Solitary intraductal papilloma: findings at MR imaging and MR galactography.
The purpose of this article is to describe MR findings in surgically proven solitary intraductal papillomas of the breast, including findings on MR galactography. Women with spontaneous nipple discharge and solitary intraductal papilloma show, on MR imaging, dilated ducts with an associated enhancing, well-circumscribed mass.


Effects of chronic pain on quality of life and depression in patients with spinal cord injury.
A cross-sectional study. To assess the effects of pain on quality of life (QoL), functional independence and depression in patients with spinal cord injury (SCI). An inpatient rehabilitation center. A total of 140 patients (104 M, 36 F) with SCI who underwent inpatient rehabilitation treatment were examined. A questionnaire including clinical variables was applied. Motor score of Functional Independence Measure was used to assess daily-life activities, the 36-Item Medical Outcomes Short-Form Health (SF-36) for QoL and Beck Depression Inventory (BDI) for depression. Patients were then divided into those having chronic pain (Group I) and those without any pain (Group II), and groups were compared according to demographic and clinical variables. The most common causes of SCI were falls (35.0%) and motor vehicle accidents (34.2%). Chronic pain was present in 78% of patients. Patients employed before injury and patients who had complete injury had lower Numerical Rating Scale scores (P<0.05). SCI patients with chronic pain had higher depression ratings and their BDI scores were correlated with some of the SF-36 domains (general health, vitality, social functioning and mental health). Only bodily pain and social functioning (P<0.05) scores were found to be lower in Group I (P<0.05) when compared with Group II. As mood and QoL are negatively affected with pain in SCI patients, we suggest that chronic pain should always be treated in a multidisciplinary setting where pharmacological, physical and psychological therapies are combined.


Formation of cage-like hollow spherical silica via a mesoporous structure by calcination of lysozyme-silica hybrid particles.
Calcination of lysozyme-silica hybrid hollow particles gives novel cage-like hollow spherical silicas with differently patterned through-holes on their shell structure.


Cumulative procedural pain and brain development in very preterm infants: A systematic review of clinical and preclinical studies.
Very preterm infants may manifest neurodevelopmental impairments, even in the absence of brain lesions. Pathogenesis is complex and multifactorial. Evidence suggests a role of early adversities on neurodevelopmental outcomes, via epigenetic regulation and changes in brain architecture. In this context, we focused on cumulative pain exposure which preterm neonates experience in neonatal intensive care unit (NICU). We systematically searched for: i) evidence linking pain with brain development and exploring the potential pathogenetic role of epigenetics; ii) preclinical research supporting clinical observational studies. Nine clinical neuroimaging studies, during neonatal or school age, mostly from the same research group, revealed volume reduction of white and gray matter structures in association with postnatal pain exposure. Three controlled animal studies mimicking NICU settings found increased cell death or apoptosis; nevertheless, eligible groups were limited in size. Epigenetic modulation (SLC6A4 promoter methylation) was identified in only two clinical trials. We call for additional research and, although knowledge gaps, we also point out the urgent need of minimizing painful procedures in NICUs.


MarA and ramA regulate virulence in Salmonella enterica serovar Choleraesuis.
Salmonella enterica serovar Choleraesuis is considered as an important porcine pathogen that causes serious systemic infections and exhibits poor response to treatment because of an increase in multidrug resistance (MDR). Among the various regulators of resistance, multiple antibiotic resistance factor A (marA) and regulator of acetate metabolism A (ramA) are the most effective in conferring antibiotic tolerance by activation of multidrug efflux pumps. Here we investigated the regulation of virulence in Salmonella Choleraesuis through these two transcriptional regulators. We showed that marA andramA are important for the survival of Salmonella Choleraesuis in an environment of acid and bile salts, since marA- or ramA-deficient Salmonella Choleraesuis strains failed to increase protective responses, as observed by quantitative RT-PCR (qPCR). Further, reduced invasion and survival in host cells was observed in the marA and ramA mutant strains. The results from in vitrostudies with marA- and ramA-deficient strains showed attenuated characteristics in comparison to those in the wild-type strain of Salmonella Choleraesuis when it was used to challenge BALB/c mice. The mutant strains had higher LD50 and presented poor clearance efficiency compared to the parental strain. These findings indicate that MarA and RamA not only regulate drug resistance but also play a role in the virulence of SalmonellaCholeraesuis.


Oxford phase 3 unicondylar knee arthroplasty through a minimally invasive approach: long-term results.
Surgical treatment options for medial compartment osteoarthritis of the knee include high tibial osteotomy, total knee arthroplasty or unicompartmental knee arthroplasty (UKA), depending on the patient's age, level of physical activity and the degree of deformity. In this study, we evaluated the long-term results of patients who underwent the Oxford cemented meniscal-bearing unicondylar knee prosthesis through a minimally invasive approach including a clinical, functional and radiographic assessment. Favourable clinical and radiological outcomes were registered overall at ten years after surgery. Overall results of UKA according to the American Knee Society (AKS) using Insall's criteria showed an excellent or good outcome for 492 knees (96.28 %), fair for 11 (2.15 %) and poor for eight (1.57 %) in the post-operative long term. We believe that with appropriate surgical technique, patient selection, prosthetic design and specific training, surgeons should achieve good outcomes with the added advantages of a minimally invasive approach. High volume for this technique is important in our opinion.


Age and hippocampal volume predict distinct parts of default mode network activity.
Group comparison studies have established that activity in the posterior part of the default-mode network (DMN) is down-regulated by both normal ageing and Alzheimer's disease (AD). In this study linear regression models were used to disentangle distinctive DMN activity patterns that are more profoundly associated with either normal ageing or a structural marker of neurodegeneration. 312 datasets inclusive of healthy adults and patients were analysed. Days of life at scan (DOL) and hippocampal volume were used as predictors. Group comparisons confirmed a significant association between functional connectivity in the posterior cingulate/retrosplenial cortex and precuneus and both ageing and AD. Fully-corrected regression models revealed that DOL significantly predicted DMN strength in these regions. No such effect, however, was predicted by hippocampal volume. A significant positive association was found between hippocampal volumes and DMN connectivity in the right temporo-parietal junction (TPJ). These results indicate that postero-medial DMN down-regulation may not be specific to neurodegenerative processes but may be more an indication of brain vulnerability to degeneration. The DMN-TPJ disconnection is instead linked to the volumetric properties of the hippocampus, may reflect early-stage regional accumulation of pathology and might be of aid in the clinical detection of abnormal ageing.


Can Immune-related adverse events serve as clinical biomarkers of PD-1/PD-L1 inhibitor efficacy in Pan-Cancer Patients?
Although PD-1/PD-L1 inhibitors are widely used as first-line treatment for patients with advanced tumors or as adjuvant therapy for patients with early-stage tumors, their efficacy is only 15-60%. Increasing evidence has demonstrated that biomarkers such as PD-L1 expression levels, microsatellite instability, and tumor mutation burden may assist in predicting the anti-tumor efficacy of PD-1/PD-L1 inhibitors. However, their clinical application value is limited, and there is currently a dearth of specific clinical markers to monitor or predict the efficacy of PD-1/PD-L1 inhibitors. Recently, studies have exposed that the efficacy of PD-1/PD-L1 inhibitors is positively correlated with immune-related adverse events (irAEs), suggesting that the latter may effectively predict anti-tumor efficacy. While there are controversies, a systematic understanding of the reasons and influencing factors of its correlation is still lacking. Therefore, this review aimed to introduce and discuss the latest research on the correlation between the efficacy of PD-1/PD-L1 inhibitors and irAEs. We identified that this positive correlation might be related to adipose tissue, T cells, pharmacokinetic characteristics, and antigen spread. In addition, the severity of irAEs, the duration of the use of PD-1/PD-L1 inhibitors, the comprehensive evaluation method of the severity of irAEs, and the genetic determinants are potentially the most significant bias factors when evaluating this correlation.


Water structure in vitro and within Saccharomyces cerevisiae yeast cells under conditions of heat shock.
The OH stretch mode from water and organic hydroxyl groups have strong infrared absorption, the position of the band going to lower frequency with increased H-bonding. This band was used to study water in trehalose and glycerol solutions and in genetically modified yeast cells containing varying amounts of trehalose. Concentration-dependent changes in water structure induced by trehalose and glycerol in solution were detected, consistent with an increase of lower-energy H-bonds and interactions at the expense of higher-energy interactions. This result suggests that these molecules disrupt the water H-bond network in such a way as to strengthen molecule-water interactions while perturbing water-water interactions. The molecule-induced changes in the water H-bond network seen in solution do not translate to observable differences in yeast cells that are trehalose-deficient and trehalose-rich. Although comparison of yeast with low and high trehalose showed no observable effect on intracellular water structure, the structure of water in cells is different from that in bulk water. Cellular water exhibits a larger preference for lower-energy H-bonds or interactions over higher-energy interactions relative to that shown in bulk water. This effect is likely the result of the high concentration of biological molecules present in the cell. The ability of water to interact directly with polar groups on biological molecules may cause the preference seen for lower-energy interactions.


The hepatobiliary manifestations of human immunodeficiency virus infection.
Liver abnormalities are common in patients with acquired immune deficiency syndrome. These relate to 1) coincident exposure to hepatotropic viruses, 2) complications, either infectious, neoplastic, or iatrogenic, of the immunosuppressed state, or 3) nonspecific changes associated with chronic debilitating illness. We review the hepatobiliary manifestations of acquired immune deficiency syndrome, and discuss our approach to the clinical evaluation of these problems.


Timed limb coordination performance is associated with walking speed in healthy older adults: a cross-sectional exploratory study.
Walking speed reflects quality of life, health status and physical function in older adults but interpreting measures of walking speed is affected by several confounders such as gender, age and height. Additionally, walking speed is influenced by neurologic conditions that impair limb coordination. In absence of defined pathology, it is less clear how varying levels of limb coordination influence walking speed. The purpose of this study was to examine the relationship between limb coordination and walking speed in older adults, controlling for effects of gender, age and height. Sixty-nine healthy, community-dwelling individuals over the age of 60 participated in the study. Participants completed a battery of timed upper and lower limb coordination tests. Normal and fast walking speed were measured over the inner six meters of a 10 m walkway. Correlation and regression analyses were used to examine the relationship between limb coordination performance and walking speed. Controlling for gender, age and height, variance in normal walking speed was accounted for by variance in pronation-supination performance (partial r = -0.396, partial r(2) = 0.16) and variance in fast walking speed was accounted for by variance in finger-to-nose performance (partial r = -0.356, partial r(2) = 0.13). The findings support our hypothesis that limb coordination performance would correlate with walking speed in healthy older adults. Moreover, limb coordination performance attenuated the effects of gender, age and height on walking speed. Limb coordination may be a modifiable determinant of walking speed in older adults.


