Cyclophosphamide for treating rheumatoid arthritis.
To assess the short-term effects of cyclophosphamide for the treatment of rheumatoid arthritis. We searched the Cochrane Musculoskeletal Group's Register, the Cochrane Controlled Trials Register (issue 3, 2000), Medline and Embase up to and including August 2000. We also carried out a handsearch of the reference lists of the trials retrieved from the electronic search. All randomized controlled trials (RCTs) and controlled clinical trials (CCTs) comparing oral cyclophosphamide against placebo (or an active drug at a dosage considered to be ineffective) in patients with rheumatoid arthritis. Data abstraction was carried out independently by two reviewers. The same two reviewers using a validated checklist (Jadad 1996) assessed the methodological quality of the RCTs and CCTs. Rheumatoid arthritis outcome measures were extracted from the publications for baseline and end-of-study. The pooled analysis was performed using standardized mean differences (SMDs) for joint counts. Weighted mean differences (WMDs) were used for erythrocyte sedimentation rate (ESR). Toxicity was evaluated with pooled odds ratios for withdrawals. A chi-square test was used to assess heterogeneity among trials. Fixed effects models were used throughout. A total of 70 patients were included in the pooled analysis of two trials, 31 receiving cyclophosphamide. A statistically significant benefit was observed for cyclophosphamide when compared to placebo for tender and swollen joint scores: SMDs were -0.57 and -0.59 respectively. The difference in ESR also favoured the active drug but did not reach statistical significance (-12 mm, 95%CI: -26 to 2.5). One trial reported the number of patients developing new or worse erosions: the OR for cyclophosphamide compared to placebo was 0.17 (95% CI: 0.05 to 0.57). Patients receiving placebo were six times more likely to discontinue treatment because of lack of efficacy than patients receiving cyclophosphamide. Withdrawals from adverse reactions were higher in the cyclophosphamide group (Odds ratio=2.9), although this difference was not statistically significant. Side effects from cyclophosphamide included hemorrhagic cystitis, nausea, vomiting, leucopenia, thrombocytopenia, alopecia, amenorrhea and herpes zoster infections. Cyclophosphamide appears to have a clinically and statistically significant benefit on the disease activity of patients with RA, similar to some disease modifying antirheumatic drugs (DMARDs) such as antimalarials or sulfasalazine, but lower than methotrexate. Toxicity however is severe, limiting its use given the low benefit-risk ratio compared to other antirheumatic agents.


Upregulation of CELSR1 expression promotes ovarian cancer cell proliferation, migration, and invasion.
Cadherin epidermal growth factor and laminin-G seven-pass G-type receptor 1 (CELSR1) is a planar cell polarity protein involved in the transmission of directional cues to align either individual cells within an epithelial sheet or multicellular clusters. CELSR1 has been suggested to play a role in glioma, breast cancer, and chronic lymphocytic leukemia development; however, whether it has a role in the pathogenesis of ovarian cancer remains unknown. The aim of this study was to determine the role of CELSR1 in ovarian cancer and elucidate its underlying molecular mechanisms. By analyzing gene expression data downloaded from the Cancer Genome Atlas database, we found that CELSR1 expression was upregulated in ovarian cancer tissues compared to that in normal ovarian tissues. High CELSR1 expression levels were associated with poor prognosis in patients with ovarian cancer. Cell proliferation, scratch, and transwell assays revealed that CELSR1 promoted the proliferation, migration, and invasion of ovarian cancer cells in vitro. In addition, transcriptome sequencing analysis revealed that CELSR1 knockdown in T29H cells resulted in the dysregulation of the expression of 1320 genes. Further analysis revealed that genes involved in proliferation- and migration-associated signaling pathways were regulated by CELSR1. Our study demonstrates that CELSR1 is highly expressed in ovarian cancer cells and regulates their proliferation and migration, suggesting its potential as a diagnostic marker and therapeutic target.


Time multiplexing of high power laser diodes with single crystal photo-elastic modulators.
Time-multiplexing is a method to increase the brilliance of diode lasers, i.e. a sequence of laser pulses emitted from different laser diodes at different times is guided onto a common optical path via a cascade of polarizing cube beam splitters and polarization switches. The latter are made of piezo-electric crystals oscillating in resonance and making use of the photo-elastic effect to obtain the desired modulation of polarization. We realized a demonstrator for time multiplexing of four laser diodes with such self-excited photo-elastic modulators. The latter is a new alternative to conventional photo-elastic modulators used in ellipsometers.


Mechanical thrombectomy as the primary treatment for acute basilar artery occlusion: experience from 5 years of practice.
Most studies of the treatment for acute basilar occlusion focus on intravenous or intra-arterial thrombolysis whereas data on mechanical thrombectomy as the preferred treatment for acute basilar occlusion are scarce. In this study, data are presented on 28 patients treated with mechanical thrombectomy as the preferred treatment for basilar artery occlusion. Retrospective study comprising all patients who were treated for acute basilar occlusion at the Karolinska University Hospital from September 2005 to November 2010. Favorable outcome was defined as a modified Rankin score of ≤2 at 3-8 months after thrombectomy. Of 28 patients treated with mechanical thrombectomy, the proportion reaching a favorable outcome was 57% (95% CI 37% to 75%), and if there were no signs of acute infarction prior to treatment the proportion was 73% (95% CI 50% to 89%). Only 21% died (95% CI 8% to 41%). The results for mechanical thrombectomy for basilar artery occlusion were superior to those presented previously for intravenous and intra-arterial thrombolysis. The study suggests that mechanical thrombectomy is a method distinct from therapies based on thrombolysis and that any randomized clinical trial on treatment for acute basilar occlusion must consider mechanical thrombectomy as a separate entity.


Celastrol inhibits hepatitis C virus replication by upregulating heme oxygenase-1 via the JNK MAPK/Nrf2 pathway in human hepatoma cells.
Celastrol, a quinone methide triterpene isolated from the root extracts of Tripterygium wilfordii, can greatly induce the gene expression activity of heme oxygenase-1 (HO-1) to achieve disease prevention and control. HO-1 induction was recently shown to result in anti-HCV activity by inducing type I interferon and inhibiting hepatitis C virus (HCV) NS3/4A protease activity. The aim of the present study is to evaluate the anti-HCV activity of celastrol and characterize its mechanism of inhibition. The anti-HCV activity of celastrol was evaluated using the HCV subgenomic replicon and HCVcc infection systems. The anti-HCV mechanism of celastrol targeting HO-1 expression was clarified using specific inhibitors against several signaling pathways. The transcriptional regulation of celastrol on target gene expression was determined using promoter-based reporter activity assay. The synergistic effect of celastrol and a numbers of clinically used anti-HCV drugs was determined via a drug combination assay. Celastrol inhibited HCV replication in both the HCV subgenomic and HCVcc infection systems with EC50 values of 0.37 ± 0.022 and 0.43 ± 0.019 μM, respectively. Celastrol-induced heme oxygenase 1 (HO-1) expression promoted antiviral interferon responses and inhibition of NS3/4A protease activity, thereby blocking HCV replication. These antiviral effects were abrogated by treatment with the HO-1-specific inhibitor SnMP or silencing of HO-1 expression by transfection of shRNA, which indicates that HO-1 induction contributes to the anti-HCV activity of celastrol. JNK mitogen-activated protein kinase and nuclear factor erythroid 2-related factor 2 (Nrf2) were confirmed to be involved in the inductive effect of celastrol on HO-1 expression. Celastrol exhibited synergistic effects in combination with interferon-alpha, the NS5A inhibitor daclatasvir, and the NS5B inhibitor sofosbuvir. Celastrol can serve as a potential supplement for blocking HCV replication. Targeting the JNK/Nrf2/HO-1 axis presents a promising strategy against HCV infection.


