Hunter and Schmidt. The syntax for equations was transposed into a Microsoft Excel spreadsheet for data entry, analysis and graph creation. No articles or paper addressing unique tools for ascertaining critical decision making skills met the inclusion criteria. Standard tools, which were represented in the literature, assess critical decision making skills via prediction of academic and clinical success, which indicates the presence of critical decision making skills in graduate healthcare students. A total of 16 studies addressing standard tools were included in this review. All were retrospective case series studies. The date range for the included studies was 1970 to 2009. The strongest relationship was undergraduate grade point average's correlation to graduate grade point average (small effect size with an 'r' value of 0.27, credibility interval of 0.18-0.37). The second strongest relationship was between Graduate Record Examination's verbal section and graduate grade point average (small effect size with an r value of 0.24, CrI of 0.11-0.37). An applicant's undergraduate GPA has the strongest correlation with graduate healthcare program success of the indicators analyzed (r = 0.27, small effect size). The next best predictor of graduate healthcare program success was the GRE Verbal score (r = 0.24, small effect size). However, all of the variables carried positive correlations with graduate success, just of lesser effect size strength. This review supports the continued use of traditional indicators of graduate school potential in the undergraduate grade point average and the various sections of the Graduate Record Examination for the selection of graduate healthcare applicants. Primary studies should be funded and performed to assess the use of unique tools in assessing critical thinking in graduate healthcare students.


Homogeneous blue pigmentation in dermatofibroma simulating a blue naevus.
A case with a pigmented skin lesion that was diagnosed as a blue naevus on clinical and dermoscopic grounds and histopathologically confirmed as a dermatofibroma is presented. By means of this case, we define dermatofibroma as a new exception for 'homogeneous blue pigmentation' on dermoscopy.


Bilateral acute depigmentation of the iris.
To report on five cases of unusual bilateral stromal depigmentation of the iris and pigment dispersion masquerading as uveitis. We describe the clinical features of five consecutive patients who presented with acute depigmentation of the iris stroma between June and October 2003. Four patients were female, one was male. Age at presentation ranged from 15 to 25 years. Presenting symptoms were sudden-onset ocular discomfort and red eye in four patients and change of eye color in one patient. All patients had bilateral involvement, with a symmetrical diffuse depigmentation of the iris stroma in three cases and patchy areas of iris depigmentation in two. Other common features were mild ciliary injection (seven eyes), Krukenberg spindle (seven eyes), circulating pigment in the anterior chamber (eight eyes), and heavy pigment deposition in the angle (ten eyes). No eyes had iris transillumination defects, inflammatory keratic precipitates or inflammatory cells in the anterior chamber. Systemic laboratory work-up was unrewarding in all cases, and PCR analysis of the aqueous humor for HSV1 and 2 was negative in one patient. Four patients were treated with a short course of topical corticosteroids and three with oral acyclovir. One patient was lost to follow-up. The remaining four patients were followed up for 6-19 months with a stable clinical picture. In contrast to pigment dispersion syndrome, pigment seemed to be released from iris stroma in the five cases described here. Although patchy depigmentation of the iris resembled the lesions seen in herpetic iridocyclitis in two of the patients, symmetrical bilateral involvement and lack of intraocular inflammation were the differentiating features. The patients described here could represent a new entity or an unusual presentation of herpetic eye disease.


Investigation with able-bodied subjects suggests Myosuit may potentially serve as a stair ascent training robot.
Real world settings are seldomly just composed of level surfaces and stairs are frequently encountered in daily life. Unfortunately, ~ 90% of the elderly population use some sort of compensation pattern in order to negotiate stairs. Because the biomechanics required to successfully ascend stairs is significantly different from level walking, an independent training protocol is warranted. Here, we present as a preliminary investigation with 11 able-bodied subjects, prior to clinical trials, whether Myosuit could potentially serve as a stair ascent training robot. Myosuit is a soft wearable exosuit that was designed to assist the user via hip and knee extension during the early stance phase. We hypothesized that clinical studies could be carried out if the lower limb kinematics, sensory feedback via plantar force, and electromyography (EMG) patterns do not deviate from the user's physiological stair ascent patterns while reducing hip and knee extensor demand. Our results suggest that Myosuit conserves the user's physiological kinematic and plantar force patterns. Moreover, we observe approximately 20% and 30% decrease in gluteus maximus and vastus medialis EMG levels in the pull up phase, respectively. Collectively, Myosuit reduces the hip and knee extensor demand during stair ascent without any introduction of significant compensation patterns.


Self-perceived halitosis among young adults undergoing orthodontic treatment.
Halitosis is a common oral health problem that significantly impacts the quality of life of the affected individuals. In most cases, poor oral hygiene is responsible for the problem. Orthodontic therapy aims to correct malocclusion using different devices. It has been suggested that orthodontic treatment can promote gingival health by facilitating daily oral hygiene measures. However, the treatment may harm gingival health as these appliances may lead to a more significant accumulation of plaque, increasing the microbial load in the subgingival environment leading to halitosis. The primary goal of this survey is to assess the prevalence of self-perceived halitosis in patients undergoing orthodontic treatment. An online questionnaire was randomly distributed to patients undergoing orthodontic treatment. A total of 289 subjects completed the questionnaire. It included questions about: demographic data, medical history, social habits, past dental treatment and oral hygiene habits. Descriptive statistics as frequency distributions and percentages were calculated for the study variables. The prevalence of self-perceived halitosis was 41.5%. The majority of the participants started to notice this problem during and after orthodontic treatment (62.5%). A statistically significant correlation was found between the regular dental visits and halitosis in patients with fixed orthodontic appliances (p-value = 0.010). Also, those patients had a substantial increase in tongue coating formation (p- value = 0.010). Self-perceived halitosis is a common problem in patients receiving orthodontic treatment.


Integration of transcriptomics and metabolomics analysis for unveiling the toxicological profile in the liver of mice exposed to uranium in drinking water.
Uranium is a contaminate in the underground water in many regions of the world, which poses health risks to the local populations through drinking water. Although the health hazards of natural uranium have been concerned for decades, the controversies about its detrimental effects continue at present since it is still unclear how uranium interacts with molecular regulatory networks to generate toxicity. Here, we integrate transcriptomic and metabolomic methods to unveil the molecular mechanism of lipid metabolism disorder induced by uranium. Following exposure to uranium in drinking water for twenty-eight days, aberrant lipid metabolism and lipogenesis were found in the liver, accompanied with aggravated lipid peroxidation and an increase in dead cells. Multi-omics analysis reveals that uranium can promote the biosynthesis of unsaturated fatty acids through dysregulating the metabolism of arachidonic acid (AA), linoleic acid, and glycerophospholipid. Most notably, the disordered metabolism of polyunsaturated fatty acids (PUFAs) like AA may contribute to lipid peroxidation induced by uranium, which in turn triggers ferroptosis in hepatocytes. Our findings highlight disorder of lipid metabolism as an essential toxicological mechanism of uranium in the liver, offering insight into the health risks of uranium in drinking water.


Perinatal management of critical aortic valve stenosis diagnosed by fetal echocardiography.
A case of critical aortic valve stenosis was diagnosed in utero by echocardiography and managed successfully by early elective caesarean section and aortic valvotomy.


Measurement of left portal vein blood-flow velocity by Doppler sonography in a patient with acute fatty liver of pregnancy.
Acute fatty liver of pregnancy was diagnosed in a 32-year-old primipara in her 34th week of gestation. The pulsed Doppler sonogram showed that mean maximum portal blood-flow velocity obtained at the umbilical-point of the left portal vein (the U-point) decreased during the acute phase of the disease and returned to the normal range accompanied by improvement in her condition. Findings of portal blood dynamics obtained by pulsed Doppler sonography and those of the hyperechoic hepatic parenchyma obtained by conventional sonography could prove useful in following up patients in their third trimester of pregnancy.