Epidemiological and clinical assessment of patients undergoing Videolaparoscopic Cholecystectomy at a Curitiba teaching hospital.
to assess clinical and epidemiological factors of patients undergoing video cholecystectomy at the Hospital da Cruz Vermelha do Paraná, Curitiba unit, operated from September 2016 to September 2018, as well as the influence of comorbidities, sex and advanced age on the postoperative prognosis, while in the hospital. Analytic retrospective study. The analyzed variables were obtained by the review of medical records. Statistical analyses were performed considering the significance level p < 0.05. 389 patients, of whom 265 were women and 124 men, were included. The mean age was 51.5 years, 58.8% of the patients were diagnosed with at least one comorbidity, and 74.6% were overweight or obese. The incidence of intraoperative complications was 1.3%, postoperative 3.8% and, mortality, 0.3%. Some risk factors were identified as worse postoperative prognosis, such as Diabetes Mellitus, hypertension, presence of one or more comorbidities and mainly, advanced age, which was related to longer hospitalization times (p < 0,001), need of intensive therapy (p < 0,001), conversion to open surgery (p = 0,003) and postoperative complications (p < 0,001). Furthermore, the male sex was predictive of longer hospitalization times (p = 0,003) and need of intensive therapy (p = 0,01). the presence of comorbidities, male sex, and advanced age are predictive factors of bad prognosis for patients undergoing video laparoscopic cholecystectomy.


Lacidipine attenuates caffeine-induced anxiety-like symptoms in mice: Role of calcium-induced oxido-nitrosative stress.
Anxiety is a disorder of multi-factorial pathogenesis involving interrelated pathways of neurotransmitters, oxidative stress and metamorphosed calcium-signaling that negatively affects brain functions. Modulation of Ca2+-channels outlines a promising strategy to curb the progression of anxiety-like disorders through attenuation of redox-imbalance. The current research scheme was designed to explore the anxiolytic effects of lacidipine (L-type Ca2+-channel blocker; LCD) pretreatment in caffeine-induced anxiety-like symptom model in mice. Forty-two Swiss albino mice (25-30 g) were distributed to 7 groups (n = 6): Vehicle control, caffeine, alprazolam + caffeine, lacidipine(0.3, 1 and 3 mg/kg, ip)+caffeine and Bay-K8644+LCD(3)+caffeine. Caffeine (25 mg/kg, ip) was administered from day 8 to 14 to induce anxiety-like symptoms in mice. Lacidipine (0.3, 1 and 3 mg/kg, ip) and alprazolam (0.25 mg/kg, ip) were administered from day 1 to 14 in separate groups. Bay-K8644 (Ca2+-channel agonist) was injected on day 14 to delineate the role of Ca2+ in anti-anxiety effect of LCD in caffeine-treated mice. Elevated zero maze and mirror chamber test were employed to assess anxiety-like behavior. Afterwards, the mice were sacrificed and whole brains were harvested for estimation of biomarkers of oxido-nitrosative stress, such as TBARS, GSH, SOD, catalase and total nitrite content. An increase in brain oxido-nitrosative stress and anxiety-like behavior was observed in caffeine treated mice. LCD pretreatment attenuated the brain oxido-nitrosative stress and anxiety-like behavior in mice in caffeine treated mice. Anxiolytic effect of LCD was attenuated by Bay-K8644 (0.5 mg/kg) in caffeine treated mice. LCD (L-type Ca2+-channel antagonist) pretreatment attenuated caffeine-induced oxido-nitrosative stress and anxiety-like behavior.


Carbon implications of marginal oils from market-derived demand shocks.
Expanded use of novel oil extraction technologies has increased the variability of petroleum resources and diversified the carbon footprint of the global oil supply1. Past life-cycle assessment (LCA) studies overlooked upstream emission heterogeneity by assuming that a decline in oil demand will displace average crude oil2. We explore the life-cycle greenhouse gas emissions impacts of marginal crude sources, identifying the upstream carbon intensity (CI) of the producers most sensitive to an oil demand decline (for example, due to a shift to alternative vehicles). We link econometric models of production profitability of 1,933 oilfields (~90% of the 2015 world supply) with their production CI. Then, we examine their response to a decline in demand under three oil market structures. According to our estimates, small demand shocks have different upstream CI implications than large shocks. Irrespective of the market structure, small shocks (-2.5% demand) displace mostly heavy crudes with ~25-54% higher CI than that of the global average. However, this imbalance diminishes as the shocks become bigger and if producers with market power coordinate their response to a demand decline. The carbon emissions benefits of reduction in oil demand are systematically dependent on the magnitude of demand drop and the global oil market structure.


Radiographic femoral bicondylar width predicts anterior cruciate ligament insertion site sizes.
The purpose of this study was to determine whether radiographic femoral bicondylar width predicts intra-operative anterior cruciate ligament (ACL) insertion site sizes. Seventy-three consecutive patients (39 males and 34 females; mean age 25.2 years ± 10.2) who underwent anatomic ACL reconstruction were retrospectively reviewed. Femoral condyle width was measured using a pre-operative anteroposterior (AP) radiograph of the operative knee. Lines were drawn through the anatomic axis of the femur, as well as perpendicularly through the condyles. Bicondylar width was measured as the maximum width across both the medial and lateral femoral condyles utilizing this perpendicular line. The ACL insertion site lengths (in the AP direction) of both the tibia and the femur were measured intra-operatively using a commercially available arthroscopic ruler. The average bicondylar width was significantly smaller for females compared to males (p < 0.05). The average tibial and femoral insertion site sizes were significantly smaller for females compared to males (p < 0.05). Regression analysis predicted tibial (r 2 = 0.88) and femoral (r 2 = 0.90) insertion site sizes based on femoral bicondylar width measurements. A simple radiographic measurement of femoral bicondylar width can predict intra-operative tibial and femoral insertion site sizes, which has the potential to assist surgeons in performing individualized ACL reconstruction in cases where MRI scan is unavailable. IV.


A meta-analysis of the association of glutathione S-transferase P1 gene polymorphism with the susceptibility of breast cancer.
Glutathione S-transferase P1 (GSTP1) is one of the important mutant sites for the cancer risk at present. The conclusions of the published reports on the relationship between GSTP1 A/G gene polymorphism and the risk of breast cancer are still debated. This meta-analysis was performed to evaluate the association between GSTP1 and the risk of breast cancer. The association reports were identified from PubMed and Cochrane Library, and eligible studies were included and synthesized using meta-analysis method. 35 investigations were included into this meta-analysis for the association of GSTP1 A/G gene polymorphism and breast cancer susceptibility, consisting of 40,347 subjects (18,665 patients with breast cancer and 21,682 controls). The association between GSTP1 A/G gene polymorphism and breast cancer risk was not found for overall population, Caucasians and Africans. Interestingly, the GSTP1 A/G gene polymorphism was associated with the susceptibility of breast cancer in Asians (G allele: OR = 1.10, 95 % CI: 1.04-1.17, P = 0.001; GG genotype: OR = 1.36, 95 % CI: 1.14-1.62, P = 0.0008; AA genotype: OR = 0.92, 95 % CI: 0.85-0.98, P = 0.02). Furthermore, the GSTP1 A/G gene polymorphism was associated with the susceptibility of breast cancer for the analysis of the controls from hospital. In conclusion, GSTP1 A/G gene polymorphism is associated with the breast cancer susceptibility in Asians. However, more studies on the relationship between GSTP1 A/G gene polymorphism and the risk of breast cancer should be performed in further.


A novel approach to patients with acute odontoid fractures: atlantoaxial instability as a prognostic variable.
Liu S, Liu L. Re: Evaniew N, Yarascavitch B, Madden K, Ghert M, Drew B, Bhandari M, et al. Atlantoaxial instability in acute odontoid fractures is associated with nonunion and mortality. Spine J 2015;15:1160 (in this issue).


Attention demands during reading and the occurrence of brief (express) fixations.
Eye movements were recorded while subjects read passages of text repeatedly (Experiment 1) and while normal text and strings of homogeneous letters were fixated (Experiment 2). Text repetition decreased fixation durations and increased saccade size, presumably because it decreased attention demands. Irrespective of repetition, however, no distinct distribution of brief (express) fixations emerged. In Experiment 2, fixation durations were shorter and saccades were larger when strings of homogeneous letters were "read," indicating that this condition decreased attention demands. Again, however, no distinct distribution of express fixations emerged. These findings pose problems for the view that attentional processes determine the occurrence of brief (express) fixation durations in reading. Supplementary analyses of Experiments 1 and 2 suggested that visuospatial processing affected fixation durations, irrespective of linguistic processing demands.


Age-associated decline in RAB-10 efficacy impairs intestinal barrier integrity.
The age-related decline in the ability of the intestinal barrier to maintain selective permeability can lead to various physiological disturbances. Adherens junctions play a vital role in regulating intestinal permeability, and their proper assembly is contingent upon endocytic recycling. However, how aging affects the recycling efficiency and, consequently, the integrity of adherens junctions remains unclear. Here we show that RAB-10/Rab10 functionality is reduced during senescence, leading to impaired adherens junctions in the Caenorhabditis elegans intestine. Mechanistic analysis reveals that SDPN-1/PACSINs is upregulated in aging animals, suppressing RAB-10 activation by competing with DENN-4/GEF. Consistently, SDPN-1 knockdown alleviates age-related abnormalities in adherens junction integrity and intestinal barrier permeability. Of note, the inhibitory effect of SDPN-1 on RAB-10 requires KGB-1/JUN kinase, which presumably enhances the potency of SDPN-1 by altering its oligomerization state. Together, by examining age-associated changes in endocytic recycling, our study sheds light on how aging can impact intestinal barrier permeability.