Photosystem II damage induced by chemically generated singlet oxygen in tobacco leaves.
In the present work, we investigated the role of chemically generated singlet oxygen, produced by photodynamic effect of rose bengal, in damaging the PSII complex in tobacco leaves in which protein synthesis-dependent repair was inhibited by infiltration with lincomycin. A 30-min exposure to low-intensity (150 micromol m(-2) s(-1)) photosynthetically active radiation (PAR) induced singlet oxygen production as detected by quenching of 3-[N-(beta-diethylaminoethyl)-N-dansyl]aminomethyl-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole fluorescence in leaves infiltrated with both lincomycin and rose bengal. This light treatment caused photoinhibition of PSII, as revealed by the marked loss both of the photochemical yield and the amount of D1 protein in PSII reaction center. When rose bengal was not present in the leaves, these symptoms of photodamage were not induced by the same low-intensity PAR. However, when excitation pressure on PSII was increased to 1500 micromol m(-2) s(-1), irreversible photodamage of PSII was also observed, showing that the lincomycin treatment applied in vivo was sufficiently inhibiting protein repair. Our results show that singlet oxygen is able to cause oxidative damage in PSII directly, as suggested earlier and argue against its recently hypothesized role exclusive to inhibiting PSII protein repair (Nishiyama et al. 2006).


Newer therapies for the treatment of metastatic breast cancer: a clinical update.
Breast cancer is the foremost common malignancy among the female population around the world. Female breast cancer incidence rates have increased since 1980, slowed in 1990, the rate of increase have leveled off since 2001. In spite of the advances in the early detection, treatment, surgery and radiation support, almost 70% of the patients develop metastasis and die of the disease. Around 10% of the patients when diagnosed with breast cancer have metastases. Survival among the breast cancer patients have increased due to the introduction of novel single agent, combination of chemotherapeutic agents and targeted biologic agents, which is breast cancer specific. The staging of tumor-node-metastasis is significant for the prognosis and treatment. Predominantly the combination of chemotherapeutic regimen is given to improve the rate of clinical benefit and the overall survival rate. Novel mono-therapeutic options are being used often in metastatic setting as they will not be able to endure the toxicity of the combination regimen. Usually, endocrine therapy is recommended for hormone-responsive breast cancer due to efficacy and favorable side effect profile but chemotherapy becomes an option when endocrine therapy fails. This review summarizes the newer therapeutic options for early breast cancer and advanced breast cancer that are pretreated heavily on other chemotherapeutic agents. Further it provides monotherapies and other emerging novel combination regime which can be opted for first line or second line setting.


Unique evolution of the UPR pathway with a novel bZIP transcription factor, Hxl1, for controlling pathogenicity of Cryptococcus neoformans.
In eukaryotic cells, the unfolded protein response (UPR) pathway plays a crucial role in cellular homeostasis of the endoplasmic reticulum (ER) during exposure to diverse environmental conditions that cause ER stress. Here we report that the human fungal pathogen Cryptococcus neoformans has evolved a unique UPR pathway composed of an evolutionarily conserved Ire1 protein kinase and a novel bZIP transcription factor encoded by HXL1 (HAC1 and XBP1-Like gene 1). C. neoformans HXL1 encodes a protein lacking sequence homology to any known fungal or mammalian Hac1/Xbp1 protein yet undergoes the UPR-induced unconventional splicing in an Ire1-dependent manner upon exposure to various stresses. The structural organization of HXL1 and its unconventional splicing is widely conserved in C. neoformans strains of divergent serotypes. Notably, both C. neoformans ire1 and hxl1 mutants exhibited extreme growth defects at 37°C and hypersensitivity to ER stress and cell wall destabilization. All of the growth defects of the ire1 mutant were suppressed by the spliced active form of Hxl1, supporting that HXL1 mRNA is a downstream target of Ire1. Interestingly, however, the ire1 and hxl1 mutants showed differences in thermosensitivity, expression patterns for a subset of genes, and capsule synthesis, indicating that Ire1 has both Hxl1-dependent and -independent functions in C. neoformans. Finally, Ire1 and Hxl1 were shown to be critical for virulence of C. neoformans, suggesting UPR signaling as a novel antifungal therapeutic target.


Functional analysis LRP6 novel mutations in patients with coronary artery disease.
Genetic architecture of coronary artery disease (CAD) is still to be defined. Since low density lipoprotein receptor-related protein 6 (LRP6) gene play critical roles in Wnt signal transduction which are important for vascular development and endodermis specification, we therefore resequenced it to search for mutations in CAD patients. We systemically sequenced all the exons and promoter region of LRP6 gene in a sample of 380 early onset CAD patients and 380 control subjects in Chinese. In total, we identified 5 patient-specific mutations including K82N (two patients), S488Y (one patient), P1066T (two patients), P1206H (two patients) and I1264V (one patient) All these mutations located at the extracellular domain of LRP6 gene. In vitro functional analysis of patient-specific mutations demonstrated that these mutations resulted in a significant reduction in both protein level transporting to cell membrane and downstream Wnt signal activity. Furthermore, we found that LRP6 novel mutations attenuated proliferation and migration of human umbilical vein endothelial cells (HUVECs) when compared with wild type (WT) LRP6. Our results demonstrated that these loss-of-function variants might contribute to disease liability in a subset of CAD and defects in Wnt signal activation might be important contributing factors for the onset of CAD.


Double lumen endotracheal tube for percutaneous tracheostomy.
Percutaneous dilational tracheostomy is normally a bronchoscope-guided procedure. The insertion of a bronchoscope into an endotracheal tube (ETT) affects resistance, flow, and alveolar pressure. To improve airway management and ventilation during percutaneous tracheostomy, we developed a double lumen endotracheal tube (DLET). The aim of this in vitro study was to compare the linear constant of the Rohrer equation (K1), the nonlinear constant of the Rohrer equation (K2), the inspiratory and expiratory airway resistance, and ventilatory and airway pressures using the DLET with different standard sized ETTs. A trachea and lung model was used to compare the DLET to ETTs with 7, 7.5, and 8 mm inner diameters with and without a bronchoscope (4.5 mm external diameter), and 4 and 5 mm inner diameter ventilation tubes (F4, F5) of a translaryngeal tracheostomy. For each device, the pressure drop across the device and the Rohrer equation linear constant (K1) and nonlinear constant (K2) were calculated during a continuous flow of 10-90 L/min, the inspiratory and expiratory airway resistance values were calculated during volume controlled mechanical ventilation, and respiratory airway pressure values were calculated during volume and pressure controlled mechanical ventilation. DLET had lower K2, pressure drop, and inspiratory and expiratory airway resistance compared with conventional ETTs plus fiberoptic bronchoscope. Furthermore, during mechanical ventilation, DLET had a lower value of peak pressure, mean pressure, and intrinsic PEEP than the other ETTs plus fiberoptic bronchoscope. Use of the DLET during percutaneous dilational tracheostomy allows fiberoptic bronchoscopy without imposing excessive airway resistance. Reduced tube resistance during this procedure may confer additional safety in what is well known to be a hazardous procedure.


Osmotic activity of tissues during fetal and post-natal growth.
The osmotic pressure maintained by liver tissue of the white rat preceding birth is less than that of the maternal blood serum and shortly after birth approximates this level. Following birth osmotic pressure of liver tissue, continuing to increase, reaches after about 60 to 90 days the level found in the liver of mature animals and is then isotonic with solutions of sodium chloride with concentration slightly more than twice that isotonic with blood serum. Osmotic pressure maintained by kidney tissue pursues with growth a similar course but at a lower level and about 35 to 60 days after birth reaches that found in the mature animal being represented by isotonicity with a concentration of sodium chloride slightly less than twice that isotonic with blood serum. The tissues of the whole fetus are isotonic with sodium chloride solutions less concentrated than that isotonic with the maternal blood serum.


Oncofertility to Evidence-Based Practice: Changes in Fertility Intention and Symptom Burden in Reproductive-Age Women With Breast Cancer.
Infertility is negatively related to the quality of life in reproductive-age women with breast cancer. The nurses who care for these patients lack a comprehensive understanding of the changes in fertility intention that patients undergo from the time of cancer diagnosis, throughout treatment, and after treatment. A fertility intention assessment is the first step in discerning the patient's ideas toward future pregnancy. This study examined the changes in fertility intention and symptom burden in reproductive-age women with breast cancer before, during, and after treatment. We also explored predictors of fertility intention among the women. The study was guided by the theory of planned behavior. A longitudinal and observational study was conducted with 151 women with breast cancer who were treated at a teaching hospital in Taipei. The participants were interviewed using a structured questionnaire before, during, and after chemotherapy from July 2016 to March 2018. Fertility intention was assessed using the Fertility Intention Scale. The M.D. Anderson Symptom Inventory-Taiwanese version was used to measure the symptom burden. The generalized linear mixed model was used for multivariate analysis. Patients had significantly lower scores for fertility intention after treatment than before treatment. The study patients had substantially worse symptom burden during treatment than before or after treatment. Symptom burden scores, especially for symptom interference, correlated significantly with fertility intention. A higher Fertility Intention Scale score was significantly associated with younger age. Fertility intention decreased over time in women with breast cancer. Understanding fertility intention and controlling symptom burden throughout the course of treatment and beyond might help nurses provide better care for preserving fertility and maintaining fertility options for these women with breast cancer.