Reference markers of bone turnover for prediction of fracture: a meta-analysis.
To explore whether bone turnover biomarkers (BTMs), i.e., C-terminal telopeptide of type I collagen (CTX) and procollagen type I aminoterminal propeptide (PINP), are associated with fracture. We searched electronic database including PubMed, Embase and Cochrane Library, and the reference lists of relevant articles published from inception to August 22, 2018. An updated meta-analysis was performed to assess the prediction value of CTX and PINP in fracture. Nine articles met our inclusion criteria and were included in the meta-analysis. The crude and adjusted effect size between PINP and fracture were extracted from two and five studies, respectively. PINP was not associated with fracture incidence without adjusting covariates (crude GR, 1.03; 95% CI, 0.91-1.17). After adjusting for potential confounders, PINP demonstrated a significant positive association with fracture (adjusted GR, 1.28; 95% CI, 1.15-1.42). In the subgroup analysis of studies after adjusting covariates, there were significant associations in women. Both the crude (1.16, 95%CI, 1.04-1.20) and adjusted GR (1.20, 95%CI, 1.05-1.37) shown positive relationships between CTX and fracture, which were extracted from four and six studies, separately. The sensitivity analysis confirmed the stability of the results. In the subgroup analysis of studies after adjusting covariates, there were significant associations in the subgroups of elderly, female, and hip fracture patients. Our results indicate a statistically significant but modest association between BTMs (s-PINP or s-CTX) and future fracture risk after adjusting for BMD and clinical risk factors. The causal relationship between the two clinical conditions requires future validation with more standardized studies. CRD42018107879.


Alcohol use and grey matter structure: Disentangling predispositional and causal contributions in human studies.
Alcohol use is a growing global health concern and economic burden. Alcohol involvement (i.e., initiation, use, problematic use, alcohol use disorder) has been reliably associated with broad spectrum grey matter differences in cross-sectional studies. These findings have been largely interpreted as reflecting alcohol-induced atrophy. However, emerging data suggest that brain structure differences also represent pre-existing vulnerability factors for alcohol involvement. Here, we review evidence from human studies with designs (i.e., family-based, genomic, longitudinal) that allow them to assess the plausibility that these correlates reflect predispositional risk factors and/or causal consequences of alcohol involvement. These studies provide convergent evidence that grey matter correlates of alcohol involvement largely reflect predisposing risk factors, with some evidence for potential alcohol-induced atrophy. These conclusions highlight the importance of study designs that can provide causal clues to cross-sectional observations. An integrative model may best account for these data, in which predisposition to alcohol use affects brain development, effects which may then be compounded by the neurotoxic consequences of heavy alcohol use.


Bioclimate change across the protected area network of Finland.
Protected areas (PAs) are crucial in conserving biodiversity under climate change. In boreal regions, trends of biologically relevant climate variables (i.e., bioclimate) in PAs have remained unquantified. We investigated the changes and variability of 11 key bioclimatic variables across Finland during the period 1961-2020 based on gridded climatology. Our results suggest significant changes in annual mean and growing season temperatures over the entire study area, whereas, e.g., annual precipitation sum and April-September water balance have increased especially in the central and northern parts of Finland. We found substantial variation in bioclimatic changes over the 631 studied PAs; in the northern boreal zone (NB) the number of snow-covered days has decreased on average by 5.9 days between 1961-1990 and 1991-2020, while in the southern boreal zone (SB) the corresponding decrease has been 16.1 days. The number of frost days in spring with absent snow cover has decreased in the NB (on average -0.9 days) while increasing in the SB (0.5 days), reflecting the changing exposure of biota to frost. The observed increases in accumulation of heat in the SB and more frequent rain-on-snow events in the NB can affect drought tolerance and winter survival of species, respectively. Principal component analysis suggested that the main dimensions of bioclimate change in PAs vary across vegetation zones; for example, in the SB the changes are related to annual and growing season temperatures, whereas in the middle boreal zone the changes are linked to altered moisture and snow conditions. Our results highlight the substantial spatial variation in bioclimatic trends and climate vulnerability across the PAs and vegetation zones. These findings provide a basis for the understanding of the multifaceted changes the boreal PA network is facing and help to develop and direct conservation and management.


Resolving Fine-Scale Heterogeneity of Co-seismic Slip and the Relation to Fault Structure.
Fault slip distributions provide important insight into the earthquake process. We analyze high-resolution along-strike co-seismic slip profiles of the 1992 Mw = 7.3 Landers and 1999 Mw = 7.1 Hector Mine earthquakes, finding a spatial correlation between fluctuations of the slip distribution and geometrical fault structure. Using a spectral analysis, we demonstrate that the observed variation of co-seismic slip is neither random nor artificial, but self-affine fractal and rougher for Landers. We show that the wavelength and amplitude of slip variability correlates to the spatial distribution of fault geometrical complexity, explaining why Hector Mine has a smoother slip distribution as it occurred on a geometrically simpler fault system. We propose as a physical explanation that fault complexity induces a heterogeneous stress state that in turn controls co-seismic slip. Our observations detail the fundamental relationship between fault structure and earthquake rupture behavior, allowing for modeling of realistic slip profiles for use in seismic hazard assessment and paleoseismology studies.


A modified T-vector for simplified assembly of hairpin RNAi constructs.
We describe a modified T-vector, pGFPm-T, for direct cloning of RT-PCR products to generate bidirectional restriction fragments for assembly of hairpin-containing RNAi vectors in the popular pFGC and pGSA binary vector backbone. Green fluorescence protein (GFP) is used as a visual reporter for direct selection of recombinants under UV illumination. The simplified cloning process enables a seamless workflow from candidate gene selection and RT-PCR verification to inverted repeat cloning, using a single pair of gene-specific primers.


A comparison of cryopreserved vein allografts and prosthetic grafts for hemodialysis access.
In hemodialysis patients with insufficient vasculature for creation of a native arteriovenous fistula (AVF), a polytetrafluoroethylene (PTFE) graft is commonly utilized. Because of PTFE complications, our group and others have used cryopreserved cadaver femoral vein allografts (Synergraft [SYN], CryoLife, Marietta, GA) in selected patients. Based on our experience with these allografts, we hypothesized that they were more resistant to thrombosis than PTFE grafts. The purpose of this study was to compare the thrombosis rates of SYN and PTFE grafts in a prospective, randomized fashion. Our study was interrupted when the FDA ordered CryoLife, Inc. to retain certain vascular tissue products, and patient accrual stopped in 2003. Most patients referred for hemodialysis access are evaluated with bilateral, upper extremity Doppler ultrasound. Starting in 2001, those with insufficient vasculature for native AVF were offered randomization into the PTFE or SYN groups. All accesses were placed in the upper extremity, above the elbow. Access patency and complications were recorded, and failure was defined as access removal, abandonment, or replacement of > 50% with a new conduit. Prior to FDA interruption of the study, 27 patients were randomized into each group. Patient characteristics were similar, but there were significantly more males and African-Americans in the SYN group. No significant differences were seen in primary or secondary patency, number of thrombectomies, revisions, or total interventions. Significantly more fistulagrams were performed in the SYN group (p < 0.05). No infections were seen in either group, but 2 aneurysms occurred in the SYN group. Nine (33%) patients in each group died with functioning access. Access failures: In the SYN group, 8 of 27 (30%) failed, with 5 failing from multiple access stenoses unresponsive to balloon angioplasty; in the PTFE group 4 of 27 (18%) failed, with 2 failing from multiple stenoses. In conclusion, for initial hemodialysis access in patients without sufficient vasculature for native AVF, our results do not support the routine use of SYN allografts in the general dialysis population.