EEG-rhythm dynamics during a 2-back working memory task and performance.
Working memory is an essential component of human cognition and determines to a large extent an individual's intellectual ability. In this paper, the human brain oscillatory response system associated with working memory performance is evaluated in an experimental and analysis setting involving 10 volunteers performing a visual 2-back task. Event-related dynamics in three bands: theta (3.5-7 Hz), alpha (7.5-12 Hz) and upper beta (17-29 Hz) at 32 locations distributed over the scalp are examined analyzing the event-related desynchronization (ERD)/synchronization (ERS) in these bands. Both global dynamics as well as trial- and subject-specific trends were considered. The overall across participants trend shows that the theta level synchronizes during working memory engagement, whereas beta and alpha desynchronizes. While common features seem to emerge, different subjects exhibit equally significant but opposite in direction correlation between reaction time and power dynamics.


Minimally Invasive Forefoot Surgery in France.
Study groups have been formed in France to advance the use of minimally invasive surgery. These techniques are becoming more frequently used and the technique nuances are continuing to evolve. The objective of this article was to advance the awareness of the current trends in minimally invasive surgery for common diseases of the forefoot. The percutaneous surgery at the forefoot is less developed at this time, but also will be discussed.


Evaluating the efficacy of moving cupping for chronic low back pain using shear wave elastography: A parallel-arm, randomized controlled trial.
Chronic low back pain (CLBP) is a common condition that affects millions of people worldwide. Moving cupping has gained popularity as a complementary therapy for managing CLBP owing to its noninvasive and cost-effective nature. However, the lack of objective measures to assess its therapeutic effect has been a considerable challenge in evaluating the effectiveness of moving cupping for CLBP management. We developed a randomized controlled trial (RCT) protocol for evaluating the effectiveness of a noninvasive treatment using moving cupping by assessing muscle relaxation with shear wave elastography (SWE). It involves the recruitment of 68 patients with CLBP and randomly assigns them to either the treatment or control group. The treatment group will receive moving cupping therapy for 2 weeks, while the control group will receive placebo treatment. It will utilize SWE to evaluate muscle relaxation at baseline, after 2 weeks of treatment, and 1 week after the end of treatment. Subjective reports of pain intensity and quality of life are also recorded at each time point. The protocol developed here utilizes SWE to objectively measure muscle stiffness, and coupled with moving cupping therapy, may be effective in conveying relative comparisons before and after treatment. Moving cupping therapy is expected to promote muscle relaxation and pain relief in patients with CLBP. This study has the potential to contribute to the development of objective measures for evaluating the therapeutic effects of traditional therapies and to provide valuable insight into their efficacy.


Current practice in management of Crohn's disease in Wales.
Crohn's disease (CD) demonstrates great heterogeneity in its presentation and severity. Management of CD is similarly diverse but the aim remains the same--remission of disease activity and improvement of health related quality of life (HR-QoL). Treatment options include steroids, 5-ASA derivatives, immunomodulators and surgery. The aim of this study was to define the variation in practice of consultant gastroenterologists and colorectal surgeons treating CD in Wales. Consultant gastroenterologists and colorectal surgeons treating CD in Wales were sent a questionnaire aimed at determining their current practice and their responses were analysed. Eighty-eight consultants--46 (52%) gastroenterologists and 42 (48%) surgeons-- were invited to participate in the survey. Sixty-one (69%) of them responded. Coherent practice was seen across Wales, especially with respect to diagnosis of CD in line with British Society of Gastroenterology guidelines. Variation was detected in disease severity assessment and some aspects of management. Practice in Wales is in line with the guidelines for managing CD. While the diagnostic process follows a standard approach, variations exist in treatment and monitoring of disease. Validated disease measurement instruments are seldom used in routine practice. Disease assessment tools need to be simpler to use if they are to help objective measurement of disease activity and treatment decisions.


Bladder cancer cell implantation in reconstructed bladder in vitro: a model of tumour recurrence.
To evaluate the involvement of umbrella cells in tumour adhesion and growth, by examining whether human urinary bladder carcinoma cells (HUBCC) can grow on reconstructed urinary bladder mucosa in vitro, as the implantation of tumour cells after resection is thought to be a cause of bladder tumour recurrence. Normal transitional epithelial cells isolated from porcine bladder were cultured on reconstructed lamina propria using fibroblasts in type I collagen gel. The urothelium thus reconstructed was artificially injured either by a scalpel or by dilute acid, after which transitional epithelial cells began to grow in a stratified fashion within a few days of culture. A HUBCC line (HT-1197) was seeded onto this impaired mucosa to determine whether the cells could become implanted. Cultured cells on the reconstructed mucosa were evaluated by histological observation of vertical paraffin sections. The inoculated transitional epithelial cells grew in a stratified fashion and closely resembled urothelium in vivo. The superficial cells that were in contact with the medium solution differentiated into umbrella cells. HUBCC were unable to adhere to reconstructed mucosa which had not been injured, but these cells could adhere to and become implanted on the reconstructed mucosa after it had been injured either by a scalpel or by dilute acid. After acid injury, only the surface-covering cells were removed sporadically, while the lower epithelial cell layer remained intact. The bladder cancer cells adhered to and proliferated within these stripped regions. These results suggest that the urothelium, especially umbrella cells, seems to be important in preventing the adhesion and growth of urinary bladder tumour cells.


Low-frequency somatic copy number alterations in normal human lymphocytes revealed by large-scale single-cell whole-genome profiling.
Genomic-scale somatic copy number alterations in healthy humans are difficult to investigate because of low occurrence rates and the structural variations' stochastic natures. Using a Tn5-transposase-assisted single-cell whole-genome sequencing method, we sequenced over 20,000 single lymphocytes from 16 individuals. Then, with the scale increased to a few thousand single cells per individual, we found that about 7.5% of the cells had large-size copy number alterations. Trisomy 21 was the most prevalent aneuploid event among all autosomal copy number alterations, whereas monosomy X occurred most frequently in over-30-yr-old females. In the monosomy X single cells from individuals with phased genomes and identified X-inactivation ratios in bulk, the inactive X Chromosomes were lost more often than the active ones.


6-tips diet: a simplified dietary approach in patients with chronic renal disease. A clinical randomized trial.
The beneficial effects of dietary restriction of proteins in chronic kidney disease are widely recognized; however, poor compliance to prescribed low-protein diets (LPD) may limit their effectiveness. To help patients to adhere to the dietary prescriptions, interventions as education programmes and dietary counselling are critical, but it is also important to develop simple and attractive approaches to the LPD, especially when dietitians are not available. Therefore, we elaborated a simplified and easy to manage dietary approach consisting of 6 tips (6-tip diet, 6-TD) which could replace the standard, non-individualized LPD in Nephrology Units where dietary counselling is not available; hence, our working hypothesis was to evaluate the effects of such diet vs a standard moderately protein-restricted diet on metabolic parameters and patients' adherence. In this randomized trial, 57 CKD patients stage 3b-5 were randomly assigned (1:1) to receive the 6-TD (Group 6-TD) or a LPD containing 0.8 g/kg/day of proteins (Group LPD) for 6 months. The primary endpoint was to evaluate the effects of the two different diets on the main "metabolic" parameters and on patients' adherence (registration number NCT01865526). Both dietary regimens were associated with a progressive reduction in protein intake and urinary urea excretion compared to baseline, although the decrease was more pronounced in Group 6-TD. Effects on serum levels of urea nitrogen and urinary phosphate excretion were greater in Group 6-TD. Plasma levels of phosphate, bicarbonate and PTH, and urinary NaCl excretion remained stable in both groups throughout the study. 44 % of LPD patients were adherent to the dietary prescription vs 70 % of Group 6-TD. A simplified diet, consisting of 6 clear points easily managed by CKD patients, produced beneficial effects either on the metabolic profile of renal disease and on patients' adherence to the dietary plan, when compared to a standard LPD.


Shoulder strength after open versus arthroscopic stabilization.
With current techniques, the main difference between arthroscopic and open shoulder stabilization is the violation of the subscapularis tendon. No studies have looked at strength differences of internal and external rotation between these groups. Internal rotation strength deficits will exist in patients having undergone an open shoulder stabilization procedure compared with an arthroscopic one. Piggy-back randomized controlled trial; Level of evidence, 1. Forty-eight patients (38 men, 10 women), average age, 30.6 years (range, 18-59 years), were randomized to either open (n = 24) or arthroscopic (n = 24) shoulder stabilization. Rehabilitation protocols were standardized. At a mean follow-up of 19.4 months (range, 12-36 months) from surgery, patients underwent isokinetic strength testing (concentric and eccentric peak moments at 60 deg/s and 180 deg/s). Measurements were body-mass normalized. Primary outcome was internal rotation strength at 60 deg/s. There were no significant differences between groups with respect to age, gender, or operative limb. There were no statistical differences between operative groups for the primary outcome of internal concentric strength at 60 deg/s (mean difference, 0.011 N.m/kg; 95% confidence interval, -0.043 to 0.066; P = .677) or secondary strength measures. When compared with the contralateral limb, strength deficits existed for both surgical groups for both internal and external rotation. Regression analysis demonstrated that arm dominance is a factor in strength deficits. The results of this trial suggest there are no side-to-side isokinetic strength deficits between patients having an open stabilization using a subscapularis splitting approach versus arthroscopic stabilization for anterior traumatic shoulder instability at 1 year after surgery. Strength deficits exist in both groups when compared with the contralateral limb.


Inhibition of intrinsic thrombin generation.
The contact phase of coagulation is of physiologic/pathophysiologic importance, whenever unphysiologic polynegative substances such as cell fragments (microparticles) get in contact with blood. There are several clinically used inhibitors of intrinsic thrombin generation. Here the inhibitory concentrations 50% (IC50) of these anticoagulants are measured by the highly specific thrombin generation assay INCA. Unfrozen pooled normal citrated plasma in polystyrole tubes was supplemented at 23°C in duplicate with 0-2 IU/ml low molecular weight heparin (dalteparin), 0-2 IU/ml unfractionated heparin, 0-500 KIU/ml aprotinin, or 0-40 mM arginine. 50 μl plasma or 1 IU/ml thrombin standard were pipetted into a polystyrole microtiter plate with flat bottom. 5 μl SiO(2)/CaCl(2) - reagent (INCA activator) were added and after 0-30 min incubation at 37°C 100 μl 2.5 M arginine, pH 8.6, were added; arginine inhibits hemostasis activation and depolymerizes generated fibrin within 20 min at 23°C. The in the physiologic 37°C incubation phase generated thrombin was then chromogenically detected. The intra-assay CV values were < 5%. The approximate IC50 were 0.01 IU/ml dalteparin, 0.02 IU/ml heparin, 25 KIU/ml aprotinin, and 12 mM arginine. The efficiency of any anticoagulant on intrinsic thrombin generation should be measured for each individual patient.