The bacterial rhizobiome of hyperaccumulators: future perspectives based on omics analysis and advanced microscopy.
Hyperaccumulators are plants that can extract heavy metal ions from the soil and translocate those ions to the shoots, where they are sequestered and detoxified. Hyperaccumulation depends not only on the availability of mobilized metal ions in the soil, but also on the enhanced activity of metal transporters and metal chelators which may be provided by the plant or its associated microbes. The rhizobiome is captured by plant root exudates from the complex microbial community in the soil, and may colonize the root surface or infiltrate the root cortex. This community can increase the root surface area by inducing hairy root proliferation. It may also increase the solubility of metals in the rhizosphere and promote the uptake of soluble metals by the plant. The bacterial rhizobiome, a subset of specialized microorganisms that colonize the plant rhizosphere and endosphere, makes an important contribution to the hyperaccumulator phenotype. In this review, we discuss classic and more recent tools that are used to study the interactions between hyperaccumulators and the bacterial rhizobiome, and consider future perspectives based on the use of omics analysis and microscopy to study plant metabolism in the context of metal accumulation. Recent data suggest that metal-resistant bacteria isolated from the hyperaccumulator rhizosphere and endosphere could be useful in applications such as phytoextraction and phytoremediation, although more research is required to determine whether such properties can be transferred successfully to non-accumulator species.


Experimental results for 2D magnetic resonance electrical impedance tomography (MR-EIT) using magnetic flux density in one direction.
Magnetic resonance electrical impedance tomography (MR-EIT) is an emerging imaging technique that reconstructs conductivity images using magnetic flux density measurements acquired employing MRI together with conventional EIT measurements. In this study, experimental MR-EIT images from phantoms with conducting and insulator objects are presented. The technique is implemented using the 0.15 T Middle East Technical University MRI system. The dc current method used in magnetic resonance current density imaging is adopted. A reconstruction algorithm based on the sensitivity matrix relation between conductivity and only one component of magnetic flux distribution is used. Therefore, the requirement for object rotation is eliminated. Once the relative conductivity distribution is found, it is scaled using the peripheral voltage measurements to obtain the absolute conductivity distribution. Images of several insulator and conductor objects in saline filled phantoms are reconstructed. The L2 norm of relative error in conductivity values is found to be 13%, 17% and 14% for three different conductivity distributions.


Oleylamine-functionalized graphene oxide as an electron block layer towards high-performance and photostable fullerene-free polymer solar cells.
Oleylamine-functionalized graphene oxide (GO) has a shallower energy level of conduction band (ECB) and a deeper energy level of the valence band (EVB) as compared to common hole extraction layer (HEL) materials, which make the electron block layer (EBL). Photoluminescence, X-ray photoelectron spectroscopy (XPS), and current density-voltage (J-V) curves with a large reverse bias voltage range obtained under dark conditions are used to determine whether GO layers play important roles in blocking the electron transport to the MoO3/Ag composite anode and prevent MoO3 diffusion into a photoactive layer under light illumination. Moreover, GO inserted between a photoactive layer and an HEL enhances charge carrier transport and collection and avoids the monomolecular recombination between the photoactive layer and HEL. Photovoltaic parameters and photostability measurements of inverted and forward PSCs have shown that upon introduction of GO, the performance and photostability of PSCs are improved. On adding GO to PSCs, the power conversion efficiency (PCE) increases approximately 5% and 4% and reduces the decay ratio to approximately 50% and 65% of the initial value for the inverted and forward PSCs, respectively.


Maternal and neonatal outcomes in women with history of coronary artery disease.
Pregnancy outcomes in women with pre-existing coronary artery disease (CAD) are poorly described. There is a paucity of data therefore on which to base clinical management to counsel women, with regard to both maternal and neonatal outcomes. We conducted a retrospective multicentre study of women with established CAD delivering at 16 UK specialised cardiac obstetric clinics. We included pregnancies of 24 weeks' gestation or more, delivered between January 1998 and October 2018. Data were collected on maternal cardiovascular, obstetric and neonatal events. 79 women who had 92 pregnancies (94 babies including two sets of twins) were identified. 35.9% had body mass index >30% and 24.3% were current smokers. 18/79 (22.8%) had prior diabetes, 27/79 (34.2%) had dyslipidaemia and 21/79 (26.2%) had hypertension. The underlying CAD was due to atherosclerosis in 52/79 (65.8%), spontaneous coronary artery dissection (SCAD) in 11/79 (13.9%), coronary artery spasm in 7/79 (8.9%) and thrombus in 9/79 (11.4%).There were six adverse cardiac events (6.6% event rate), one non-ST elevation myocardial infarction at 23 weeks' gestation, two SCAD recurrences (one at 26 weeks' gestation and one at 9 weeks' postpartum), one symptomatic deterioration in left ventricular function and two women with worsening angina. 14% of women developed pre-eclampsia, 25% delivered preterm and 25% of infants were born small for gestational age. Women with established CAD have relatively low rates of adverse cardiac events in pregnancy. Rates of adverse obstetric and neonatal events are greater, highlighting the importance of multidisciplinary care.


Successful treatment of severe sympathetically maintained pain following anterior spine surgery.
Sympathetic dysfunction is one of the possible complications of anterior spine surgery; however, it has been underestimated as a cause of complications. We report two successful experiences of treating severe dysesthetic pain occurring after anterior spine surgery, by performing a sympathetic block. The first patient experienced a burning and stabbing pain in the contralateral upper extremity of approach side used in anterior cervical discectomy and fusion, and underwent a stellate ganglion block with a significant relief of his pain. The second patient complained of a cold sensation and severe unexpected pain in the lower extremity of the contralateral side after anterior lumbar interbody fusion and was treated with lumbar sympathetic block. We aimed to describe sympathetically maintained pain as one of the important causes of early postoperative pain and the treatment option chosen for these cases in detail.


Encoding of variability of landmark-based spatial information.
Recent evidence suggests humans optimally weight visual and haptic information (i.e., in inverse proportion to their variances). A more recent proposal is that spatial information (i.e., distance and direction) may also adhere to Bayesian principles and be weighted in an optimal fashion. A fundamental assumption of this proposal is that participants encode the variability of spatial information. In a three-dimensional virtual-environment open-field search task, we provide evidence that participants encoded the variability of landmark-based spatial information. Specifically, participants searched for a hidden goal location in a 5 × 5 matrix of raised bins. Participants experienced five training phases in which they searched for a hidden goal that maintained a unique spatial relationship to each of four distinct landmarks. Each landmark was assigned an a priori value of locational uncertainty such that each varied in its ability to predict a goal (i.e., varied in number of potential goal locations). Following training, participants experienced conflict trials in which two distinct landmarks were presented simultaneously. Participants preferentially responded to the landmark with the lower uncertainty value (i.e., smaller number of potential goal locations). Results provide empirical evidence for the encoding of variability of landmark-based spatial information and have implications for theoretical accounts of spatial learning.