Bioactive materials: In vitro investigation of different mechanisms of hydroxyapatite precipitation.
Bioactive materials, able to induce hydroxyapatite precipitation in contact with body fluids, are of great interest for their bone bonding capacity. . The aim of this paper is to compare bioactive materials with different surface features to verify the mechanisms of action and the relationship with kinetics and type of precipitated hydroxyapatite over time. Four different surface treatments for Ti/Ti6Al4V alloy and a bioactive glass were selected and a different mechanism of bioactivity is supposed for each of them. Apart from the conventional techniques (FESEM, XPS and EDX), less common characterizations (zeta potential measurements on solid surfaces and FTIR chemical imaging) were applied. The results suggest that the OH groups on the surface have several effects: the total number of the OH groups mainly affects hydrophilicity of surfaces, while the isoelectric points, surface charge and ions attraction mainly depend on OH acidic/basic strength. Kinetics of hydroxyapatite precipitation is faster when it involves a mechanism of ion exchange while it is slower when it is due to electrostatic effects . The electrostatic effect cooperates with ion exchange and it speeds up kinetics of hydroxyapatite precipitation. Different bioactive surfaces are able to differently induce precipitation of type A and B of hydroxyapatite, as well as different degrees of crystallinity and carbonation. STATEMENT OF SIGNIFICANCE: The bone is made of a ceramic phase (a specific type of hydroxyapatite), a network of collagen fibers and the biological tissue. A strong bond of an orthopedic or dental implant with the bone is achieved by bioactive materials where precipitation and growth of hydroxyapatite occurs on the implant surface starting from the ions in the physiological fluids. Several bioactive materials are already known and used, but their mechanism of action is not completely known and the type of precipitated hydroxyapatite not fully investigated. In this work, bioactive titanium and bioglass surfaces are compared through conventional and innovative methodologies. Different mechanisms of bioactivity are identified, with different kinetics and the materials are able to induce precipitation of different types of hydroxyapatite, with different degree of crystallinity and carbonation.


Effects of cerebellar vermal lesions on species-specific fear responses, neophobia, and taste-aversion learning in rats.
The cerebellar vermis has extensive anatomical connections with many brain stem and forebrain structures which have been implicated in emotional or affective behavior. Previous reports indicate that lesions of the vermis in a variety of experimental animals result in altered emotional behavior. The studies reported here attempted to clarify the nature of the change in emotional behavior following vermal lesions in rats by testing the animals in a variety of fear-eliciting situations. As compared with controls, vermal-lesioned rats froze less in the presence of a cat and showed fewer signs of fear in an open field. However, their responses to footshock did not differ fundamentally from controls. They recovered more quickly than controls from the neophobic response to a novel taste but showed robust taste-aversion learning. The results are discussed in terms of the role of the cerebellum in the modulation of fear-related behaviors and in terms of similarities and differences with the effects of amygdala lesions. The results expand the body of data implicating the cerebellum in the modulation of complex motivational behavior.


Increased belongingness among college students during COVID-19: a potential cohort effect?
Speculation about the effects of COVID-19, especially on youth social development, has been mixed. This study aimed to examine change in loneliness and belongingness into the first month of stay-at-home orders (January through April 2020). College students (N = 73, mean age = 19.03 years, SD = 1.44 years) enrolled in a life-span development course. Participants completed online surveys at the beginning and the end of the semester assessing change in well-being. Results revealed that loneliness scores significantly decreased, and belongingness scores significantly increased from Time 1 to Time 2. Among those who experienced increased belongingness, loneliness significantly decreased while there was not a significant change in loneliness among those who decreased in belongingness. These findings suggest that increasing belongingness should be a focus when trying to combat loneliness, especially in young adults experiencing a dramatic life event during a critical time for social development.


Basic principles for the development of a common standardised method for determining the radon diffusion coefficient in waterproofing materials.
Paper presents the principles for unified test methods for determining the radon diffusion coefficient in waterproof materials in order to increase the accuracy, repeatability and reproducibility of the results. We consider this very important, because an assessment of the radon diffusion coefficient is required by several national technical standards when waterproofing acts as a radon-proof membrane. The requirements for key parameters for one test method performed under non-stationary conditions and for two methods performed under stationary conditions are described in this paper.


Synthesis and anti-HSV-1 evaluation of new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines.
Herpes simplex virus type-1 (HSV-1) is the primary cause of facial lesions (mouth, lips, and eyes) in humans. The widespread use of acyclovir and nucleoside analogues has led to emergence of HSV strains that are resistant to these drugs. Recently, non-nucleoside anti-HSV compounds have received considerable attention. 1,6-Naphthyridines are a class of heterocyclic compounds that exhibit a broad spectrum of biological activities such as inhibitor of HIV-1 integrase, HCMV, FGF receptor-1 tyrosine kinase, and the enzyme acetylcholinesterase. We previously reported the synthesis, SAR studies, and evaluation anti-HSV-1 activity of 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines. In the course of our search for new 1,6-naphthyridines derivatives with potential activity against HSV-1, we have synthesized and evaluated new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c). A known synthetic approach was used for preparing new 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines (1a-k) and 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines (2a-c), starting from ethyl 4-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (7). All compounds were identified by FTIR, 1H NMR, and mass spectrometry. The antiviral effect on HSV-1 virus replication was determined. The compounds 1d, 1f, 1g, and 1h exhibited the highest anti-HSV-1 activity. In general, 3H-benzo[b]pyrazolo[3,4-h]-1,6-naphthyridines were more effective inhibitors than their corresponding 3H-pyrido[2,3-b]pyrazolo[3,4-h]-1,6-naphthyridines. The compound 1h reduced the virus yield in 91% at 50 μM and exhibited a low cytotoxicity (CC50 600 μM).


Subdural hematoma secondary to ruptured intracranial aneurysm: computed tomographic diagnosis.
This case report illustrates a cerebral aneurysm that bled into the subdural space without any clinical or radiographic evidence of subarachnoid hemorrhage. Both the aneurysm and the subdural hematoma were easily demonstrated on computed tomography scan. The incidence of this lesion and its possible etiology are discussed.


A general chemical method to regulate protein stability in the mammalian central nervous system.
The ability to make specific perturbations to biological molecules in a cell or organism is a central experimental strategy in modern research biology. We have developed a general technique in which the stability of a specific protein is regulated by a cell-permeable small molecule. Mutants of the Escherichia coli dihydrofolate reductase (ecDHFR) were engineered to be degraded, and, when this destabilizing domain is fused to a protein of interest, its instability is conferred to the fused protein resulting in rapid degradation of the entire fusion protein. A small-molecule ligand trimethoprim (TMP) stabilizes the destabilizing domain in a rapid, reversible, and dose-dependent manner, and protein levels in the absence of TMP are barely detectable. The ability of TMP to cross the blood-brain barrier enables the tunable regulation of proteins expressed in the mammalian central nervous system.


Repression of the mitochondrial peroxiredoxin antioxidant system does not shorten life span but causes reduced fitness in Caenorhabditis elegans.
The mitochondrial free radical theory of aging proposes that aging is a consequence of progressive mitochondrial dysfunction caused by lifelong accumulation of oxidative damage. Aging is therefore expected to accelerate if the rate of this oxidative damage accumulation increases. Studies attempting to test this prediction through modulation of oxidative damage by altering antioxidant defenses have reported conflicting results. Here we investigated the effects of repressing prdx-3, responsible for the detoxification of mitochondrial hydrogen peroxide, in developmentally normal wild-type Caenorhabditis elegans. We report that life span and levels of oxidative protein damage were not altered when prdx-3 was repressed in adult nematodes. We further found evidence that mitochondrial uncoupling increased in response to repression of prdx-3. Nevertheless repression of prdx-3 led to reductions in steady-state levels of ATP, motility, and brood size, indicating the importance of this enzyme to normal life in C. elegans.


Allergy to pollen from different deciduous trees in Sweden. An investigation with skin tests, provocation tests and the radioallergosorbent test (RAST) in springtime hay fever patients.
92 adult patients with springtime allergy were investigated with skin tests, provocation tests and the RAST. Allergen extracts from 12 different deciduous trees were used. Positive reactions, often of high intensity, were most often found with birch, alder, bog-myrtle, beech and hazel allergens whereas oak, aspen, linden, elm, sallow, maple and poplar allergens more often gave negative or only weak positive test results. Cross sensitizations were found between botanically related as well as between less related species of the trees. Almost all patients with a clinically relevant tree pollen allergy had positive provocation tests with birch pollen. No patient had positive reactions to all the 12 allergens included in the study. 68% had positive provocation tests with the combination birch, alder and hazel. It is concluded that for diagnostic screening purposes it is sufficient to use birch pollen allergen. If the majority of relevant tree pollens are to be included in a diagnostic or therapeutic programme in Western Sweden it should contain birch, alder, hazel, beech and bog-myrtle allergens.