Development and verification of an enzyme-linked immunosorbent assay for the quantification of toxoid A and toxoid B from Clostridioides difficile.
Clostridioides difficile (C. difficile) is the most common cause of nosocomial antibiotic associated diarrhoea. The incidence of C. difficile infection (CDI) has been rising worldwide over the last 20 years with consequent rises in morbidity, mortality and healthcare costs, although the incidence has fallen in the UK over the last few years. Confirmation of diagnosis and early intervention are critical to the management of CDI. The standard treatment for CDI is the administration of antibiotics. However, vaccination has been recognized as the most cost-effective treatment for the prevention and possible long-term protection against CDI episode. There are several promising vaccine candidates in various stages of development. Many of these vaccines have displayed good efficacy for CDI under laboratory conditions or in clinical trials. With the emergence of vaccines against C. difficile, here we describe the development and verification of an Enzyme Linked Immunosorbent Assay (ELISA) that can be used for the quality control testing of candidate vaccines against C. difficile through the measurement of vaccine antigen content. Verification of the assay was performed by assessment of specificity, sensitivity, intermediate precision and relative accuracy. The ELISAs were specific for the toxoids being detected and the detection limit of the assay for toxoid A was 4.88 ng/mL and 3.91 ng/mL for toxoid B. The geometric coefficients of variation for intermediate precision did not exceed 25% and relative accuracy was within 77-130%. We therefore conclude that the ELISA described here is sufficiently sensitive, specific, precise and accurate for use for the quality control testing of candidate C. difficile vaccines.


Investigations on the 4-quinolone-3-carboxylic acid motif part 5: modulation of the physicochemical profile of a set of potent and selective cannabinoid-2 receptor ligands through a bioisosteric approach.
Three heterocyclic systems were selected as potential bioisosteres of the amide linker for a series of 1,6-disubstituted-4-quinolone-3-carboxamides, which are potent and selective CB2 ligands that exhibit poor water solubility, with the aim of improving their physicochemical profile and also of clarifying properties of importance for amide bond mimicry. Among the newly synthesized compounds, a 1,2,3-triazole derivative (1-(adamantan-1-yl)-4-[6-(furan-2-yl)-1,4-dihydro-4-oxo-1-pentylquinolin-3-yl]-1H-1,2,3-triazole) emerged as the most promising in terms of both physicochemical and pharmacodynamic properties. When assayed in vitro, this derivative exhibited inverse agonist activity, whereas, in the formalin test in mice, it produced analgesic effects antagonized by a well-established inverse agonist. Metabolic studies allowed the identification of a side chain hydroxylated derivative as its only metabolite, which, in its racemic form, still showed appreciable CB2 selectivity, but was 150-fold less potent than the parent compound.


The Family Questionnaire: development and validation of a new self-report scale for assessing expressed emotion.
The level of expressed emotion (EE) as assessed in the Camberwell Family Interview (CFI) has proved to be one of the best predictors of relapse in schizophrenia. The present study describes the development and validation of the Family Questionnaire (FQ), a brief self-report questionnaire measuring the EE status (criticism, emotional overinvolvement) of relatives of patients with schizophrenia. The FQ classifications in the initial sample of relatives (N=76) correlated significantly with the ratings in the CFI subcategories 'criticism' (78% correct classifications) and 'emotional overinvolvement' (71% correct classifications), as well as with the overall CFI EE ratings (74% correct classifications). A validation study in an independent second sample (N=79) yielded similar results. The overall correct classification rate of 74% remained unchanged. The FQ had better agreement with the CFI on emotional overinvolvement than did other short EE questionnaires.


MeCIPK10 regulates the transition of the K+ transport activity of MeAKT2 between low- and high-affinity molds in cassava.
AKT1 is an inward-rectifying K+ channel that was originally thought to function only within a low-affinity K+ concentration range. However, the growth of an akt1 mutant of Arabidopsis was shown to be severely inhibited within a high-affinity range. This suggested that AKT1 may also be a high-affinity K+ transporter, but it remains unclear how the two modes of AKT1 coordinate to uptake K+. One gene (MeAKT2) encodes for a putatively inward-rectifying K+ channel and was isolated from cassava. Relative to other tissues, the MeAKT2 gene was expressed mainly in roots, and its transcriptional level was observed to be significantly increased under low-K+ conditions. Functional analyses were performed using a yeast expression system. When MeAKT2 was expressed alone in yeast cells, transgenic yeast could grow only in nutrient media supplied with >0.5 mM potassium. A yeast two-hybrid assay showed that both MeCIPK10 and MeCIPK12 clearly interacted with MeAKT2. Additionally, 0.05 mM K+ was sufficient for the growth of yeast cells co-expressing MeAKT2 with MeCIPK10, but also their co-expression significantly enhanced the growth capacity of yeast cells in the low range of K+ concentrations. Change in K+ uptake rate in co-transgenic yeast cells grown across a wide range of K+ concentrations showed that MeAKT2-mediated K+ uptake displayed a biphasic pattern, but also the switching from low-to high-affinity K+ uptake was regulated by CIPK10. This indicated that MeAKT2 functioned as a dual-affinity transporter to uptake K+ under both low- and high-affinity K+ conditions.


CD40 ligand-dependent activation of cytotoxic T lymphocytes by adeno-associated virus vectors in vivo: role of immature dendritic cells.
Recombinant adeno-associated virus type 2 (rAAV) is being explored as a vector for gene therapy because of its broad host range, good safety profile, and persistent transgene expression in vivo. However, accumulating evidence indicates that administration of AAV vector may initiate a detectable cellular and humoral immune response to its transduced neo-antigen in vivo. To elucidate the cellular basis of the AAV-mediated immune response, C57BL/6 mouse bone marrow-derived immature and mature dendritic cells (DCs) were infected with AAV encoding beta-galactosidase (AAV-lacZ) and adoptively transferred into mice that had received an intramuscular injection of AAV-lacZ 10 days earlier. Unexpectedly, C57BL/6 mice but not CD40 ligand-deficient (CD40L(-/-)) mice adoptively transferred with AAV-lacZ-infected immature DCs developed a beta-galactosidase-specific cytotoxic T-lymphocyte (CTL) response that markedly diminished AAV-lacZ-transduced gene expression in muscle fibers. In contrast, adoptive transfer of AAV-lacZ-infected mature DCs failed to elicit a similar CTL response in vivo. Our findings indicate, for the first time, that immature DCs may be able to elicit a CD40L-dependent T-cell immunity to markedly diminish AAV-lacZ transduced gene expression in vivo when a sufficient number of DCs capturing rAAV vector and/or its transduced gene products is recruited.


A marginal structural model analysis for the effect modification by education on the association between cancer diagnosis history and major depressive symptoms: Findings from Midlife Development in the U.S. (MIDUS).
Limited research has employed a longitudinal approach to investigate the role of education level as an effect modifier on the relationship between cancer diagnosis history and the experience of major depressive disorder (MDD) with a nationally representative sample. We harnessed data from three installments of the MIDUS Longitudinal study (n = 7108). A Marginal Structural Model facilitated the investigation of associations between a history of cancer diagnosis, MDD, and potential modifying effects of education level. Inverse probability weighting helped manage confounding factors. Findings indicated that a cancer diagnosis made one year prior was linked with 3.741 times greater odds of experiencing MDD (95 % CI: 1.411-9.918, p < 0.01). This connection was absent for diagnoses made two years earlier. Among individuals with education up to high school, a recent cancer diagnosis significantly increased the likelihood of MDD in the subsequent wave by 3.45 times (95 % CI: 1.31-9.08, p < 0.05). This pattern was not apparent among better-educated individuals. As the exposure variable was dependent on self-reported questionnaires, recall bias could be a potential limitation. Moreover, unaccounted variables like genetic factors could introduce confounding. A recent cancer diagnosis, particularly among less educated individuals, correlated with an increased probability of MDD, while the impact was not observed for older diagnoses. These findings emphasize that the timing of a cancer diagnosis and education level need consideration in the mental health assessment of cancer survivors.


Identification of pyrrolo[2,3-g]indazoles as new Pim kinase inhibitors.
The synthesis and Pim kinase inhibition potency of a new series of pyrrolo[2,3-g]indazole derivatives is described. The results obtained in this preliminary structure-activity relationship study pointed out that sub-micromolar Pim-1 and Pim-3 inhibitory potencies could be obtained in this series, more particularly for compounds 10 and 20, showing that pyrrolo[2,3-g]indazole scaffold could be used for the development of new potent Pim kinase inhibitors. Molecular modeling experiments were also performed to study the binding mode of these compounds in Pim-3 ATP-binding pocket.


Renaissance of Allostery to Disrupt Protein Kinase Interactions.
Protein-protein interactions often regulate the activity of protein kinases by allosterically modulating the conformation of the ATP-binding site. Bidirectional allostery implies that reverse modulation (i.e., from the ATP-binding site to the interaction and regulatory sites) must also be possible. Here, we review both the allosteric regulation of protein kinases and recent work describing how compounds binding at the ATP-binding site can promote or inhibit protein kinase interactions at regulatory sites via the reverse mechanism. Notably, the pharmaceutical industry has been developing compounds that bind to the ATP-binding site of protein kinases and potently disrupt protein-protein interactions between target protein kinases and their regulatory interacting partners. Learning to modulate allosteric processes will facilitate the development of protein-protein interaction modulators.


Vascular malformations of the spinal cord: intrathecal perimedullary arteriovenous fistulas fed by medullary arteries.
We studied eleven patients with intrathecal extramedullary arteriovenous fistulas identified by selective angiography and myelography. The fistulas were located on the surface of the cord, fed by medullary arteries. Angiography distinguished three separate types that gave identical clinical disorders. Therapeutic results of surgery and embolization allowed specific indications to be defined for treatment of each type of fistula.