Quantum Transport and Band Structure Evolution under High Magnetic Field in Few-Layer Tellurene.
Quantum Hall effect (QHE) is a macroscopic manifestation of quantized states that only occurs in confined two-dimensional electron gas (2DEG) systems. Experimentally, QHE is hosted in high-mobility 2DEG with large external magnetic field at low temperature. Two-dimensional van der Waals materials, such as graphene and black phosphorus, are considered interesting material systems to study quantum transport because they could unveil unique host material properties due to the easy accessibility of monolayer or few-layer thin films at the 2D quantum limit. For the first time, we report direct observation of QHE in a novel low-dimensional material system, tellurene. High-quality 2D tellurene thin films were acquired from recently reported hydrothermal method with high hole mobility of nearly 3000 cm2/(V s) at low temperatures, which allows the observation of well-developed Shubnikov-de Haas (SdH) oscillations and QHE. A four-fold degeneracy of Landau levels in SdH oscillations and QHE was revealed. Quantum oscillations were investigated under different gate biases, tilted magnetic fields, and various temperatures, and the results manifest the inherent information on the electronic structure of Te. Anomalies in both temperature-dependent oscillation amplitudes and transport characteristics were observed that are ascribed to the interplay between the Zeeman effect and spin-orbit coupling, as depicted by the density functional theory calculations.


Monolithic lithium disilicate complete single crowns with feather-edge preparation design in the posterior region: A multicentric retrospective study up to 12 years.
This retrospective study evaluated the clinical success and survival of monolithic lithium disilicate single crowns in the posterior region fabricated with feather-edge margins and cemented with resin-based self-etching cement. In total, 627 pressed monolithic lithium disilicate restorations on posterior teeth (110 first premolars, 151 second premolars, 240 first molars, 121 second molars, 5 third molars) were placed in 335 patients. All teeth were prepared with feather-edge margins and restored with single crowns. The modified California Dental Association criteria were used to clinically evaluate subjects during regular maintenance recalls. The mean follow-up time was 48.17 months (SD, 27.7; range, 6 to 144). Nine crowns were replaced during the follow-up period due to bulk fracture of the material (overall 97.93% survival rate), and four teeth were extracted. No other technical or biologic failure was observed. In this retrospective evaluation, monolithic lithium disilicate crowns with feather-edge margins yielded clinical outcomes similar to those reported with other margin designs and materials. Following the same clinical protocol, crowns on second molars showed lower survival rates when compared to restorations on other teeth in the posterior region. Careful evaluation is mandatory in high-risk patients and terminal teeth. Alternative restorative materials, such as full-contour zirconia crowns, should be considered for the restoration of second molars.


Frozen Sections for Margins During Partial Nephrectomy Do Not Influence Recurrence Rates.
Frozen sections (FS) are routinely employed to assess margin status during partial nephrectomy (PN) for clinically localized renal cell carcinoma (CLRCC); however, their oncologic benefit remains unclear. There have been no studies investigating the long-term impact of FS on local or metastatic recurrence. We wished to determine whether the utilization of FS for this purpose during PN influenced recurrence rates. We performed a retrospective review of 1090 patients with (n = 172) and without (n = 918) FS during open and robotic PN between 2006 and 2016 for CLRCC at a single tertiary care institution. Standard follow-up protocols were employed, with imaging used to guide subsequent biopsy for confirmation. Univariate and multivariate competing-risk regression analysis predicting the association of FS status and clinicodemographic characteristics with recurrence, with adjustment for all-cause mortality, were performed. Administrative data were reviewed to calculate costs of FS. Forty-five out of 1090 (4.13%) patients had recurrence. There was no difference in the cumulative incidence of recurrence between patients with and without FS (χ2 = 0.001, p = 0.97). On multivariable competing risk analysis, FS was not associated with recurrence (hazard ratio [HR], 1.56; 95% confidence interval [CI], 0.65-3.76). However, tumor grade (g3-4 vs 1-2: HR, 2.45; 95% CI, 1.16-5.14) and stage (>pT2 vs pT1a: HR, 2.86; 95% CI, 1.13-7.26) were associated with recurrence. The average direct charge per patient undergoing FS was $902. Intraoperative FS for margins during PN did not predict decreased recurrence rates in a single-institution high-volume center. Given the lack of associated benefit, and the added cost, the utilization of FS during PN should be limited.


[Angiogenic factors and their role in pathogenesis and prediction of preeclampsia].
Angiogenic factors like placental growth factor (PlGF) and its anti-angiogenic antagonists soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng) are closely related to the pathogenesis of preeclampsia and intrauterine growth restriction (IUGR). The discovery and investigation of these angiogenic factors could characterize important pathogenetic mediators of preeclampsia or even the cause for placental dysfunctions. These anti-angiogenic proteins are dramatically elevated in maternal circulation weeks prior to the onset of the syndrome preeclampsia. Since it is known that altered maternal sFlt1, sEng and PlGF levels are detectable weeks prior to the onset of these pregnancy complications, it was the aim of the study to investigate the predictive value of these markers in high-risk second trimester pregnancies characterized by abnormal uterine perfusion. Using both factors, sFlt1 and PlGF, early-onset preeclampsia can be predicted with 83% sensitivity and 95% specificity. Combined analysis of sEng and sFlt1 is able to predict early-onset PE even with a sensitivity of 100% and a specificity of 93.3%. This shows, that the concurrent measurement of uterine perfusion and angiogenic factors allows an efficient prediction of early-onset pregnancy complications, particularly preeclampsia. The next step will be the development of therapeutic tools that have positive impact on the clinical symptoms via the inhibition of sFlt1 and or sEng.


Effect of Hydrolyzed Bird's Nest on β-Cell Function and Insulin Signaling in Type 2 Diabetic Mice.
Type 2 diabetes mellitus is characterized by both resistance to the action of insulin and defects in insulin secretion. Bird's nest, which is derived from the saliva of swiftlets are well known to possess multiple health benefits dating back to Imperial China. However, it's effect on diabetes mellitus and influence on the actions of insulin action remains to be investigated. In the present study, the effect of standardized aqueous extract of hydrolyzed edible bird nest (HBN) on metabolic characteristics and insulin signaling pathway in pancreas, liver and skeletal muscle of db/db, a type 2 diabetic mice model was investigated. Male db/db diabetic and its euglycemic control, C57BL/6J mice were administered HBN (75 and 150 mg/kg) or glibenclamide (1 mg/kg) orally for 28 days. Metabolic parameters were evaluated by measuring fasting blood glucose, serum insulin and oral glucose tolerance test (OGTT). Insulin signaling and activation of inflammatory pathways in liver, adipose, pancreas and muscle tissue were evaluated by Western blotting and immunohistochemistry. Pro-inflammatory cytokines were measured in the serum at the end of the treatment. The results showed that db/db mice treated with HBN significantly reversed the elevated fasting blood glucose, serum insulin, serum pro-inflammatory cytokines levels and the impaired OGTT without affecting the body weight of the mice in all groups. Furthermore, HBN treatment significantly ameliorated pathological changes and increased the protein expression of insulin, and glucose transporters in the pancreatic islets (GLUT-2), liver and skeletal muscle (GLUT-4). Likewise, the Western blots analysis denotes improved insulin signaling and antioxidant enzyme, decreased reactive oxygen species producing enzymes and inflammatory molecules in the liver and adipose tissues of HBN treated diabetic mice. These results suggest that HBN improves β-cell function and insulin signaling by attenuation of oxidative stress mediated chronic inflammation in the type 2 diabetic mice.


Pravastatin reduces microvascular basal lamina damage following focal cerebral ischemia and reperfusion.
Transient ischemia has been shown to damage the basal lamina of the cerebral microvasculature. Other studies proved statins to be beneficial to non-cerebral microvessels. The aim of this study was to determine whether pravastatin pretreatment ameliorates microvascular basal lamina damage following transient ischemia. Using the suture model, we subjected 15 rats to focal ischemia (3 h) and reperfusion (24 h). Rats received pravastatin (20 mg/kg/day) or saline for 4 weeks prior to the experiment. The outcome was determined by a behavior test and the infarct size. Collagen type IV, a marker for an intact basal lamina, and hemoglobin extravasation were measured by Western blot analysis. A ratio (in percentage) between ischemic and contralateral hemispheres was calculated. Pravastatin pretreatment resulted in a significantly better neurological outcome and reduced infarct size (15 +/- 0.5 and 59 +/- 10 mm(3), respectively) compared with controls (12.25 +/- 0.4 and 167 +/- 13 mm(3), respectively, P < 0.01 for both). In controls, loss of collagen type IV was seen in the basal ganglia and in the cortex (43 +/- 4 and 64 +/- 5%, respectively). Pravastatin prevented significant collagen loss (basal ganglia: 106 +/- 17%; cortex: 112 +/- 14%, P < 0.01 for both) and significantly reduced the hemoglobin extravasation compared with controls in the basal ganglia (198 +/- 49 vs. 553 +/- 47%, P < 0.01). Pravastatin pretreatment resulted in a reduction of microvascular basal lamina damage and hemoglobin extravasation following transient ischemia. Pravastatin seems to protect the cerebral microvascular system.