[Microfluorimetric analysis of dynamics of genomic changes of Chinese hamster fibroblasts CHL V-79 RJK with multidrug resistance].
Results of karyological analysis of cells CHL V-79 RJK selected for resistance to ethidium bromide (EB) causing multidrug resistance (MDR) (line Vebr-5) were compared with the data of microfluorimetric determination of DNA content in individual chromosomes of the karyotype. The analysis was performed at the 11th and 88th passages. Karyotyping of Vebr-5 has shown the presence of an additional genetic material (ADM) in the form of homogenously or differentially stained regions (HSRs and DSRs, respectively) in two chromosomes (Z1 and Z6, loci 1 p29-31 and 1q26, respectively). HSRs in Z6, in the region of localization of the wild type of gene mdr, had unstable length and structure characteristic of morphological markers of amplification of genes of the family mdr. During long cultivation of Vebr-5 in the presence of EB (88 passages), the instability of HSRs in Z6 increased. Results of microfluorimetric analysis of Vebr-5 at the 11th passage have shown an increase in the DNA content not only in chromosomes Z1 and Z6 marked by HSRs, but also in three chromosomes (Z5, Z12 and Z13) that have no visual morphological changes. The corresponding analysis at the 88th passage has also revealed non-random changes in the DNA content in four more chromosomes: an increase in Z14, while a decrease in chromosomes 8, Z7, and Z9. A decrease of the DNA content in chromosomes is considered to be a result of a partial loss of genetic material, while its increase is a result of its translocation and (or) amplification. Coefficient of variation of the DNA content changes for large chromosomes amounted to about 9%. while for small chromosomes it is about 26%, which indicates that small chromosomes have greater potential for instability than the large ones. The data obtained not only confirm, but also enlarge the concept of directions and character of destabilization of the cell genetic apparatus in the process of neoplastic transformation due to the MDR acquisition by cells.


Persistence of contact allergy among Danish adults: an 8-year follow-up study.
In 1990, a random sample of 567 persons of the 15-69-year-old population living in the Western part of Copenhagen County, Denmark, was patch tested in a cross-sectional study. In 1998, a follow-up study was performed. Out of 540 invited, 365 (68%) were re-patch tested. In the follow-up study, the persistence of allergic contact sensitivity, defined as 1 or more positive patch tests in both surveys, was 71% (37 out of 52 subjects). Nickel allergy persisted in 79% (19 out of 24 subjects), while 60% (21 out of 35 subjects) had a positive patch test reaction to 1 or more allergens, other than nickel, in both surveys. The lowest persistence was 50% (5 out of 10 subjects) and this was found for patch test reactivity to 1 or more of the cosmetic ingredients included in the patch test series. 8 years after the baseline study had demonstrated allergic contact sensitivity, 71% of the subjects still had at least 1 positive patch test. Nickel allergy persisted in 79%. Allergen avoidance should probably be lifelong to prevent elicitation of contact dermatitis.


Pancreas duct abnormalities in patients with ulcerative colitis: a magnetic resonance pancreatography study.
The presumed etiology and prevalence of pancreatic abnormalities in patients with ulcerative colitis (UC) have been controversial. We conducted a controlled (cross-sectional) study of patients with UC compared with non-UC controls to determine the prevalence of pancreatic duct abnormalities in patients with UC and to determine if these are specific to UC using magnetic resonance cholangiopancreatography. Magnetic resonance cholangiopancreatography was performed on 79 unselected patients with UC and 45 non-UC controls, without a history of pancreatitis attack, between February 2000 and May 2003. Among patients with UC, the prevalence of pancreatic duct abnormalities was 16.4% (95% confidence interval, 8.3%-24.6%): coexisting dilatation and narrowing of the main pancreatic duct were found in 5; diffuse narrowing of pancreatic ducts in 5; and dilatation of pancreatic ductal branches in 3. These abnormalities were compatible with chronic pancreatitis. Among the controls, no pancreatic duct abnormality was found. Changes in the pancreatic duct were found in approximately one-sixth of patients with UC, none of whom had a history of overt pancreatitis. These pancreatic duct abnormalities are likely to be specific to patients with UC.


A second B cell-specific enhancer 3' of the immunoglobulin heavy-chain locus.
The expression of immunoglobulin heavy-chain (IgH) genes is generally thought to be regulated by the combination of the VH promoter with the enhancer element which is located in the JH-CH intron. This is probably an oversimplification: there are cell lines that transcribe IgH genes despite the deletion of the intron-enhancer. These findings could imply that other enhancer element(s) exist in the IgH locus. Here we show that a strong B-cell-specific enhancer is indeed located at the 3'-end of the rat IgH locus, 25 kilobases downstream of C alpha. This enhancer should be retained downstream of all rearranged IgH genes, regardless of the VH or CH segment used. Taken together with analogous findings for the mouse kappa locus, the results prompt a re-evaluation of the mechanism of regulation of immunoglobulin gene transcription. Furthermore, unlike the intron-enhancer, the IgH 3' enhancer would become linked to a c-myc that rearranges into an IgH switch region. The IgH 3' enhancer could therefore play a part in the activation of the translocated c-myc genes in rat immunocytomas, mouse plasmacytomas and Burkitt lymphomas.


Association of plasma C-reactive protein with ischaemic stroke: a Mendelian randomization study.
Elevated C-reactive protein (CRP) is associated with an increased risk of ischaemic stroke (IS). However, the causality of this association is uncertain. The aim is to investigate whether genetically raised plasma CRP concentration levels are associated with IS on the basis of the Mendelian randomization method. Based on the National Center for Biotechnology Information single nucleotide polymorphism (SNP) database, the Chinese online genetic database as well as previously published studies, four CRP-associated SNP alleles (rs1130864, rs1205, rs876537 and rs3093059) with minor allele frequency ≥0.15 were selected and the concentration levels of CRP were measured in 378 first-ever IS patients and 613 healthy controls. Three SNPs were chosen and used as instrumental variables. The adjusted odds ratios (ORs) [95% confidence interval (95% CI)] of IS per addition of the modelled allele were 1.07 (0.79-1.45) for rs876537, 0.99 (0.73-1.35) for rs1205 and 1.08 (0.71-1.65) for rs3093059. The OR (95% CI) of IS for plasma CRP ≥2.0 mg/l was 2.19 (1.06-4.53) compared with <2.0 mg/l. The adjusted OR (95% CI) of IS per genetically predicted 10% higher CRP concentration, based on the three SNPs as the instruments, was 1.02 (0.94-1.11). Furthermore, similar results were obtained with adjusted ORs (95% CI) of 1.00 (0.88-1.13) and 1.04 (0.93-1.16), respectively, for large-artery atherosclerosis and small-artery occlusion per genetically predicted 10% higher CRP concentration. This Mendelian randomization study provides no clear support that elevated CRP concentration is causally associated with the risk of IS.


Syndactyly with Larsen's syndrome.
The association of syndactyly with Larsen's syndrome is reported. A revised listing of syndromes which may be associated with syndactyly is presented.


Chemotherapy promotes astrocytic response to Aβ deposition, but not Aβ levels, in a mouse model of amyloid and APOE.
Many cancer survivors experience cancer-related cognitive impairment (CRCI), which is characterized by problems of attention, working memory, and executive function following chemotherapy and/or hormonal treatment. APOE4, the strongest genetic risk factor for Alzheimer's Disease (AD), is also a risk factor for CRCI, especially among survivors exposed to chemotherapy. We explored whether the effects of APOE genotype to chemotherapy were associated with an increase in AD pathological processes, using a mouse model of amyloid (5XFAD) along with the E3 or E4 alleles of human APOE (E3FAD and E4FAD). Six-month-old female E3FAD mice (control n = 5, treated n = 5) and E4FAD (control n = 6, treated n = 6) were treated with two doses of doxorubicin (total 10 mg/kg) or DMSO vehicle. After six weeks, mice were euthanized and brains were analyzed by immunohistochemistry and biochemical assays. Doxorubicin-treated mice had the same level of Aβ in the brain as control mice, as measured by 6E10 immunohistochemistry, Aβ40 and Aβ42 ELISAs, and plaque morphologies. Doxorubicin significantly increased the level of the astrocytic response to Aβ deposits, which was independent of APOE genotype; no effects of doxorubicin were observed on the microglial responses. These data are consistent with a model in which the effects of doxorubicin on risk of CRCI are unrelated amyloid accumulation, but possibly related to glial responses to damage.