Adverse obstetric symptoms and rural-urban difference in cesarean delivery in Rupandehi district, Western Nepal: a cohort study.
The burden of maternal morbidity is high in developing countries including Nepal. This study investigated obstetric complications and rural-urban difference in cesarean delivery rate in Western Nepal. A community-based cohort study was conducted in the Rupandehi district of Western Nepal during January-October, 2014, by interviewing 735 mothers within one month postpartum. The prevalence of obstetric complications was reported via frequency distribution, while factors associated with cesarean delivery were assessed using logistic regression analysis. The prevalence of adverse obstetric symptoms during antenatal, intranatal and postnatal periods were 19.7%, 27.8% and 21.6%, respectively. In total, 81 (11.0%) mothers reported having stillbirths. The cesarean delivery rate was 14.1% overall but was four times higher in the urban (23.0%) than in the rural areas (5.8%). Prolonged labor (19.0%) and heavy bleeding (16.7%) were common among rural women. Logistic regression analysis confirmed that cesarean section was more likely for mothers residing in urban areas than in rural areas (adjusted odds ratio 3.41; 95 % confidence interval 2.01 to 5.78). About one in five mothers reported some adverse obstetric symptoms. Obstetric problems were more common in the rural areas, whereas cesarean delivery rate was much higher in the urban areas. Further investigations are required to determine whether these cesarean sections are medically warranted or provider induced.


Structure-activity relationships of αs-casein peptides with multifunctional biological activities.
Multifunctional bioactive peptides have a wider role in modulating physiological functions and possess multiple biological activities. Peptides from bovine milk with sequences QKALNEINQF [p10] and TKKTKLTEEEKNRL [p14] from α-S2 casein f (79-88) and α-S2 casein f (148-161) were identified to be having multifunctional biological activities and were synthesized. These synthesized peptides show various biological activities like angiotensin-converting enzyme inhibition, prolyl endopeptidase inhibition, antioxidant, and antimicrobial activities. The mode of antimicrobial mechanism was studied and p10 shows depolarization of cell membrane, whereas p14 was found to display DNA-binding activity. Structural studies envisaged backbone flexibility, for differences in their mode of action. Peptide structure function studies were correlated to understand their multifunctional biological activity.


Effects of captopril on fibrinolytic function in healthy humans.
Several lines of evidence point to an interrelation of the renin angiotensin system (RAS) with the endogenous fibrinolytic system. In the present study, we have therefore investigated the effect of the ACE-inhibitor captopril on various parameters of the fibrinolytic system in healthy volunteer subjects. 10 male subjects aged 28-38 years were given captopril 25 mg b.i.d. over 2 weeks. Venous blood was drawn before and at the end of the treatment period at 09.00 AM, after the volunteers had received their last dose of captopril by 07. 30 AM. Blood samples were processed for the determination of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Both parameters were determined with respect to their abundance (as antigen concentrations) and function (activity). In addition, the concentration and activity of the von Willebrand factor were also determined. Two weeks of captopril treatment had no significant effect on any of the above mentioned parameters. Our results thus show that short-term treatment with the ACE-inhibitor captopril, at least in healthy subjects on an unrestricted NaCl intake, does not affect the fibrinolytic balance between t-PA and PAI-1 or the von Willebrand factor.


Structure-activity relationships in corpora allata of the cockroach Diploptera punctata: roles of mating and the ovary.
Morphometric studies were made on corpora allata of the cockroach Diploptera punctata from animals in which increasing gland size is not coupled to hormone synthesis (ovariectomized mated females; last-instar larvae) and in which gland size is coupled to hormone synthesis (normal mated and virgin females; penultimate-instar larvae). Cell number, gland volume, and juvenile hormone synthesis were measured. From electron micrographs, nuclear, cytoplasmic, and extracellular volumes; and cell membrane area were calculated; and fine structure described. Low-activity glands of ovariectomized mated females resembled high-activity glands from mated females in high cell number, large overall and cytoplasmic volume, and low nuclear-cytoplasmic ratio; they differed in having organelles typical of low-activity glands, mitochondria with dense matrices and large whorls of smooth endoplasmic reticulum. Inactive last-instar larval glands resembled mated ovariectomized female glands in increased cell number and organelles characteristic of inactive glands; however, their nuclear-cytoplasmic volume ratio was much higher. Penultimate larval glands with high activity per cell resembled active glands of normal mated females. Ovariectomy did not change morphometric parameters of virgin female glands; thus mating results in increase in size of adult female glands whereas the growing ovary is needed for changes in mitochondria and endoplasmic reticulum associated with high juvenile hormone synthesis.


Methamphetamine impurity profiling using a 0.32 mm i.d. nonpolar capillary column.
Classification of seized methamphetamine by impurity profiling can provide very useful information in criminal investigations of drug traffic routes, sources of supply and relationships between seizures. The aim of this study is to improve and develop an analytical method for detecting impurities such as starting materials and by-products in illegally prepared methamphetamine.HCl samples. A 50mg sample of methamphetamine.HCl was dissolved in 1 ml of buffer solution (four parts 0.1M phosphate buffer pH 7.0 and one part 10% Na2CO3). Impurities were extracted with 0.5 ml of ethyl acetate containing four internal standards (ISs) (n-decane, n-pentadecane, n-nonadecane and n-hexacosane) and analyzed by gas chromatography (GC) using a flame ionization detector (FID) on a DB-5 capillary column (0.32 mmi.d. x 30 m, film thickness 1.0 microm). The use of a middle-bore column offered better separation of the impurity peaks. The correction of the retention times of impurity peaks with four ISs made peak identification very accurate for subsequent data processing. Twenty-four characteristic peaks were selected for comparison and similarity and/or dissimilarity between samples, and the data were evaluated by the Euclidean distance of the relative peak areas after logarithmic transformation. The results indicate that the present method would be useful for methamphetamine impurity profiling.


Hormonal control of female sexual behavior in the Japanese quail.
Four experiments were carried out to study the hormonal control of female receptivity and proceptivity in Japanese quail. Both aspects of reproductive behavior can be activated in a dose-dependent manner by injections of estradiol benzoate (EB). Progesterone (P) given in addition to suboptimal doses of EB has little additional stimulatory effect. Other aspects of the reproductive physiology such as enlargement of the cloacal diameter and growth of the oviduct also seem to be controlled primarily by estrogens with little or no additive effect of P. These conclusions were confirmed by injecting egg-laying females with an antiestrogen, tamoxifen, or an antiprogestin, RU38486. Only the former had marked effects on sexual receptivity, cloacal diameter, and oviduct weight. The inhibiting effects of tamoxifen could easily be reversed by injecting females with large doses of estrogen, which demonstrates that tamoxifen acts on an estrogen-dependent mechanism and not through nonspecific effects.


Pentheus rather than Oedipus: on perversion, survival and analytic 'presencing'.
Following an introductory review of the main developments in the psychoanalytic thinking on perversion, the author focuses on her own understanding of perversion and its treatment, based on the psychoanalytic treatment of patients with severe sexual perversions. This paper uses the term 'autotomy' (borrowed from the field of biology) to describe perversion formation as an 'autotomous' defence solution involving massive dissociative splitting in the service of psychic survival within a violent, traumatic early childhood situation; thus, a compulsively enacted 'desire for ritualised trauma' ensues. The specific nature of the perverse scenario embodies the specific experiential core quality of the traumatic situation. It is an actual repetition in the present of the imprint of a past destructive experience which is pre-arranged and stage-managed; it thus encounters haunting scenes of dread or psychic annihilation while, at the same time, controlling, sanitising and disavowing them. Hence, the world of severe perversion is no longer oedipal, but rather the world of Pentheus, Euripides's most tragic hero--a world dominated by a mixture of a mother's madness, devourment, destruction and rituals of desire. According to this view, the (difficult) psychoanalytic treatment of perversion focuses on patient-analyst interconnectedness--brought about by the analyst's 'givenness to being present' or 'presencing'--at a deep, primary level of contact and impact (the emphasis being on the ontological dimension of experience). This evolving therapeutic entity creates and actualises a new, alternative experiential-emotional reality within the pervert's alienated world, eventually generating a change in the perverse essence. The author illustrate this approach with three clinical vignettes.


Cloning and nucleotide sequence of a full-length cDNA for human 14 kDa beta-galactoside-binding lectin.
A full-length cDNA for a 14K-type human lung beta-galactoside-binding lectin was cloned. The cDNA includes a 405 bp open reading frame coding 135 amino acids including the initiator methionine, and having a single internal EcoRI site and a polyadenylation signal. The deduced amino-acid sequence agreed completely with the sequence of a human placenta lectin determined by direct amino-acid sequence analysis (Hirabayashi, J. and Kasai, K. (1988) J. Biochem. 104, 1-4). It showed extensive sequence similarity with other vertebrate 14K-type lectins and a 35K-type lectin (carbohydrate-binding protein 35) of mouse 3T3 cell. Search of a Genbank sequence data base revealed significant sequence similarity between the beta-galactoside-binding lectins and the carboxyl-terminal half of an IgE-binding protein, the cDNA of which has been cloned from rat basophilic leukemia cells. Thus, 14K-type lectin, 35K-type lectin and IgE-binding protein appeared to form a superfamily of proteins. Almost all invariant residues are located in the central region of the 14K-type lectins, so this region may constitute an essential part of the lectins, such as the sugar-binding domain.