Real-time digital subtraction angiography for therapeutic neuroradiologic procedures.
Procedural control during therapeutic neuroradiologic procedures is generally based on repeated angiograms to assess the degree to which embolization has reduced abnormal blood flow. Due to the complex craniofacial skeletal anatomy that is superimposed over lesions in this area, subtraction studies are usually required to see the vessels and visualize a tumor stain satisfactorily. We have used a device incorporating continuous recursive digital video filtration, which allows the operator to view a subtracted fluoroscopic image of each control angiographic sequence in real time. The advantages of this technique for therapeutic procedures are described.


Timing and Risk Factors for Venous Thromboembolism After Rotator Cuff Repair in the 30-Day Perioperative Period.
To analyze the American College of Surgeons National Surgical Quality Improvement Program database to evaluate the incidence of deep venous thrombosis and pulmonary embolism in patients undergoing rotator cuff repair surgery. In addition, we aim to identify risk factors associated with the development of thromboembolic events following rotator cuff repair. A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program database was performed. Current Procedural Terminology codes were used to identify patients who underwent rotator cuff repair between 2005 and 2017. The presence of deep venous thrombosis or pulmonary embolism during the 30-day perioperative period were the primary outcomes assessed. Logistic regression analysis was performed to identify risk factors for postoperative venous thromboembolic events (VTEs). In total, 39,825 rotator cuff repairs (RCRs) were performed and 117 (0.3%) VTE events occurred. VTE was identified at a mean of 11.5 ± 7.4 days. A total of 31,615 RCRs were performed arthroscopically. There was no significant difference of VTE between groups comparing arthroscopic RCR VTE 0.3% (94) with open RCR 0.3% (23) (P = .81). RCR in patients with an American Society of Anesthesiologists classification of III or IV was associated with >1.5-fold increase risk of VTE (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.14-2.45). Increased risks of VTE included surgery >80 minutes (OR 2.10, 95% CI 1.42-3.15), performed under general anesthesia (OR 4.38, 95% CI 1.18-36.6), and in the outpatient setting (OR 6.09, 95% CI 1.06-243.7), male sex (OR 1.53, 95% CI 1.01-2.33), bleeding disorders (OR 2.87, 95% CI 1.17-7.05), or dyspnea (OR 1.51, 95% CI 1.02-2.23). The biggest risk for VTE was unplanned reoperation OR 16.6 (95% CI 5.13-53.5). Venous thromboembolism is a rare complication following rotator cuff repair 0.3%. Understanding the risk factors: duration of surgery >80 minutes, male sex, body mass index >30 kg/m2, ASA III or IV, RCR as an inpatient under general anesthesia, bleeding disorder, or dyspnea may be useful in guiding treatment to prevent VTE. The largest risk for VTE is a patient with unplanned reoperation. RCR surgery performed in an outpatient setting resulted in a significantly lower incidence of VTE. III Retrospective Comparative Study.


Low skeletal mass is an important predictor of osteoporosis in HIV-infected men in India.
This study evaluated prevalence and predictors of osteoporosis and sarcopenia in men with HIV. 220 men with HIV were screened, of which 115 men, 30-50 years-age, having at least 1-year follow-up, underwent hormonal and DEXA analysis. 40 controls were also evaluated. Males with HIV had significantly lower BMD and Z-scores at all sites. Osteoporosis was diagnosed in 64.35%; commonest site being radius total (49.56%), followed by radius 33% (45.21%), radius ultra distal (36.52%), lumbar spine (19.13%), neck of femur (17.39%), total femur and greater trochanter (7.82% each). HIV patients had significantly lower fat mass (FM), lean mass (LM), total fat percent, bone mineral content, gynoid fat, percent skeletal muscle mass (PSMM). Men with osteoporosis had higher use of anti retroviral therapy (ART), immune reconstitution inflammatory syndrome (IRIS), tuberculosis, lower FM, LM and PSMM. Logistic regression revealed PSMM, age and delta (Δ) CD4 count (change in CD4 count after 6-12 months of ART, compared to pre-ART) were best predictors of osteoporosis. Greater PSMM was associated with decreased osteoporosis, without adjusting for any variable (Model-1), adjusting for disease duration, tuberculosis and IRIS (Model-2), and model-2 plus gonadotropins and sex steroids (Model-3). Greater ΔCD4 count and age were associated with increased osteoporosis after adjusting for different models. Sarcopenia was observed in 40% men and none in controls. Men with decreased skeletal mass, age, severe immune dysfunction at diagnosis, having rapid increase in CD4 count following ART and IRIS have higher risk of osteoporosis in the long run.


Loss of neuronal integrity: a cause of hypometabolism in patients with traumatic brain injury without MRI abnormality in the chronic stage.
Traumatic brain injury (TBI) causes brain dysfunction in many patients. However, some patients have severe brain dysfunction but display no abnormalities on magnetic resonance imaging (MRI). There have been some reports of hypometabolism even in such patients. The purpose of this study was to investigate the relationship between metabolic abnormality and loss of neuronal integrity in TBI patients with some symptoms but without MRI abnormalities. The study population comprised ten patients with TBI and ten normal volunteers. All of the patients were examined at least 1 year after the injury. ( 15)O-labelled gas PET and [(11)C]flumazenil (FMZ) positron emission tomography (PET) were carried out. The cerebral metabolic rate of oxygen (CMRO(2)) and binding potential (BP) images of FMZ were calculated. Axial T2WI, T2*WI and FLAIR images were obtained. Coronal images were added in some cases. All of the patients had normal MRI findings, and all showed areas with abnormally low CMRO(2). Low uptake on BP images was observed in six patients (60%). No lesions that showed low uptake on BP images were without low CMRO(2). On the other hand, there were 14 lesions with low CMRO(2) but without BP abnormalities. These results indicate that there are metabolic abnormalities in TBI patients with some symptoms after brain injury but without abnormalities on MRI. Some of the hypometabolic lesions showed low BP, indicating a loss of neuronal integrity. Thus, FMZ PET may have potential to distinguish hypometabolism caused by neuronal loss from that caused by other factors.


Structure of Lung-Mimetic Multilamellar Bodies with Lipid Compositions Relevant in Pneumonia.
The hierarchical assembly of lipids, as modulated by composition and environment, plays a significant role in the function of biological membranes and a myriad of diseases. Elevated concentrations of calcium ions and cardiolipin (CL), an anionic tetra-alkyl lipid found in mitochondria and some bacterial cell membranes, have been implicated in pneumonia recently. However, their impact on the physicochemical properties of lipid assemblies in lungs and how it impairs alveoli function is still unknown. We use small- and wide-angle X-ray scattering (S/WAXS) and solid-state nuclear magnetic resonance (ssNMR) to probe the structure and dynamics of lung-mimetic multilamellar bodies (MLBs) in the presence of Ca2+ and CL. We conjecture that CL overexpressed in the hypophase of alveoli strongly affects the structure of lung-lipid bilayers and their stacking in the MLBs. Specifically, S/WAXS data revealed that CL induces significant shrinkage of the water-layer separating the concentric bilayers in multilamellar aggregates. ssNMR measurements indicate that this interbilayer tightening is due to undulation repulsion damping as CL renders the glycerol backbone of the membranes significantly more static. In addition to MLB dehydration, CL promotes intrabilayer phase separation into saturated-rich and unsaturated-rich lipid domains that couple across multiple layers. Expectedly, addition of Ca2+ screens the electrostatic repulsion between negatively charged lung membranes. However, when CL is present, addition of Ca2+ results in an apparent interbilayer expansion likely due to local structural defects. Combining S/WAXS and ssNMR on systems with compositions pertinent to healthy and unhealthy lung membranes, we propose how alteration of the physiochemical properties of MLBs can critically impact the breathing cycle.