Flow-induced phase effects and compensation technique for slice-selective pulses.
Flowing spins experience a time-varying frequency during the application of slice-selective radiofrequency (RF) pulses. As a result the flowing spins accumulate phase relative to stationary spins as the spins are rotated toward the transverse plane. Using finite difference techniques to solve the Bloch equations for flowing spins, the phase of the transverse magnetization after a slice-selective pulse was evaluated for varying flow velocities and for tip angles which ranged between 0 degrees and 180 degrees. The following results were obtained for constant slice thickness: (1) For a fixed tip angle, the phase varies nonlinearly with velocity. (2) For a fixed velocity, the phase varies nonlinearly with tip angle. For small tip angles the nonlinearity in the variation as a function of velocity is very small but increases for tip angles greater than 90 degrees and becomes especially severe near 180 degrees. A method is proposed to desensitize the phase of flowing spins during the application of slice-selective pulses. The compensation scheme depends upon tip angle but is virtually independent of flow velocity. The technique was tested and verified with clinical images.


Sensitive electrochemical detection of A549 exosomes based on DNA/ferrocene-modified single-walled carbon nanotube complex.
Exosome is an emerging tumor marker, whose concentration level can reflect the occurrence and development of tumors. The development of rapid and sensitive exosome detection platform is of great significance for early warning of cancer occurrence. Here, a strategy for electrochemical detection of A549-cell-derived exosomes was established based on DNA/ferrocene-modified single-walled carbon nanotube complex (DNA/SWCNT-Fc). DNA/SWCNT-Fc complexes function as a signal amplification platform to promote electron transfer between electrochemical signal molecules and electrodes, thereby improving sensitivity. At the same time, the exosomes can be attached to DNA/SWCNT-Fc nanocomposites via the established PO43--Ti4+-PO43- method. Moreover, the application of EGFR antibody, which can specifically capture A549 exosomes, could improve the accuracy of this sensing system. Under optimal experimental conditions, the biosensor showed good linear relationship between the peak current and the logarithm of exosomes concentration from 4.66 × 106 to 9.32 × 109 exosomes/mL with a detection limit of 9.38 × 104 exosomes/mL. Furthermore, this strategy provides high selectivity for exosomes of different cancer cells, which can be applied to the detection of exosomes in serum samples. Thus, owing to its advantages of high sensitivity and good selectivity, this method provides a diversified platform for exosomes identification and has great potential in early diagnosis and biomedical applications.


Tuberose sclerosis complex: analysis of growth rates aids differentiation of renal cell carcinoma from atypical or minimal-fat-containing angiomyolipoma.
To study the radiological characteristics of renal masses in individuals with tuberous sclerosis complex (TSC) using serial CT, and to examine how renal cell carcinoma (RCC) may be differentiated from indeterminate cysts or masses. This was a retrospective study of 12 cases of TSC in which dedicated renal CT followed after US had demonstrated cystic or sonographically unusual renal masses. The CT density of all masses was measured and the masses categorized as simple cysts, complex cysts, angiomyolipomas or indeterminate solid masses. Subjects were maintained on regular follow-up with repeat CT or MRI and interval renal US. Indeterminate masses that showed rapid growth were considered suspicious for renal cell carcinoma and biopsy or nephrectomy followed. Comparative data were available for a median of 4 years. In each case the renal masses were multiple and bilateral; mean mass diameter was 3.6 cm. Among a total of 206 masses, 18 were simple cysts and 3 were complex cysts. Of the complex cysts, 1 proved to be an angiomyolipoma on histology and the other 2 showed no growth. Of the solid masses, 133 were typical angiomyolipomas (AMLs) and 52 were indeterminate. On follow-up, only 3 indeterminate masses showed rapid growth (>0.5 cm/year), of which only 1 proved to be an RCC on biopsy. The other 2 were minimal-fat AMLs, and the remainder of the masses showed no or slow growth. Many renal masses associated with TSC are radiologically indeterminate. A growth threshold of >0.5 cm/year identified the only RCC in this study (0.5% of all masses). Yearly radiological follow-up of indeterminate renal masses is recommended for individuals with TSC.


The epidemiology of injuries in English professional squash; A retrospective analysis between 2004 and 2015.
There have been no reported comprehensive injury reports of elite squash players during training and competition. We reviewed the reported injuries during training and competition during 2004-2015. A retrospective analysis of the injury records was carried out between the periods of 2004-2015 of all athletes who were funded by England squash. In competition and training. Elite England Squash players, 67 athletes (45 males, 22 females), with an age range of 18-35 (average 25 years). The players' age, sex, location, region affected and description of each injury. Injury data was collected from The main region of the body injured was the lower limb: 76.48%, broken down further as: ankle/heel - 20.81%; thigh - 12.69%; knee -10.83%; hip/groin - 9.48%; buttock - 7.45%; lower leg - 7.61%; and foot - 7.61%. Professional squash players have a high incidence of lower limb injuries from participation in their sport. The majority of these injuries occur around the ankle and heel, and are of soft tissue in nature.


Limited humoral and cellular responses to Q fever vaccination in older adults with risk factors for chronic Q fever.
In the Netherlands, people at risk for chronic Q fever were vaccinated against Coxiella burnetii with the inactivated whole cell vaccine Q-vax®. We aimed to measure the immune responses to C. burnetii six and twelve months after vaccination in this relevant population. In 260 vaccinees, antibody responses were assessed by immunofluorescence assay (IFA), complement fixation test and ELISA. The cellular immune responses were assessed by measuring C. burnetii-specific interferon (IFN)-γ production in blood. Serological results of 200 individuals with past Q fever were used for comparison. At six months, 46% of vaccinees showed low IFA antibody titres and 67% had a positive IFN-γ assay; At twelve months, both were 60%. In contrast, individuals with a past Q fever were seropositive in 99.5% at six and twelve months, with relatively higher IFA titres. Interestingly, vaccinees with positive IFN-γ assay pre-vaccination, showed a higher seroconversion rate than IFN-γ negative vaccinees: 74% vs. 41% (p < 0.001). The immune response after Q-vax® vaccination is lower and restricted to a smaller proportion than found after past Q fever and than previously described after vaccination, suggesting decreased vaccine immunogenicity in this high-risk population. A positive IFN-γ assay before vaccination in seronegative vaccinees likely points to pre-existing immunity resulting in boosting by vaccination.


Diabetic retinopathy: a quadtree based blood vessel detection algorithm using RGB components in fundus images.
Blood vessel detection in retinal images is a fundamental step for feature extraction and interpretation of image content. This paper proposes a novel computational paradigm for detection of blood vessels in fundus images based on RGB components and quadtree decomposition. The proposed algorithm employs median filtering, quadtree decomposition, post filtration of detected edges, and morphological reconstruction on retinal images. The application of preprocessing algorithm helps in enhancing the image to make it better fit for the subsequent analysis and it is a vital phase before decomposing the image. Quadtree decomposition provides information on the different types of blocks and intensities of the pixels within the blocks. The post filtration and morphological reconstruction assist in filling the edges of the blood vessels and removing the false alarms and unwanted objects from the background, while restoring the original shape of the connected vessels. The proposed method which makes use of the three color components (RGB) is tested on various images of publicly available database. The results are compared with those obtained by other known methods as well as with the results obtained by using the proposed method with the green color component only. It is shown that the proposed method can yield true positive fraction values as high as 0.77, which are comparable to or somewhat higher than the results obtained by other known methods. It is also shown that the effect of noise can be reduced if the proposed method is implemented using only the green color component.