Attenuated DHEA and DHEA-S response to acute psychosocial stress in individuals with depressive disorders.
In recent years, a relationship between depression and basal dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) levels has frequently been suggested, but responses of these adrenal steroids to psychosocial stress have not been examined in individuals with depressive disorders. In this study, we examined salivary DHEA, DHEA-S, and cortisol/DHEA response to the Trier Social Stress Test (TSST) in individuals with depressive disorders and in healthy controls to discover whether the responses of DHEA and DHEA-S to acute psychosocial stress could be a more sensitive marker of HPA dysfunction in depressive disorders. We compared salivary cortisol, DHEA, DHEA-S, and cortisol/DHEA levels to the TSST tests between 38 individuals with depression and 43 healthy controls aged 18.4-25.9 years. Depression severity was assessed by the self-reported Beck Depression Inventory-II (BDI-II). Salivary samples were evaluated at four time points: the baseline (-10 time point), before the TSST started (0 time point), the end of the TSST (+20 time point), and the recovery (+50 time points). No significant differences existed in the basal adrenal hormonal levels between subjects with depressive disorders and controls; however, at the end of TSST, attenuated DHEA and DHEA-S response was identified in subjects with depressive disorders compared to that found in healthy subjects. The differences in the DHEA and DHEA-S levels at the +20 time point, as well as the differences in the cortisol/DHEA at the +50 time point, exhibited negative correlations with depression severity. Attenuated DHEA and DHEA-S response to acute psychosocial stress was identified in subjects with depressive disorders. These findings help us to discover the bi-directional relationship between depression and the hypothalamic-pituitary-adrenal (HPA) axis function, hence furthering our understanding of whether altered DHEA and DHEA-S response to psychosocial stress may be a more sensitive method than basal adrenal steroid analysis for detecting HPA axis dysfunction in depressive disorders. As this is a case control study, we could only draw the conclusion of the bi-directional relationship between the depression and the altered DHEA (S) response to stress, and could not identify whether depression was due to the HPA dysfunction, or vice versa. Prospective studies such as such as cohort studies or epidemiology experiments are needed to further test the cause of depression or HPA dysfunction; and the mechanisms responsible for altered DHEA and DHEA-S in response to acute psychosocial stress in individuals with depressive disorders are also needed to be clarified.


[The genetics of spinocerebellar ataxias].
Spinocerebellar ataxias are genetically heterogeneous autosomal dominant ataxia disorders. To date more than 30 different subtypes are known. In Germany particularly SCA1, SCA2, SCA3 and SCA6 are prevalent, as well as the less frequent subtypes SCA5, SCA14, SCA15, SCA17 and SCA28. Genetic causes range from coding repeat expansions (polyglutamine diseases), to non-coding expansions as well as conventional mutations. In some subtypes the genetic background is currently unknown. Age of onset, typical clinical findings and geographic distribution may help to reach a correct diagnosis; however a definitive diagnosis requires molecular genetic testing.


Extraglycemic effects of glp-1-based therapeutics: addressing metabolic and cardiovascular risks associated with type 2 diabetes.
To examine whether widespread tissue expression of the glucagon-like peptide (GLP)-1 receptor supports the possibility of differential effects of GLP-1-based therapeutics on cardiac function, blood pressure, food intake, gastric emptying, and other regulatory activities. GLP-1 receptor agonists (RAs) have demonstrated pleiotropic effects on overweight/obesity, hypertension, dyslipidemia, and cardiovascular (CV) disease. Food-regulatory effects have been demonstrated in preclinical and clinical trials, including reduced gastric motility and food intake leading to body weight reductions. Native GLP-1 and GLP-1 RAs have demonstrated cardioprotective effects in preclinical models. Using PubMed, we performed a search of the recent literature on GLP-1 and GLP-1 RAs. Preliminary clinical data indicate native GLP-1 has beneficial effects on endothelial cell function and vascular inflammation. Native GLP-1 and GLP-1 RAs have demonstrated renoprotective and antihypertensive effects, and reductions in lipid parameters. The GLP-1 RA liraglutide has also demonstrated positive effects on such markers of endothelial dysfunction as tumor necrosis factor-α and plasminogen activator inhibitor-1. Preliminary data suggest GLP-1 RAs could benefit type 2 diabetes patients at risk for CV comorbidities. Additional studies are needed to confirm the extraglycemic and extrapancreatic effects and determine whether outcomes will translate into beneficial effects for patient care.


In vivo confocal microscopy in the patients with cornea farinata.
To report in vivo corneal confocal microscopic findings of patients with cornea farinata. Two unrelated patients, a 47-year-old man and a 77-year-old woman, with cornea farinata were studied. Examination with a confocal microscope was performed in addition to routine slit-lamp biomicroscopy. In both cases, slit-lamp biomicroscopy showed numerous small, faint opacities in the deep stroma in both eyes. Using confocal microscopy, highly reflective small particles were observed in the cytoplasm of keratocytes in the deep stroma adjacent to the corneal endothelial layer. No abnormalities could be detected in the epithelial layer, in the mid-stromal layer, at the level of Descemet's membrane, and in the endothelial layer. In vivo corneal confocal microscopy is useful for observing stromal abnormalities in cornea farinata. Further investigation of posterior stromal opacities using confocal microscopy may be useful to understand and differentiate various corneal conditions involving primarily deep stromal layers.


Construction of a cytogenetically anchored microsatellite map in rabbit.
Rabbit (Oryctolagus cuniculus) represents a valuable source of biomedical models and corresponds to a small but active economic sector in Europe for meat and fur. The rabbit genome has not been thoroughly studied until recently, and high-resolution maps necessary for identification of genes and quantitative trait loci (QTL) are not yet available. Our aim was to isolate over 300 new and regularly distributed (TG)n or (TC)n rabbit microsatellites. To achieve this purpose, 164 microsatellite sequences were isolated from gene-containing bacterial artificial chromosome (BAC) clones previously localized by fluorescence in situ hybridization (FISH) on all the rabbit chromosomes. In addition, 141 microsatellite sequences were subcloned from a plasmid genomic library, and for 41 of these sequences, BAC clones were identified and FISH-mapped. TC repeats were present in 62% of the microsatellites derived from gene-containing BAC clones and in 22% of those from the plasmid genomic library, with an average of 42.9% irrespective of the microsatellite origin. These results suggest a higher proportion of (TC)n repeats and a nonhomogeneous distribution of (TG)n and (TC)n repeats in the rabbit genome compared to those in man. Among the 305 isolated microsatellites, 177 were assigned to 139 different cytogenetic positions on all the chromosomes except rabbit Chromosome 21. Sequence similarity searches provided hit locations on the Human Build 35a and hypothetical assignments on rabbit chromosomes for ten additional microsatellites. Taken together, these results report a reservoir of 305 new rabbit microsatellites of which 60% have a cytogenetic position. This is the first step toward the construction of an integrated cytogenetic and genetic map based on microsatellites homogeneously anchored to the rabbit genome.


Memory retrieval and the parietal cortex: a review of evidence from a dual-process perspective.
Although regions of the parietal cortex have been consistently implicated in episodic memory retrieval, the functional roles of these regions remain poorly understood. The present review presents a meta-analysis of findings from event-related fMRI studies reporting the loci of retrieval effects associated with familiarity- and recollection-related recognition judgments. The results of this analysis support previous suggestions that retrieval-related activity in lateral parietal cortex dissociates between superior regions, where activity likely reflects the task relevance of different classes of recognition test items, and more inferior regions where retrieval-related activity appears closely linked to successful recollection. It is proposed that inferior lateral parietal cortex forms part of a neural network supporting the 'episodic buffer' [Baddeley, A. D. (2000). The episodic buffer: A new component of working memory? Trends in Cognitive Sciences, 4, 417-423].


Coronavirus infects and causes demyelination in primate central nervous system.
Two species of primates, Owl and African green monkeys, were inoculated intracerebrally with either the neurotropic mouse hepatitis virus JHM or the putative multiple sclerosis brain coronavirus isolate SD. These viruses caused an acute to subacute panencephalitis and/or demyelination in the infected animals. The course of pathogenesis and sites of detected viral RNA and antigen was dependent both on animal species and virus strain but the results clearly showed that these viruses replicated and disseminated in the central nervous system (CNS) of these primates. This study suggests that human CNS may be susceptible to coronavirus infection.


Prevalence and Correlates of Family Cancer History Knowledge and Communication Among US Adults.
Knowing one's family cancer history (FCH) plays an important role in cancer prevention. Communicating health histories with relatives can increase awareness about familial cancer risk and aid health care providers in personalizing cancer prevention recommendations. This study used data from the National Cancer Institute's 2018 Health Information National Trends Survey. We calculated frequencies and weighted population estimates for key FCH communication variables. Multivariable logistic regression models estimated associations between sociodemographic characteristics and FCH communication. Findings provide the first nationally representative estimates of FCH communication. Less than one-third (31.1%) of the population reported knowing FCH very well, 70.0% had discussed FCH with at least 1 biological relative, 39.0% had discussed FCH with a health care provider, and 22.2% reported being completely confident in completing FCH on medical forms. Findings also identified key demographic factors, including sex, household income, education level, and race and ethnicity, associated with these FCH measures among the US adult population. Results can be used to target and tailor FCH communication interventions for patients, families, and providers.


Adoption of improved cook stoves by households in informal settlements of Woreda 12, Yeka subcity, Addis Ababa.
This study analyzed the factors affecting the use of improved cook stoves (ICS) in informal settlements of Addis Ababa based on the data generated from 450 households drawn from Woreda (Woreda is a local term used to describe the lowest administrative unit of Addis Ababa City Administration, Ethiopia.) 12 of Yeka subcity. It examined the interactive effect of households' socio-economic backgrounds and energy sources on the adoption of ICS. The data were analyzed using descriptive methods and the multinomial logit model. Demographic and economic factors such as sex of the household head,[Household head is the one who has an income and decision-making power in family affairs (a husband for married people)], family size and family income have no relationships with households' ICS use while education level, number of years lived in the area, type of home owned, and stove-operating costs have a significant influence on the choice of an ICS. Households that live in a good home (made from wood and cement) used more Mirt (Mirt is an improved firewood stove mainly used to bake Injera and bread.) and Lakech [Lakech also called Tikikil is an improved charcoal stove used to cook different kinds of dishes (non-Injera)] stoves than the traditional three-stone stoves. On the other hand, household heads with higher levels of education and who have lived more than 7 years in the area in a better home owned more ICS than the traditional three-stone stoves. The availability, affordability, durability and simplicity to operate stoves, and subsidies affect the choice of an ICS. Energy sources that are commonly used by households in informal settlements also have a strong influence on the choice of energy-efficient stoves. Compared to ICS, heavy use of traditional three-stone stoves by households that already have access to electricity, directs government policies to focus on providing reliable electric service and subsidize those using ICS.