Therapeutic antibody targeting of individual Notch receptors.
The four receptors of the Notch family are widely expressed transmembrane proteins that function as key conduits through which mammalian cells communicate to regulate cell fate and growth. Ligand binding triggers a conformational change in the receptor negative regulatory region (NRR) that enables ADAM protease cleavage at a juxtamembrane site that otherwise lies buried within the quiescent NRR. Subsequent intramembrane proteolysis catalysed by the gamma-secretase complex liberates the intracellular domain (ICD) to initiate the downstream Notch transcriptional program. Aberrant signalling through each receptor has been linked to numerous diseases, particularly cancer, making the Notch pathway a compelling target for new drugs. Although gamma-secretase inhibitors (GSIs) have progressed into the clinic, GSIs fail to distinguish individual Notch receptors, inhibit other signalling pathways and cause intestinal toxicity, attributed to dual inhibition of Notch1 and 2 (ref. 11). To elucidate the discrete functions of Notch1 and Notch2 and develop clinically relevant inhibitors that reduce intestinal toxicity, we used phage display technology to generate highly specialized antibodies that specifically antagonize each receptor paralogue and yet cross-react with the human and mouse sequences, enabling the discrimination of Notch1 versus Notch2 function in human patients and rodent models. Our co-crystal structure shows that the inhibitory mechanism relies on stabilizing NRR quiescence. Selective blocking of Notch1 inhibits tumour growth in pre-clinical models through two mechanisms: inhibition of cancer cell growth and deregulation of angiogenesis. Whereas inhibition of Notch1 plus Notch2 causes severe intestinal toxicity, inhibition of either receptor alone reduces or avoids this effect, demonstrating a clear advantage over pan-Notch inhibitors. Our studies emphasize the value of paralogue-specific antagonists in dissecting the contributions of distinct Notch receptors to differentiation and disease and reveal the therapeutic promise in targeting Notch1 and Notch2 independently.


The Dominant Role of Visual Motion Cues in Bumblebee Flight Control Revealed Through Virtual Reality.
Flying bees make extensive use of optic flow: the apparent motion in the visual scene generated by their own movement. Much of what is known about bees' visually-guided flight comes from experiments employing real physical objects, which constrains the types of cues that can be presented. Here we implement a virtual reality system allowing us to create the visual illusion of objects in 3D space. We trained bumblebees, Bombus ignitus, to feed from a static target displayed on the floor of a flight arena, and then observed their responses to various interposing virtual objects. When a virtual floor was presented above the physical floor, bees were reluctant to descend through it, indicating that they perceived the virtual floor as a real surface. To reach a target at ground level, they flew through a hole in a virtual surface above the ground, and around an elevated virtual platform, despite receiving no reward for avoiding the virtual obstacles. These behaviors persisted even when the target was made (unrealistically) visible through the obstructing object. Finally, we challenged the bees with physically impossible ambiguous stimuli, which give conflicting motion and occlusion cues. In such cases, they behaved in accordance with the motion information, seemingly ignoring occlusion.


Clinical characteristics and management of vascular anomalies: findings of a multidisciplinary vascular anomalies clinic.
To describe the scope of the University of California, San Francisco (UCSF), Vascular Anomalies Clinic (VAC), including the types of diagnoses, characteristics, and management of patients seen in the clinic. Case series. Referral, outpatient, multidisciplinary clinic in a university system. Consecutive sample of 175 patients seen in the VAC at UCSF from January 2001 to July 2003. Diagnosis before and after clinic visit, symptoms, treatment recommendations, age of onset, age at clinic visit, location of lesion, sex, and type of referring physician. A total of 96% of patients had cutaneous involvement, 71% of patients had vascular malformations, and 14% had infantile hemangiomas. Fifty-eight percent of patients were referred from outside the UCSF system. Of the patients who had not been previously seen by members of the VAC team or UCSF dermatologists, only 22% had been assigned correct specific diagnoses before coming to the VAC, and 13% had incorrect specific diagnoses before coming to the VAC. Fifty-six percent of vascular malformations were first noted at birth and 17% were noted at later than 10 years of age. Eighty-seven percent of patients were symptomatic from their vascular lesion. Sixty-six percent of patients underwent prior magnetic resonance imaging of their lesion. Further diagnostic workup was recommended in 43% of cases, and treatment recommendations were made in 83% of cases. Significant confusion still exists regarding the appropriate terminology, diagnosis, and management of vascular anomalies. Multidisciplinary clinics effectively address these complicated and troubling disorders by providing accurate diagnoses, clear treatment recommendations, and counseling from a team of specialists.


Dasherkandi project studies--health of the under fifteen.
Morbidity pattern of the under fifteen of a rural community was analysed and related to socio-economic factors. This was a part of Dasherkandi project studies carried out in a village near Dhaka city. 48.26% of the population was under the age of fifteen. Infants under the age of one year had low sickness rate which rose steeply between 1 and 4 years of life and then gradually declined after the age of 5 years. Commonest morbidity was worm infestation which was followed by flu and upper respiratory tract infection. The non-agriculturist and the low income group had the highest level of sickness. It is suggested that children in rural areas suffer mainly from diseases which are related to poor nutrition and hygiene resulting from unsatisfactory socio-economic condition. All the childhood mortality occurred under the age of one year and was found to be due to tetanus in this study.


Purification of pyruvate formate-lyase from Streptococcus mutans and its regulatory properties.
Pyruvate formate-lyase (EC 126.96.36.199) from Streptococcus mutans strain JC2 was purified in an anaerobic glove box, giving a single band on disk and sodium dodecyl sulfate electrophoresis. This enzyme was immediately inactivated by exposure to the air. Enzyme activity was unstable even when stored anaerobically, but the activity was restored by preincubating the inactivated crude enzyme with S-adenosyl-L-methionine, oxamate, and reduced for ferredoxin or methylviologen. On the other hand, the purified enzyme was not reactivated. Either D-glyceraldehyde 3-phosphate or dihydroxyacetone phosphate strongly inhibited this enzyme. The inhibitory effects of these compounds were largely influenced by enzyme concentration. The inhibition of these triose phosphates in cooperation with the reactivating effect of ferredoxin and the fluctuations of both the enzyme and the triose phosphate levels may efficiently regulate the pyruvate formate-lyase activity in S. mutans in vivo.


A wearable and flexible lactic-acid/O2 biofuel cell with an enhanced air-breathing biocathode.
The performance of biocathode in an enzymatic biofuel cell (EBFC) in the real application is somehow overlooked. Herein, a wearable and flexible lactic-acid/O2 EBFC enhanced with an air-breathing biocathode is designed to solve the limitation of biocathode that arises from the low solubility and slow mass transfer of the dissolved oxygen. To improve the oxygen supply efficiency for the air-breathing biocathode, a superhydrophobic base electrode creating an efficient air-solid-liquid triphase interface is developed. The designed EBFC with an 'island-bridge' configuration is integrated by assembling the current collectors of air-breathing biocathode and bioanode on a commercial laminating film (LF) screen-printed with a noninterfering circuit. It is found that the biocathode/bioanode area ratio should exceed 9:1 so that the designed EBFC (1A//9C) can achieve the optimal performance. This EBFC delivers an open circuit voltage of ca. 0.75 V and outputs a maximum power density of ca. 1.78 mW cm-2. In addition, a scaled-up EBFC (total bioanode area: 1.5 cm2) successfully powers a self-developed low-power device of heartrate in the pulse operation mode when applied on a volunteer's arm.


Parenteral analgesic and sedative use among ED patients in the United States: combined results from the National Hospital Ambulatory Medical Care Survey (NHAMCS) 1992-1997.
This article describes parenteral analgesic and sedative (PAS) use among patients treated in US emergency departments (EDs). Data representing 6 consecutive years (1992-1997) from the National Hospital Ambulatory Medical Care Survey (NHAMCS) were combined and analyzed. Patients were identified as having received PAS if they received fentanyl, ketamine, meperidine, methohexital, midazolam, morphine, nitrous oxide, or propofol. Patients were stratified according to age (pediatric <18 yrs), race, sex, insurance, type of hospital, urgency of visit, and ICD-9 (International Classification of Diseases, 9th revision) diagnostic codes. Logistic regression was performed to determine independent associations and calculate odds ratios (OR) for receiving analgesia or sedation. A total of 43,725 pediatric and 114,207 adult ED encounters were analyzed and represented a weighted sample of 555.3 million ED visits. For patients with orthopedic fractures, African-American children covered by Medicaid insurance were the least likely to receive PAS (OR 0.2, 95% confidence interval [CI] 0.1-0.6). These results suggest that variations may be occurring among ED patients receiving PAS.