Surfactants: past, present and future.
In 1929 Kurt von Neergaard performed experiments suggesting the presence of pulmonary surfactant and its relevance to the newborn's first breath. Almost 25 years later, Richard Pattle, John Clements and Chris Macklin, each working on the effects of nerve gases on the lungs, contributed to the understanding of the physiology of pulmonary surfactant. About 5 years later Mary Ellen Avery and Jere Mead published convincing evidence that preterm neonates dying of hyaline membrane disease (respiratory distress syndrome, RDS) had a deficiency of pulmonary surfactant. The first trials of nebulized synthetic (protein-free) surfactant to prevent RDS were published soon after Patrick Bouvier Kennedy (son of President John F Kennedy) died of this disorder after treatment in Boston. These trials were unsuccessful; however, Goran Enhorning and Bengt Robertson in the early 1970s demonstrated that natural surfactants (containing proteins) were effective in an immature rabbit model of RDS. Soon after this Forrest Adams showed that a natural surfactant was also effective in an immature lamb model. Working with him was Tetsuro Fujiwara who 2 years later, after returning to Japan, published the seminal article reporting the responses of 10 preterm infants with RDS to a bolus of modified bovine surfactant. During the 1980s there were numerous randomized controlled trials of many different natural and synthetic surfactants, demonstrating reductions in pulmonary air leaks and neonatal mortality. Subsequently natural surfactants were shown to be superior to the protein-free synthetic products. Recently there have been a number of randomized trials comparing different natural surfactant preparations. Commercially available bovine surfactants may have similar efficacy but there is some evidence that a porcine surfactant used to treat RDS with an initial dose of 200 mg per kg is more effective than a bovine surfactant used in an initial dose of 100 mg per kg. Bovine and porcine surfactants have not been compared in trials of prophylaxis. Very recently a new synthetic surfactant with a surfactant protein mimic has been compared with other commercially available natural and synthetic surfactants in two trials. The new surfactant may be superior to one of the older protein-free synthetic surfactants but there is no evidence of its superiority over established natural products and it is currently not approved for clinical use. A number of other new synthetic surfactants have been tested in animal models or in treatment of adults with ARDS, but so far there have been no reports of treatment of neonatal RDS. Natural surfactants work best if given by a rapid bolus into the lungs but less invasive methods such as a laryngeal mask, pharyngeal deposition or rapid extubation to CPAP have showed promise. Unfortunately, delivery of surfactant by nebulization has so far been ineffective. Surfactant treatment has been tried in a number of other neonatal respiratory disorders but only infants with meconium aspiration seem to benefit although larger and more frequent doses are probably needed to demonstrate improved lung function. A surfactant protocol based upon early treatment and CPAP is suggested for very preterm infants. Earlier treatment may improve survival rates for these infants; however, there is a risk of increasing the prevalence of milder forms of chronic lung disease. Nevertheless, surfactant therapy has been a major contribution to care of the preterm newborn during the past 25 years.


A novel nanobody-based bio-assay using functional complementation of a split nanoluciferase to monitor Mu- opioid receptor activation.
The Mu opioid receptor (MOR) has been the subject of intense research over the past decades, especially in the field of analgesic therapeutics. It is the primary target for both clinical and recreational opioids. Recently, camelid-derived nanobodies have received significant attention due to their applicability in stabilizing the crystal structure of activated MOR, via specific recognition of and binding to the active receptor conformation. In the present study, we developed and applied a novel bio-assay to monitor MOR activation, utilizing intracellular expression of one such nanobody, Nb39. The principle of functional complementation of a split nanoluciferase was used to assess recruitment of Nb39 to MOR, following activation by a set of five synthetic opioids. The obtained pharmacological parameters-negative logarithm of EC50 (pEC50, as a measure of potency) and maximal response provoked by a ligand (Emax, as a measure of efficacy; relative to hydromorphone)-were compared with those obtained using a G protein recruitment assay, in which a mini-Gi protein (engineered GTPase domain of Gαi subunit) is recruited to activated MOR. Similar EC50 but distinct Emax values were obtained with both bio-assays, with lower Emax values for the Nb-based bio-assay. Both bio-assays may assist to gain better insight into activation of the MOR. Graphical abstract.


Super-Resolution Microscopy and Particle-Tracking Approaches for the Study of Vesicular Trafficking in Primary Neutrophils.
Neutrophils are short-lived cells after isolation. The analysis of neutrophil vesicular trafficking requires rapid and gentle handling. Recently developed super-resolution microscopy technologies have generated unparalleled opportunities to help understand the molecular mechanisms regulating neutrophil vesicular trafficking, exocytosis, and associated functions at the molecular level. Here, we describe super-resolution and total internal reflection fluorescence (TIRF) microscopy approaches for the analysis of vesicular trafficking and associated functions of primary neutrophils.


Prognostic significance of delirium in patients with heart failure: a systematic review and meta-analysis.
Delirium is a common symptom of heart failure (HF) and is associated with increased mortality, prolonged hospital stays, and heightened medical costs. The impact of delirium on the prognosis of HF patients is currently controversial. Therefore, we conducted a meta-analysis to evaluate the prognostic significance of delirium in HF. Relevant articles were systematically searched in PubMed, Cochrane Library, Web of Science, and Embase based on the PRISMA guidelines. Studies that reported mortality and hospitalization-related outcomes in HF patients with or without delirium using raw or adjusted hazard ratio (HR) and odds ratio (OD) were included. Meta-analysis was then performed to evaluate the effect of delirium in HF patients. Outcomes of interest were all-cause mortality and events of the hospitalization. Of the 1,501 studies identified, 7 eligible studies involving 12,830,390 HF patients (6,322,846 males and 6,507,544 females) were included in the meta-analysis. There were 91,640 patients with delirium (0.71%) and 12,738,750 patients without delirium (99.28%). HF patients with delirium had higher OR for in-hospital mortality (1.95, 95% CI = 1.30-2.91, P = 0.135), higher pooled HR for 90-day mortality (2.64, 95% CI = 1.06-1.56, P = 0.215), higher pooled HR for 1-year mortality (2.08, 95% CI = 1.34-3.22, P = 0.004), and higher pooled HR for 30-day readmission rate (4.15, 95% CI = 2.85-6.04, P = 0.831) than those without delirium. Current evidence suggests that combined delirium increases the risk of HF-related mortality and hospitalization-related outcomes in patients with HF. However, more research is needed to assess the impact of delirium on the prognosis of HF patients.


Thrombus in Transit within a Patent Foramen Ovale: Gone with the Cough!
Pulmonary embolism and concomitant right atrial thrombus entrapped in a patent foramen ovale (PFO) is a rare, unusual finding in echocardiography. The diagnosis of paradoxical embolism is usually presumptive when PFO is detected by echocardiography. We herein reported a case of a 53-year-old patient presenting with pulmonary embolism in which a thrombusin-transit through a PFO was found and disappeared during transesophageal echocardiography.


The coexistence of acorns with different maturation patterns explains acorn production variability in cork oak.
In dry areas such as Mediterranean ecosystems, fluctuations in seed production are typically explained by resource (water) availability. However, acorn production in cork oak (Quercus suber) populations shows a very low relationship to weather. Because cork oak trees produce acorns with different maturation patterns (annual and biennial), we hypothesized that acorn production in coexisting individuals with a different dominant acorn maturation type should respond differently to climatic factors and that disaggregating the trees according to their acorn-maturation pattern should provide a more proximal relation to weather factors. We assessed acorn production variability in fragmented cork oak populations of the eastern Iberian Peninsula by counting the total number of acorns in 155 trees during an 8-year period. An initial assessment of acorn production variability in relation to weather parameters yielded very low explained variance (7%). However, after the trees were grouped according to their dominant acorn maturation pattern, weather parameters were found to account for 44% of the variability in acorn crops, with trees with annual acorns exhibiting mast fruiting in years with reduced spring frost and shorter summer droughts and trees with biennial acorns showing the opposite pattern. Thus, conditions that negatively affect annual production could be beneficial for biennial production (and vice versa). The results highlight the importance of the resource-matching hypothesis for explaining acorn production in Quercus suber and suggest that different seed maturation types within a population may allow the species to deal with highly variable weather conditions. They also emphasize the importance of understanding acorn maturation patterns for interpreting masting cycles.