Long noncoding RNAs: emerging roles in pulmonary hypertension.
Pulmonary hypertension (PH) is a complex and progressive disease characterized by increased pulmonary vascular resistance and pulmonary artery pressure, leading to pulmonary vascular remodeling, right heart failure, and ultimately death. Although several molecular pathways related to vascular remodeling have been reported, the mechanism behind this fatal disease with poor prognosis remains largely unclear. Long noncoding RNAs (lncRNAs) have been proven to be playing crucial roles in various biological processes, and emerging studies demonstrated lncRNAs as essential epigenetic modifiers involved in the onset and development of PH. The present review summarizes the types and biogenesis of lncRNAs, focuses on the biological function of lncRNAs in vascular diseases, and highlights all proven lncRNAs as well as highly potential lncRNA candidates involved in PH. Moreover, the interaction between lncRNA and corresponding miRNA in PH is also emphasized. Finally, we discuss current challenges and future prospects of lncRNAs as potential biomarkers and therapeutic targets for PH. Current data indicate lncRNAs are vital regulators of PH and may act as promising diagnostic and therapeutic targets for PH.


Uptake of I-131 by an abdominal neurilemoma mimicking metastatic thyroid carcinoma.
I-131 whole-body imaging may show characteristic findings in functioning, metastatic differentiated thyroid carcinoma. Nonthyroidal tumor uptake of I-131 is rare, but may mislead the physician to inappropriate treatment. A case is reported of a 59-year-old woman with papillary thyroid carcinoma who demonstrated strong uptake of I-131 in an abdominal cystic neurilemoma. Her serum thyroglobulin concentration at that time was low, at 3.35 ng/ml. Although the concentrating mechanism of I-131 was not clear, several clues pointed to the possibilities of nonthyroidal tumor uptake: 1) faster clearing of radioactivity than usual thyroid tissue, 2) persistent low serum thyroglobulin concentration, and 3) the presence of a cystic component in the nonthyroidal tumor.


Indoor heating triggers bacterial ecological links with tap water stagnation during winter: Novel insights into bacterial abundance, community metabolic activity and interactions.
The overnight stagnation of tap water in plumbing systems can lead to water quality deterioration. Meanwhile, the indoor heating can improve the indoor temperature in cold areas during winter, which may affect the quality of tap water during stagnation. However, indoor heating drives bacterial ecological links with tap water stagnation during winter are not well understood. The results indicated that the water temperature increased significantly after stagnation during indoor heating periods. Moreover, the average intact cell number and total adenosine triphosphate (ATP) concentration increased 1.53-fold and 1.35-fold after stagnation, respectively (P < 0.01). In addition, the increase in the ATP per cell number indicated that the combined effects of stagnation and indoor heating could enhance the bacterial activity. Biolog data showed that the bacterial community metabolic capacity was significantly higher in stagnant water than that of fresh water. Co-occurrence networks suggested that the bacterial metabolic profile changed after stagnation during the heating periods. DNA analysis indicated that the composition of the bacterial community changed dramatically after stagnation. The abundances of potential pathogens such as Mycobacterium sp. and Pseudomonas sp. also increased after stagnation. These results will give novel insights on comprehensive understanding the combined effects of indoor heating and overnight stagnation on the water bacterial community ecology of plumbing systems, and provide a scientific basis for tap water quality management after overnight stagnation during the indoor heating periods.


Does the Gonostomum-patterned oral apparatus in hypotrichia carry a phylogenetic signal? Evidence from morphological and molecular data based on extended taxon sampling using three nuclear genes (Ciliophora, Spirotrichea).
The classification of hypotrichs based on the gonostomatid oral structure is widely accepted, but the phylogenetic signal of this character is unknown. Here, we infer the species phylogeny of those gonostomatids for which molecular data are available, plus 26 new sequences of SSU-rDNA, ITS1-5.8S-ITS2 and LSU-rDNA genes. The results indicate that: (i) the endoral is more phylogenetically informative than the paroral; (ii) the structure of the endoral and the Gonostomum-pattern adoral zone of membranelles are plesiomorphies for the hypotrichs sensu stricto; (iii) the group of species possessing these features is monophyletic in all our phylogenetic analyses, except that for the SSU-rDNA; (iv) Schmidingerotrichidae is monophyletic in all trees, suggesting that it is a well-defined family; (v) the Gonostomatidae is polyphyletic in the SSU-rDNA and ITS1-5.8S-ITS2 trees, with Gonostomum, Cladotricha, Cotterillia, Metagonostomum, Paragonostomum and Wallackia distributed among separate clades, but monophyletic in the LSU-rDNA and concatenated trees; (vi) higher hypotrich taxa such as core urostyloids and core sporadotrichids/stichotrichids might have evolved from species that possessed a gonostomatid oral apparatus.


Frequency-independent synaptic transmission supports a linear vestibular behavior.
The vestibular system is responsible for transforming head motion into precise eye, head, and body movements that rapidly stabilize gaze and posture. How do central excitatory synapses mediate behavioral outputs accurately matched to sensory inputs over a wide dynamic range? Here we demonstrate that vestibular afferent synapses in vitro express frequency-independent transmission that spans their in vivo dynamic range (5-150 spikes/s). As a result, the synaptic charge transfer per unit time is linearly related to vestibular afferent activity in both projection and intrinsic neurons of the vestibular nuclei. Neither postsynaptic glutamate receptor desensitization nor saturation affect the relative amplitude or frequency-independence of steady-state transmission. Finally, we show that vestibular nucleus neurons can transduce synaptic inputs into linear changes in firing rate output without relying on one-to-one calyceal transmission. These data provide a physiological basis for the remarkable linearity of vestibular reflexes.


Reduced anterior cingulate cognitive activation is associated with prefrontal-temporal cortical thinning in schizophrenia.
The anterior cingulate cortex plays a central role in altered processes of cognitive control in schizophrenia. However, the cortical foundations of disturbed anterior cingulate cognitive activation are poorly understood. Therefore, this study investigated the association of anterior cingulate cognitive activation and cortical thickness in schizophrenia combining functional magnetic resonance imaging (fMRI) and surface-based morphometry. Fifty-three patients with schizophrenia according to DSM-IV and 53 age- and sex-matched healthy subjects were included and underwent fMRI and high-resolution T1-weighted MRI. fMRI data was analyzed using SPM5. Cortical thickness was calculated using an automated computerized algorithm (Freesurfer Software). Statistical cortical maps were created correlating anterior cingulate activation and cortical thickness on a node-by-node basis covering the entire cortex in schizophrenia and healthy control subjects. Patients demonstrated a significantly reduced anterior cingulate cognitive activation. Significantly differing associations of anterior cingulate activation and cortical thickness were found in a pattern of dorsolateral prefrontal, superior frontal-anterior cingulate, and superior temporal cortical regions, where patients but not healthy control subjects demonstrated a significant association of reduced anterior cingulate activation and cortical thinning. A direct comparison of cortical thickness between the diagnostic groups revealed a significantly reduced cortical thickness of these prefrontotemporal regions in schizophrenia. To our best knowledge, this is the first study indicating that prefrontotemporal cortical thinning constitutes a relevant cortical pathomechanism for altered cognitive activation in schizophrenia. Our data additionally reveal a profound disruption of structural and functional integration in the prefrontotemporal system in schizophrenia.


Docking and pharmacodynamic studies on hGAT1 inhibition activity in the presence of selected neuronal and astrocytic inhibitors. Part I.
Inhibition of 4-aminobutanoic acid (GABA) uptake is a strategy for enhancing GABA transmission. The utility of this approach is demonstrated by the successful development of such agents for the treatment of epilepsy and pain. Existing reports on acute brain slice preparations indicate the intersecting of complementary channels and receptors sets between astrocytes and neurons cells. Thorough analysis of astroglial cells by means of molecular and functional studies demonstrated their active modulatory role in intercellular communication. The chemical interactions between sixteen GABA analogues and isoform of hGAT1 is outlined in the light of molecular docking results. In the in vivo part antinociceptive properties of racemic nipecotic acid, its R and S enantiomers and isonipecotic acid, each administered intraperitoneally at 3 fixed doses (10, 30 and 100 mg/kg), were assessed in a thermally-induced acute pain model i.e. the mouse hot plate test. Docking analyses provided complex binding energies, specific h-bond components, and h-bond properties, such as energies, distances and angles. In vivo tests revealed statistically significant antinociceptive properties of isonipecotic acid (10 and 30 mg/kg), R-nipecotic acid (30 and 100 mg/kg) and S-nipecotic acid (100 mg/kg) in mice. The docking data endorse the hypothesis of correlation between the strength of their chemical interactions with hGAT1 and analgesic action of studied compounds.


Competitive reaction kinetics of sulfate-reducing bacteria and methanogenic bacteria in anaerobic filters.
A kinetic model for the anaerobic filter (AF) that takes into account the mass fractions of sulfate-reducing bacteria (SRB) (fSRB) and methanogenic bacteria (MB) (fMB) and an inhibiting effect of H2S on bacterial groups is proposed. When the acetate-fed AFs were maintained at the low organic loading rate of 2.5kg COD/m3d, variations of the influent COD/SO4(2-) ratio (0.5-3.0) does not materially affect the acetate removal efficiency (all varying between 98.1% and 99.7%). With an increase in influent COD/SO4(2-) ratio, both the biofilm thickness and the specific substrate utilization rate decreased slightly but f(SRB) decreased markedly. The estimated results of fSRB and fMB showed that SRB out-competed MB for bacterial growth if the influent COD/SO4(2-) ratio was maintained at less than 1.3, whereas MB out-competed SRB for bacterial growth if the influent COD/SO4(2-) ratio was maintained at greater than 2.0. The specific substrate utilization rate of SRB (0.19-0.24mg acetate/mg VSSd) was lower than that of MB (0.31-0.59mg acetate/mg VSSd). The estimated kinetic parameters disclosed that the affinity of acetate to MB was higher and unionized H2S imposed a greater inhibiting effect on MB. The model simulation results (acetate and sulfate removal) agreed well with the experimental results.


Comparison of frequency and strain-rate domain mechanical characterization.
Indentation is becoming increasingly popular to test soft tissues and (bio)materials. Each material exhibits an unknown intrinsic "mechanical behaviour". However, limited consensus on its "mechanical properties" (i.e. quantitative descriptors of mechanical behaviour) is generally present in the literature due to a number of factors, which include sample preparation, testing method and analysis model chosen. Viscoelastic characterisation - critical in applications subjected to dynamic loading conditions - can be performed in either the time- or frequency-domain. It is thus important to selectively investigate whether the testing domain affects the mechanical results or not. We recently presented an optomechanical indentation tool which enables both strain-rate (nano-[Formula: see text]) and frequency domain (DMA) measurements while keeping the sample under the same physical conditions and eliminating any other variability factor. In this study, a poly(dimethylsiloxane) sample was characterised with our system. The DMA data were inverted to the time-domain through integral transformations and then directly related to nano-[Formula: see text] strain-rate dependent results, showing that, even though the data do not perfectly overlap, there is an excellent correlation between them. This approach indicates that one can convert an oscillatory measurement into a strain-rate one and still capture the trend of the "mechanical behaviour" of the sample investigated.