Expression profiles of MMP-9 and EMMPRIN in chronic rhinosinusitis with nasal polyps.
Metalloproteinases (MMPs) are implicated in tissue remodeling in chronic rhinosinusitis with nasal polyps (CRSwNP). This study aimed to evaluate the expression profiles of MMP-9 and the extracellular matrix metalloproteinase inducer (EMMPRIN) in nasal polyps compared to healthy mucosa. Tissue samples from 37 CRSwNP patients undergoing functional endoscopic sinus surgery and mucosal specimens from 12 healthy controls were obtained intra-operatively. MMP-9 and EMMPRIN mRNA levels were assessed by reverse transcription-polymerase chain reaction (RT-PCR) and their protein expression by Western blot analysis. MMP-9 mRNA expression levels were significantly elevated in CRSwNP compared to controls (p < 0.05). MMP-9 protein levels presented an increasing trend but with no statistical significance (p > 0.05). No statistically significant difference in EMMPRIN mRNA and protein levels was identified. Upregulation of MMP-9 in nasal polyps is evident and highlights its role in the pathogenesis of CRSwNP. The lack of concordance between MMP-9 mRNA and protein levels may be attributed to post-translational gene expression regulation. Although EMMPRIN expression was not significantly different between the two groups, its role remains to be elucidated. MMP-9 may be a valuable biomarker and treatment target in CRSwNP.


[Theories and models of the function of the hippocampus].
Different and frequently opposed theories and models of the hippocampal function have been developed. A first type of theories proposed that when some expectatives are not accomplished the hippocampus would inhibit: a) attention, b) activation or c) non-reward responses. A second type of theories supported that the hippocampal function would be the selection of the information to be stored: a) into the trace, b) into the long-term memory. A third type of theories proposed that in the hippocampus it would be stored: a) contextual maps, b) spatial maps, c) temporal maps, d) attentional-associative networks, e) contingencies detectors, f) semantics systems, g) recognition memory, h) work memory. The common element among all theories would be the detection of the differences between a neural model and a new input, as Sokolov proposed in 1960.


The Escherichia coli AmtB protein as a model system for understanding ammonium transport by Amt and Rh proteins.
The Escherichia coli ammonium transport protein (AmtB) has become the model system of choice for analysis of the process of ammonium uptake by the ubiquitous Amt family of inner membrane proteins. Over the past 6 years we have developed a range of genetic and biochemical tools in this system. These have allowed structure/function analysis to develop rapidly, offering insight initially into the membrane topology of the protein and most recently leading to the solution of high-resolution 3D structures. Genetic analysis has revealed a novel regulatory mechanism that is apparently conserved in prokaryotic Amt proteins and genetic approaches are also now being used to dissect structure/function relationships in Amt proteins. The now well-recognised homology between the Amt proteins, found in archaea, eubacteria, fungi and plants, and the Rhesus proteins, found characteristically in animals, also means that studies on E. coli AmtB can potentially shed light on structure/function relationships in the clinically important Rh proteins.


Primer on gadolinium chemistry.
Gadolinium is widely known by all practitioners of magnetic resonance imaging (MRI) but few appreciate the basic solution chemistry of this trivalent lanthanide ion. Given the recent linkage between gadolinium contrast agents and nephrogenic systemic fibrosis, some basic chemistry of this ion must be more widely understood. This short primer on gadolinium chemistry is intended to provide the reader the background principles necessary to understand the basics of chelation chemistry, water hydration numbers, and the differences between thermodynamic stability and kinetic stability or inertness. We illustrate the fundamental importance of kinetic dissociation rates in determining gadolinium toxicity in vivo by presenting new data for a novel europium DOTA-tetraamide complex that is relatively unstable thermodynamically yet extraordinarily inert kinetically and also quite nontoxic. This, plus other literature evidence, forms the basis of the fundamental axiom that it is the kinetic stability of a gadolinium complex, not its thermodynamic stability, that determines its in vivo toxicity. J. Magn. Reson. Imaging 2009;30:1240-1248. (c) 2009 Wiley-Liss, Inc.


Treatment options for HCV nonresponders and relapse patients.
The current standard-of-care treatment for chronic hepatitis C virus (HCV) infection, peginterferon plus ribavirin, results in a sustained virological response in 39-46% of genotype 1 patients, based on published reports and recently re-affirmed by findings in the IDEAL trial. While several directly targeted oral antiviral medications in development appear promising to decrease genotype 1 treatment failure, these agents are not yet approved for general clinical use, and their contribution to the management of relapsed or refractory HCV patients is uncertain. Other re-treatment approaches may include "watch and wait" or other strategies such as the use of consensus interferon plus ribavirin. Consensus interferon, a wholly synthetic interferon, was developed based on the most commonly represented amino acid sequence of the 14 different subtypes of interferon-alpha and has been shown in clinical trials to produce sustained virological responses in up to one-third of patients who do not respond to initial therapy and up to 50% of those that relapse after treatment with peginterferon plus ribavirin. In this monograph, the benefits and challenges of each of these available and future treatment options will be discussed with an eye toward optimizing therapy for an individual patient.


Immune response against Treponema spp. and ELISA detection of digital dermatitis.
The objective of this longitudinal study was to evaluate the immune response against Treponema spp. infection in dairy heifers affected with digital dermatitis (DD). In addition, the accuracy of an indirect ELISA detecting anti-Treponema IgG antibodies in identifying clinical DD status has been assessed. A cohort of 688 pregnant Holstein heifers was evaluated at least 3 times before calving during a period of 6 mo. Complete clinical assessment of DD presence on the back feet of each heifer and blood extraction were performed in a stand-up chute. Digital dermatitis cases were characterized by the M-stage classification system and size and level of skin proliferation. An ELISA was performed on blood serum samples obtained from a subcohort of 130 heifers. For description purposes, the animals were classified by the number of clinical cases experienced during the study period as type I (no clinical cases were observed), type II (only 1 acute clinical case diagnosed), and type III (at least 2 acute clinical cases diagnosed). Multivariable repeated-measures models were used to evaluate the immune response against Treponema spp. infection. A binormal Bayesian model for the ELISA data without cut-point values was used to assess the accuracy of the ELISA as a diagnostic tool. Animals that never experienced a DD event throughout the study kept a constant low level of antibody titer. A 56% increase in mean ELISA titer was observed in heifers upon a first clinical DD case diagnosis. After topical treatment of an acute DD case with oxytetracycline, the antibody titer decreased progressively in type II heifers, achieving mean levels of those observed in healthy cows after a mean of 223 d. Surprisingly, antibody titer was not increased in the presence of M1 (DD lesion <20mm in diameter surrounded by healthy skin) and M4.1 (DD lesion <20mm in diameter embedded in a circumscribed dyskeratotic or proliferative skin alteration) DD stages. Type III cows showed a slight increase in antibody levels. The presence of skin proliferation at first DD diagnosis was found to be associated with an odds ratio of 2.04 of becoming a type III heifer in relation to heifers presenting first lesions without skin proliferation. The ELISA validity was estimated by an area under the curve of 0.88. Predicted probabilities of infection are provided for a range of ELISA values and prevalence of infection. Early detection and treatment is essential to control DD and the ELISA can be used in understanding the immunopathology of DD and shows great promise for prescreening purposes during DD management programs in combination with traditional clinical inspection.


Acute toxicology report of the emerging marine biotoxin Brevetoxin 3 in mice: Food safety implications.
Brevetoxins (PbTxs) are emerging marine toxins that can lead to Neurotoxic Shellfish Poisoning in humans by the ingestion of contaminated seafood. Recent reports on brevetoxin detection in shellfish in regions where it has not been described before, arise the need of updated guidelines to ensure seafood consumers safety. Our aim was to provide toxicological data for brevetoxin 3 (PbTx3) by assessing oral toxicity in mice and comparing it with intraperitoneal administration. We followed an Up-and-Down procedure administering PbTx3 to mice and registering clinical signs, neuromuscular function, histopathology, and blood changes. Neuromuscular dysfunction like seizures and ataxia, as well as loss of limb strength were observed at 6 h. Performance and clinical signs largely improved at 24 h, time at which no blood biochemical or histological alterations were detected independently of the administration route. However, PbTx3 oral administration results in lower toxicity than intraperitoneal administration. Mortality was only observed at 4000 μg/kg bw PbTx3 administered via oral, but we still found toxicity clinical signs at low toxin doses. We could stablish an oral Lowest-Observable-Adverse-Effect-Level for PbTx3 of 100 μg/kg bw and an oral No-Observable-Adverse-Effect-Level of 10 μg/kg bw in mice. The data here reported should be considered in the evaluation of risks of PbTxs for human health.