Species-specific responses of dew fly larvae to mycotoxins.
The larval stages of saprophagous insects and filamentous fungi have been demonstrated to be serious competitors on decaying organic matter. When filamentous fungi appear to be competitively superior, fungal mycotoxins have frequently been suggested to constitute chemical weapons, causing high mortality among insect larvae. In this study, we tested whether typical fungal secondary compounds can indeed be considered as the underlying mechanism of interference competition between filamentous fungi and various saprophagous Drosophila species. In contrast to our expectation, we found no grand mycotoxin-specific effects, but insect survival appeared to be generally determined by complex interaction between toxin identity, toxin concentration and insect species. Three out of five drosophilids seemed to be equally affected by the mycotoxins used in this study, whereas two species showed toxin-specific changes in survival. Only two (Kojic acid and Ochratoxin A) out of seven mycotoxins caused insect-specific responses. Moreover, we discovered correlations between survival in toxin-free and spoiled substrates, which may indicate an interrelationship between intra-specific competitive ability and resistance to mycotoxins. We discuss the significance of mycotoxins as underlying mechanisms driving competitive insect-fungus interactions.


A retrospective study of congenital osseous anomalies at the craniocervical junction treated by occipitocervical plate-rod systems.
To evaluate the effectiveness of posterior occipitocervical reconstruction using the anchors of cervical pedicle screws and plate-rod systems for patients with congenital osseous anomalies at the craniocervical junction. Twenty patients with congenital osseous lesions who underwent posterior occipitocervical fusion using the anchors of cervical pedicle screws and plate-rod systems for reduction and fixation from 1996 to 2009 were reviewed. The lesions included os odontoideum, occipitalization of the atlas, congenital C2-3 fusion, congenital atlantoaxial subluxation, congenital basilar invagination and combined anomalies. The clinical assessment and the measurements of the images were performed preoperatively, postoperatively and at most recent follow-up. The combined deformity of flexion of the occipitoatlantoaxial complex and invagination of the odontoid process associated with congenital osseous lesions at the craniocervical junction was corrected by application of combined forces of extension and distraction between the occiput and the cervical pedicle screws. Preoperative myelopathy improved in 94.7% patients. The mean Ranawat value, Redlund-Johnnell value, atlantodental distance, occiput (O)-C2 angle, and C2-C7 lordosis angle improved postoperatively and was sustained at most recent follow-up. The mean cervicomedullary angle improved from 129.3° preoperatively to 153.3° postoperatively. The mean range of motion at the lower adjacent motion segment remained unchanged at most recent follow-up. The fusion rate was 95%. The results of the present study indicate that posterior occipitocervical reconstruction using the anchors of cervical pedicle screws and plate-rod systems is an effective technique for treatment of deformities and/or instability caused by congenital osseous anomalies at the craniocervical junction.


Selective personality-targeted prevention of suicidal ideation in young adolescents: post hoc analysis of data collected in a cluster randomised controlled trial.
To assess the efficacy of a selective, personality-targeted intervention for reducing suicidal ideation in adolescents. Post hoc analysis of survey data collected in the Climate and Preventure (CAP) study, a cluster randomised controlled trial that compared strategies for reducing alcohol misuse by adolescents, 2012-2015. Year 8 students at 16 New South Wales non-government schools and one Victorian non-government school. Preventure, a selective, personality-targeted intervention designed to help adolescents with personality risk factors for alcohol misuse, comprising two 90-minute sessions, one week apart. For our post hoc analysis, we combined data from the two CAP trial groups in which Preventure was offered (the Preventure and the Preventure/Climate Schools [a non-selective prevention strategy] groups) as the intervention group; and data from the two groups in which Preventure was not offered (usual health education only [control] and Climate Schools groups) as the control group. Difference between post hoc control and intervention groups in the change in proportions of students reporting suicidal ideation during the preceding six months (single item of Brief Symptom Inventory depression subscale) over three years. A total of 1636 students (mean age at baseline, 13.3 years; standard deviation, 0.5 years) were included in our analysis, of whom 1087 (66%) completed the suicidal ideation item in the three-year follow-up assessment. The post hoc control group included 755 students (nine schools), the intervention group 881 students (eight schools). After adjusting for nesting of students in schools and sex, reporting of suicidal ideation by students who had received Preventure had declined over three years, compared with the control group (per year: adjusted odds ratio, 0.80; 95% CI, 0.66-0.97). Personality-targeted selective prevention during early secondary school can have a lasting impact on suicidal ideation during adolescence. Australian and New Zealand Clinical Trials Registry, ACTRN12612000026820 (prospective).


Secular trends in sex ratios at birth in North America and Europe over the second half of the 20th century.
A previous study showed that significantly more boys were born in southern latitudes in Europe than in northern latitudes and the converse pattern was observed in North America. This study analyses secular trends in gender ratios for live births over the second half of the 20th century. Analysis was carried out from a World Health Organisation dataset comprising live births over the above period. This included 127034732 North American and 157947117 European live births. Analysis of trends in gender ratios for countries in both continents. The findings show a highly significant overall decline in male births in both Europe and North America (p<0.0001), particularly in Mexico (p<0.0001). Interestingly, in Europe, male births declined in North European countries (latitude>40 degrees, p<0.0001) while rising in Mediterranean countries (latitude congruent with 35-40 degrees, p<0.0001). These trends produced an overall European male live birth deficit 238693 and a North American deficit of 954714 (total male live birth deficit 1193407). No reasonable explanation/s for the observed trends have been identified and the causes for these trends may well be multifactorial.


Therapeutic effect of Soshiho-tang, a traditional herbal formula, on liver fibrosis or cirrhosis in animal models: a systematic review and meta-analysis.
Liver fibrosis has been recognized as a major lesion of the liver that leads to liver cirrhosis at the end stage. Soshiho-tang (SST) has been used to improve liver fibrosis/cirrhosis by ameliorating fibrosis-specific markers. This study aimed to assess the efficacy of SST on liver fibrosis/cirrhosis through a systematic review of the literature and meta-analysis using animal models. Studies of SST treatment in liver fibrosis/cirrhosis-induced animal models were searched by electronic data bases. The quality of the studies included was assessed and the efficacy of SST was evaluated based on markers from liver tissues and serum. Among the 838 studies identified in the literature search, 20 studies that met the inclusion criteria were included in the analysis. SST significantly reduced the elevated levels of fibrosis markers, such as the degree of fibrosis, hydroxyproline, hyaluronic acid, transforming growth factor-β1, and procollagen III in liver tissues, and aspartate aminotransferase, alanine aminotransferase, procollagen III, tissue inhibitor of metalloproteinase-1, and type IV collagen in the serum. SST was effective in decreasing pathologically increased markers in animal models of liver fibrosis/cirrhosis. A larger-scale of animals, well-designed animal study is expected to improve the methodological quality, heterogeneity, and potential biases of the meta-analysis.


Maternal insecurity and failure to thrive in Asian children.
Four Asian babies were investigated because they failed to thrive. In all four cases the failure to thrive was a result of the mother's social isolation and inability to communicate, and to the father's refusal to accept that there was a problem in the family.


Aging and respond-withhold tasks: effects on sustained potentials, P3 responses and late activity.
Differences in late event-related potentials (ERPs) during active respond-withhold tasks were tested with 16 young, 16 middle-aged, and 16 elderly subjects (mean ages were 30, 50 and 69 years, respectively). All subjects were selected for good health. While monopolar electroencephalograms were recorded from FZ, CZ, and PZ, subjects performed a signaled respond-withhold task to allow measurement of sustained potentials (SPs) and a non-signaled respond-withhold task for measurement of P3 responses and late activity (LA) which follows the P3. Respond and withhold trials were presented randomly with a probability of 0.5 in both tasks. Compared with younger subjects, the elderly group produced significantly larger negative mean SP amplitude during respond trials at CZ, significantly larger negative mean LA during respond trials at CZ, and significantly larger positive LA during withhold trials at all electrode locations. The elderly group also produced significantly larger P3 amplitude at FZ. The results are discussed in relation to the hypothesis that inhibition may be weaker in elderly subjects. Two further possible interpretations of the larger ERPs in elderly subjects are suggested: (1) the elderly group may have been more challenged by the tasks and their larger ERPs may reflect greater neural effort; and/or (2) the health selection procedures may have produced a group of elderly 'survivors' whose large ERPs may be characteristic of robust individuals or may reflect adaptations to aging-related changes in neural function.