Antibody responses to influenza vaccination in patients with chronic renal failure.
A bivalent type A inactivated influenza virus vaccine containing both sets of H3N2 and Hsw1N1 antigens was given to patients with chronic renal failure and to control subjects. The patients were divided into an azotemic group in whom dialysis was not yet required and a hemodialyzed group. Hemagglutination-inhibition (HI) antibody responses were measured at time intervals of 1,3, and 4 weeks after vaccination. We found that the mean postvaccination HI titers against both sets of antigens in the patients as a group did not differ significantly from those found in the control subjects as a group. The proportion of responders showing a fourfold or greater increase in post-vaccination antibody responses over prevaccination antibody values for either set of antigens was similar in both groups of patients and the group of control subjects. In general, an inverse correlation was found between prevaccination antibody levels and postvaccination antibody responses in both patients and control subjects. The only exception to this trend was the response of two of the azotemic patients to the H3N2 antigens who failed to respond despite low prevaccination antibody levels. These were the patients with the highest serum creatinine values.


In Situ Enzymatic Conversion of Nannochloropsis oceanica IMET1 Biomass into Fatty Acid Methyl Esters.
Conventionally, production of methyl ester fuels from microalgae occurs through an energy-intensive two-step chemical extraction and transesterification process. To improve the energy efficiency, we performed in situ enzymatic conversion of whole algae biomass from an oleaginous heterokont microalga Nannochloropsis oceanica IMET1 with the immobilized lipase from Candida antarctica. The fatty acid methyl ester yield reached 107.7% for dry Nannochloropsis biomass at biomass to t-butanol to methanol weight ratio of 1:2:0.5 and a reaction time of 12 h at 25 °C, representing the first report of efficient whole algae biomass conversion into fatty acid methyl esters at room temperature. Different forms of algal biomass including wet Nannochloropsis biomass were tested. The maximum yield of wet biomass was 81.5%. Enzyme activity remained higher than 95% after 55 days of treatment (equal to 110 cycles of reaction) under the conditions optimized for dry algae biomass conversion. The low reaction temperature, high enzyme stability, and high yield from this study indicate in situ enzymatic conversion of dry algae biomass may potentially be used as an energy-efficient method for algal methyl ester fuel production while allowing co-product recovery.


Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice.
No effective remedy has currently been realized to prevent the cognitive impairments of Alzheimer's disease (AD). The interruption of the toxic pathways of amyloid beta peptide (Abeta) still remains promising for the treatment. The involvement of tumor necrosis factor-alpha (TNF-alpha) in the toxicity of Abeta(1-40) in recent reports provide a fresh target for the interruption. In the current study, we evaluated the feasibility of a strategy that target TNF-alpha to prevent the impairment of memory induced by Abeta. The i.c.v-injection of Abeta(25-35) increased the hippocampal mRNA expression of both TNF-alpha and inducible nitric oxide synthase (iNOS), of which the former was stronger. The knock-out of TNF-alpha (TNF-alpha (-/-)) in mouse prevented the increase of iNOS mRNA induced by Abeta(25-35). Not only the inhibition of iNOS activity but also TNF-alpha (-/-) prevented the nitration of proteins in the hippocampus and the impairment of recognition memory in mice induced by Abeta(25-35). Daily treatment with thalidomide (20 mg/kg), a preferential degrader of TNF-alpha mRNA, or i.c.v.-injection of an anti-TNF-alpha antibody (10 etag/mouse) prevented the nitration of proteins in the hippocampus and the impairment of recognition memory induced by Abeta(25-35) or Abeta(1-40) in mice. These results suggested the practicability of targeting TNF-alpha as a preventive strategy against Abeta-mediated cognitive impairments.


Cortical projection of giant neostriatal neurons in the cat. Light and electron microscopic horseradish peroxidase study.
Following voluminous injections of horseradish peroxidase (HRP) in various neocortical fields, a small number of labeled large neurons are observed ipsilaterally in the putamen, striatal ponticuli, caudate nucleus, and nucleus accumbens septi. The bulk of the corticopetal cells are found in the putamen and in the striatal ponticuli. A more significant number of labeled neurons is encountered following injections in auditory and sensorimotor cortex, followed by the prefrontal and premotor cortex; very few cells project to the visual cortex. Ultrastructurally, the large HRP-labeled neurons display an eccentrically located, indented nucleus, abundant granular endoplasmic reticulum forming Nissl bodies, well developed Golgi zones, and numerous dense bodies. The simultaneous demonstration of retrogradely transported HRP and acetylcholinesterase (AChE) suggest that the large neurons are presumably cholinergic. These results provide evidence that at least some of the giant striatal neurons are efferent cells. The coincidence of cytological, histochemical, and hodological criteria invite the speculation that the giant corticopetal neostriatal neurons might be related to the magnocellular cholinergic groups of the basal forebrain (especially the Ch4 group).


Morphogenetic activity of silica and bio-silica on the expression of genes controlling biomineralization using SaOS-2 cells.
In a previous study (Schröder et al., J Biomed Mater Res B Appl Biomater 75:387-392, 2005) we demonstrated that human SaOS-2 cells, when cultivated on bio-silica matrices, respond with an increased hydroxyapatite deposition. In the present contribution we investigate if silica-based components (Na-silicate, tetraethyl orthosilicate [TEOS], silica-nanoparticles) (1) change the extent of biomineralization in vitro (SaOS-2 cells) and (2) cause an alteration of the expression of the genes amelogenin, ameloblastin, and enamelin, which are characteristic for an early stage of osteogenesis. We demonstrate that the viability of SaOS-2 cells was not affected by the silica-based components. If Na-silicate or TEOS was added together with ss-glycerophosphate, an organic phosphate donor, a significant increase in biomineralization was measured. Finally, expression levels of the amelogenin, ameloblastin, and enamelin genes were determined in SaOS-2 cells during exposure to the silica-based components. After exposure for 2 days, expression levels of amelogenin and enamelin strongly increased in response to the silica-based components, while no significant change was seen for ameloblastin. In contrast, exposure of SaOS-2 cells to ss-glycerophosphate resulted in increased expression of all three genes. We conclude that the levels of the structural molecules of the enamel matrix, amelogenin and enamelin, increase in the presence of silica-based components and substantially contribute to the extent of hydroxyapatite crystallite formation. These results demonstrate that silica-based components augment hydroxyapatite deposition in vitro and suggest that enzymatically synthesized bio-silica (via silicatein) might be a promising route for tooth reconstruction in vivo.


Is the beta estradiol receptor receiving enough attention for its metabolic importance in postmenopause?
The relationship between menopause and the development of metabolic diseases is well established. In postmenopause women, there is an expansion of visceral white adipose tissue (WATv), which highly contributes to the rise of circulating lipids. Meanwhile, muscle glucose uptake decreases and hepatic glucose production increases. Consequently, in the pancreas, lipotoxicity and glycotoxicity lead to deficient insulin production. These factors initiate an energy imbalance and enhance the probability of developing cardiovascular and metabolic diseases. Although the activation of estradiol receptors (ER) has been shown to be beneficial for the WAT stock pattern, leading to the insulin-sensitive phenotype, authors have described the risk of these receptors' activation, contributing to neoplasia development. The selective activation of beta-type ER (ERβ) seems to be a promising strategy in the treatment of energy imbalance, acting on several tissues of metabolic importance and allowing an intervention with less risk for the development of estrogen-dependent neoplasia. However, the literature on the risks and benefits of selective ERβ activation still needs to increase. In this review, several aspects related to ERβ were considered, such as its physiological role in tissues of energy importance, beneficial effects, and risks of its stimulation during menopause. PubMed, SciELO, Cochrane, and Medline/Bireme databases were used in this study.


The targeted disruption of the MYPT1 gene results in embryonic lethality.
Myosin phosphatase (MP) is a major phosphatase responsible for the dephosphorylation of the regulatory light chain of myosin II. MYPT1, a target subunit of smooth and nonmuscle MP, is responsible for activation and regulation of MP. To identity the physiological roles of MP, we have generated MYPT1-deficient mice by gene targeting. The heterozygous mice showed no changes in expression levels of MYPT1 and no distinct phenotype compared to wild-type mice was observed. None of the F2 mice were homozygous for the MYPT1 deletion, indicating that the targeted disruption of the MYPT1 gene resulted in embryonic lethality. The point of embryonic lethality is before 7.5 dpc. These findings indicate that MYPT1 is essential for mouse embryogenesis.


Experimental study of consistency degradation of different greases in mixed neutron and gamma radiation.
Many of the moving components in accelerator and target environments require lubrication. Lubricants in such environments are exposed to high fluxes of secondary radiation, which originates from beam interactions with the target and from beam losses. The secondary radiation is a mix of components, which can include significant fractions of neutrons. Lubricants are radiation-sensitive polymeric materials. The radiation-induced modifications of their structure reduce their service lifetime and impose additional facility maintenance, which is complicated by the environmental radioactivity. The study of the lubricants radiation resistance is therefore necessary for the construction of new generation accelerators and target systems. Nevertheless, data collected in mixed radiation fields are scarce. Nine commercial greases were irradiated at a TRIGA Mark II Research Reactor to serve for the construction of new accelerator projects like the European Spallation Source (ESS) at Lund (Sweden) and Selective Production of Exotic Species (SPES) at Legnaro, (Italy). Mixed neutron and gamma doses ranging from 0.1 MGy to 9.0 MGy were delivered to the greases. For an experimental quantification of their degradation, consistency was measured. Two of the greases remained stable, while the others became fluid. Post-irradiation examinations evidence the cleavage of the polymeric structure as the dominant radiation effect. Dose and fluence limits for the use of each product are presented. Apart from the scientific significance, the results represent an original and useful reference in selecting radiation resistant greases for accelerator and target applications.