MicroRNA-588 is upregulated in human prostate cancer with prognostic and functional implications.
Epigenetic factors of microRNAs (miRNAs) are important biomarkers and modulators in human prostate cancer (PCa). In this work, we characterized the expression, biomarker-potential and functional regulation of miR-588 in PCa. Endogenous miR-588 levels were quantified by qRT-PCR in both prostate-specific antigen (PSA)-negative and PSA-positive PCa cell lines, as well as human PCa tumors. The associations between endogenous miR-588 and PCa patients' clinical outcomes and postoperative overall survival were statistically examined. Moreover, in both PSA-negative DU145 and PSA-positive LNCaP, downregulation of miR-588 was achived by transduction of miR-588 inhibitor lentivirus. The subsequent effects of miR-588 downregulation on PCa cell developments were investigated both in vitro and in vivo. MiR-588 was profoundly upregulated in both PSA-negative and PSA-positive PCa cells, as well as in PCa tumors. Significant miR-588 upregulation was found to be closely associated with PCa patients' poor clinical outcomes and shorter postoperative overall survivals. In DU145 and LNCaP cell lines, lentiviral transduction markedly downregulated endogenous miR-588 levels. MiR-588 downregulation was shown to profoundly inhibit PCa proliferation in vitro and xenograft in vivo. Aberrant upregulation of endogenous miR-588 in PCa patients may be a prognostic biomarker, indicative of their poor clinical outcomes. Inhibiting endogenous miR-588 may also serve as a therapeutic target for PCa treatment. This article is protected by copyright. All rights reserved.


Morphological findings on peripheral nerve biopsies in 15 patients with human immunodeficiency virus infection.
A peripheral nerve biopsy was performed in 15 patients with human immunodeficiency virus (HIV) infection and polyneuropathy. Two cases [1 asymptomatic, 1 AIDS-related complex (ARC)] presented with chronic inflammatory demyelinating polyneuropathy; there was 1 case (asymptomatic) of mononeuropathy multiplex and 12 cases (1 asymptomatic, 1 ARC, 10 AIDS) with distal symmetrical polyneuropathy. Epi- or endoneurial microvasculitis was observed in 6 cases. Electron microscopy showed that nerve fiber lesions were mainly axonal. Severe segmental demyelination was also present in both cases of chronic inflammatory demyelinating polyneuropathy, with characteristic features of active demyelination in one. Numerous plasmacytoid cells were found in the endoneurium in 4 patients. Tubuloreticular inclusions were present in endothelial cells in the 10 cases with AIDS but absent in the other patients. Direct immunopathological examination with anti-immunoglobulin sera was negative in all cases. HIV was evidenced by in situ hybridization in 2 AIDS patients; no Epstein-Barr virus or cytomegalovirus was detected.


Oral manifestations of lipoid proteinosis: A case report and literature review.
Lipoid proteinosis is an uncommon autosomal recessive metabolic disorder that presents in early life with hoarseness and pox-like acneiform scars involving the skin and mucous membranes. Previous studies have attributed the prevalence of lipoid proteinosis to consanguineous parents. This paper reports a classical case of lipoid proteinosis with oral manifestations but without a history of consanguinity.


Transposon-based mutagenesis generates diverse adeno-associated viral libraries with novel gene delivery properties.
The engineering of novel properties and functions into viral vectors for improved gene delivery remains a barrier to the development of efficient, customized gene delivery vehicles. Rational methods for designing improved viral vectors are often experimentally challenging and laborious, particularly when knowledge of viral structure-function relationships is limited. As an alternative, high-throughput libraries may be rapidly and efficiently selected for viral variants with a desired function. Here we describe a transposon-based insertional mutagenesis approach to generate large diverse adeno- associated viral (AAV) libraries containing a randomly located peptide. Briefly, a selectable marker is randomly inserted throughout the AAV2 cap gene and the resulting "bookmarked' AAV cap gene is cloned into an AAV packaging vector. The selectable marker is then replaced with a defined oligonucleotide, and the final AAV library is used to package a diverse pool of AAV virions, which can used for functional selection.


Plasmodium falciparum malaria occurring 8 years after leaving an endemic area.
A 29-year-old patient who was born in Angola developed Plasmodium falciparum malaria 8 years after leaving Africa. She had not returned to a malaria-endemic area, and there were no apparent risks of local or nosocomial acquisition of malaria in Canada. She recovered after treatment with oral quinine sulfate and doxycycline.


From synchronous neuronal discharges to subjective awareness?
For practical clinical purposes, as well as because of their deep philosophical implications, it becomes increasingly important to be aware of contemporary studies of the brain mechanisms that generate subjective experiences. Current research has progressed to the point where plausible theoretical proposals can be made about the neurophysiological and neurochemical processes which mediate perception and sustain subjective awareness. An adequate theory of consciousness must describe how information about the environment is encoded by the exogenous system, how memories are stored in the endogenous system and released appropriately for the present circumstances, how the exogenous and endogenous systems interact to produce perception, and explain how consciousness arises from that interaction. Evidence assembled from a variety of neuroscience areas, together with the invariant reversible electrophysiological changes observed with loss and return of consciousness in anesthesia as well as distinctive quantitative electroencephalographic profiles of various psychiatric disorders, provides an empirical foundation for this theory of consciousness. This evidence suggests the need for a paradigm shift to explain how the brain accomplishes the transformation from synchronous and distributed neuronal discharges to seamless global subjective awareness. This chapter undertakes to provide a detailed description and explanation of these complex processes by experimental evidence marshaled from a wide variety of sources.


New biphenyl derivatives i: 1-(4-biphenylyl)-2-phenylethylamines as potential antispasmodic and cardiovascular agents.
A series of 1-(4-biphenylyl)-2-phenylethylamine derivatives was synthesized as potential antispasmodic and cardiovascular agents related to papaverine. Preliminary pharmacological tests, on isolated guinea pig ileum and anesthetized cat blood pressure, showed that the new compounds possess nonspecific inhibitory action on smooth muscles.


Patient preferences and shared decision making for the traditional Chinese medicine treatment of lung cancer: A discrete choice experiment study.
Traditional Chinese Medicine (TCM), integrating patient preferences into decision-making process, has been widely used in the multimodality therapy of lung cancer. This study aimed to estimate patient preferences for treatment and shared decision-making (SDM) modes concerning inpatient TCM treatment of lung cancer in Shanghai in order to provide a basis for clinical decision-making process on TCM therapy for lung cancer. This study was conducted among patients (n = 347) from nine tertiary hospitals in Shanghai by discrete-choice experiment (DCE) survey and Shared Decision-Making Questionnaire-patient version (SDM-Q-9) survey. The DCE was developed with the inclusion of the most relevant attributes at appropriate levels for the TCM treatment of lung cancer. The empirical data analyses of patients were performed using mixed logit models. Additionally, subgroup analysis was conducted. In total, 347 respondents completed the questionnaire. All attributes' coefficients were statistically significant for patients' preferences. Patients showed strong preferences for increasing disease control rate, relieving nausea and vomiting, reducing the risk of side effects, and were concerned about monthly out-of-pocket costs. Subgroup analysis indicated that patients with a lower SDM-Q-9 score and those who were satisfied with medical services emphasized more importance of higher disease control rate. Furthermore, most of the patients (90.20%) self-reported a high willingness to use SDM during the decision-making process. In Shanghai, patients mainly preferred SDM and considered disease control rate as the most essential attribute in the TCM treatment of lung cancer. The study findings could underscore the importance of considering patients' preferences and promote SDM.


Sulbactam/ampicillin versus cefotaxime as initial therapy in serious soft tissue, joint and bone infections.
In an open, randomised comparative study, 23 patients with bone, joint or soft tissue infections were treated with ampicillin 2g plus sulbactam 1g 3 times a day or cefotaxime 2g 3 times a day as an initial 2-week therapy. Monoinfections with Staphylococcus aureus were the most common bone or joint infections. Clinical cure or improvement 2 weeks after the end of therapy was observed in all 13 patients treated with sulbactam/ampicillin and in 7 of the 8 patients evaluated for efficacy after treatment with cefotaxime. Most organisms identified before the onset of therapy were susceptible to the antibiotic randomly selected for therapy, although the majority of infections due to beta-lactamase-producing staphylococci could not have been treated with ampicillin without sulbactam. Treatment failed to eradicate S. aureus in 1 patient from each group. In addition, S. aureus infection recurred in 2 patients in the cefotaxime group within 2 weeks after the end of therapy. No serious side effects were observed.