Sphenopalatine endoscopic ganglion block: a revision of a traditional technique for cluster headache.
The diagnosis of chronic cluster headache (CH), the most painful form of headache, is based on typical clinical features characterized by strictly unilateral pain with no side shift and ipsilateral oculofacial autonomic phenomena. The attacks occur several times a day for periods of 1 to 2 months in the episodic form of the disease or less frequently on a daily basis in the chronic form. The pathogenesis of CH involves the activation of parasympathetic nerve structures located within the sphenopalatine ganglion (SPG), which explains many of the associated symptoms, whereas the activation of the ipsilateral hypothalamic gray matter may explain its typical circadian and circannual periodicity. A number of surgical approaches have been tried in cases of chronic CH resistant to pharmacologic therapy, of which SPG blockade has been shown to have certain efficacy. We have adopted a new technique based on endoscopic ganglion blockade that approaches the pterigo-palatine fossa by way of the lateral nasal wall and consists of the injection of a mixture of local anesthetics and corticosteroids, which was performed in 20 selected patients with chronic CH, according to the International Headache Society criteria (18 male, 2 female; mean age 40 yr), who were selected for SPG blockade because they were totally drug resistant. The symptoms improved significantly, but always only temporarily, in 11 cases. These results should be considered rather good because, unlike other frequently used techniques, SPG blockade is not invasive and should therefore always be attempted before submitting patients to more invasive surgical approaches.


Long- and short-term monocular deprivation in the rhesus monkey: effects on visual fields and optokinetic nystagmus.
Monkeys with 1 eyelid sutured within 2 weeks of birth for 7 or 14 d (short-term monocular deprivation, n = 5) or for 18-26 months (long-term monocular deprivation, n = 5) were tested for visual and oculomotor function at approximately 2 years of age. Long-term monocularly deprived animals were behaviorally blind when visual inputs were restricted to the deprived eye. There was no sparing of the monocular segment of the visual field, and optokinetic nystagmus could not be elicited even with vertical stripes up to 15 degrees in width. These behavioral deficits could not be accounted for by optical or retinal abnormalities. In contrast, short-term monocularly deprived animals displayed normal visual fields and optokinetic nystagmus was driven by both eyes. Slow-phase gain was reduced and directional asymmetries were observed when optokinetic stimulation was restricted to the deprived eye.


Deep learning-based synthetic dose-weighted LET map generation for intensity modulated proton therapy.
The advantage of proton therapy as compared to photon therapy stems from the Bragg peak effect, which allows protons to deposit most of their energy directly at the tumor while sparing healthy tissue. However, even with such benefits, proton therapy does present certain challenges. The biological effectiveness differences between protons and photons are not fully incorporated into clinical treatment planning processes. In current clinical practice, the relative biological effectiveness (RBE) between protons and photons is set as constant 1.1. Numerous studies have suggested that the RBE of protons can exhibit significant variability. Given these findings, there is a substantial interest in refining proton therapy treatment planning to better account for the variable RBE. Dose-average Linear Energy Transfer (LETd) is a key physical parameter for evaluating the RBE of proton therapy and aids in optimizing proton treatment plans. Calculating precise LETd distributions necessitates the use of intricate physical models and the execution of specialized Monte-Carlo simulation software, which is a computationally intensive and time-consuming progress. In response to these challenges, we propose a deep learning (DL) based framework designed to predict the LETd distribution map using the dose distribution map. This approach aims to simplify the process and increase the speed of LETd map generation in clinical settings. The proposed CycleGAN model has demonstrated superior performance over other GAN-based models. The Mean Absolute Error (MAE), Peak Signal-to-Noise Ratio (PSNR) and Normalized Cross Correlation (NCC) of the LETd maps generated by the proposed method are 0.096±0.019 keV/µm, 24.203±2.683 dB, and 0.997±0.002, respectively. The MAE of the proposed method in the clinical target volume, bladder, and rectum are 0.193±0.103, 0.277±0.112, and 0.211±0.086 keV/µm, respectively. The proposed framework has demonstrated the feasibility of generating synthetic LETd maps from dose maps and has the potential to improve proton therapy planning by providing accurate LETd information。.


Vitamin B6 and cancer: synthesis and occurrence of adenosine-N6-diethylthioether-N-pyridoximine-5'-phosphate, a circulating human tumor marker.
In the course of studies aimed at deciphering the metabolic transformations of [3,4-14C] and [3H]C6-pyridoxine hydrochloride by tumor-bearing rats and tumor cells in culture, biosynthesis of a novel labeled product was observed. Its production began with the onset of tumor growth and increased as cell proliferation increased. Chemical, enzymatic, precursor labeling, and analytical tests on the isolated product indicated this product as adenosine-N6-diethylthioether-N-pyridoximine-5'-phosphate (compound 1). In confirmation, the chemical synthesis and characterization of compound 1 are presented in this study. In addition, blood samples from 28 normal subjects, 28 cancer patients with different malignancies, and 39 patients with a variety of other than cancer ailments were screened for compound 1 on a blind basis using reverse phase ion-paired high-performance liquid chromatography. The results show that the level of the vitamin B6 conjugate in the circulation of control subjects, cancer patients in remission, and patients with other diseases was only minimal. Cancer patients with active disease had 3-4-fold higher levels (P < 0.00001). Our results also confirm previous findings regarding the structure of compound 1 and show its potential value as a circulating human tumor marker that could be successfully used for cancer detection.


Role of real-time contrast-enhanced ultrasound in the assessment of metastatic portal vein thrombosis.
Patients with liver disease or systemic pathology are more prone to develop portal vein thrombosis. Non-neoplastic thrombosis is characterised by absence of intrathrombotic perfusion, corresponding to marked hypoechogenicity at contrast-enhanced ultrasound. We report two cases of portal vein thrombosis in which contrast-enhanced ultrasound showed marked hypoechogenicity in the late phase. This late phase perfusional contrast pattern is consistent with non-neoplastic thrombosis, but is actually similar to that of metastatic liver lesions. Echo-guided needle biopsy indeed yielded histological results consistent with carcinoma. Repeated contrast-enhanced ultrasound showed presence of intratumoural perfusion in the arterial phase, suggestive of the neoplastic nature of the thrombus. Our cases suggest that CEUS with second generation contrast agents in patients with portal thrombosis should include the evaluation of both arterial and portal phases in order to provide accurate non-invasive diagnosis of metastatic portal vein thrombosis.


Activities of novel nonglycosidic epipodophyllotoxins in etoposide-sensitive and -resistant variants of human KB cells, P-388 cells, and in vivo multidrug-resistant murine leukemia cells.
Previous structure-activity studies of the antitumor compound etoposide (VP-16) have suggested that replacement of the glycoside moiety could afford therapeutically active analogues with different biochemical determinants for cellular accumulation and drug resistance. In the present report, 10 analogues of VP-16 in which the glycosidyl moiety was replaced with alkyl or arylamino substituents exhibited 5-10-fold better binding affinity for topoisomerase II/DNA complex in human KB cells. A similar increase in the binding affinity was observed in an isolated-nuclei model. The analogues displayed greater or comparable potency to VP-16 in cell growth-inhibition studies and were less affected by cell membrane-associated drug resistance mechanisms, as exemplified by overexpressions of P-glycoprotein multidrug-resistance gene or multidrug resistance-associated protein. Interestingly, in animal studies, analogues least affected by the membrane transport-deficiency phenotypes exhibited low therapeutic index values, thus suggesting that highly efficient modulation of cellular membrane transport defects could perturb the selectivity of antitumor agents for cancer cells. This report also suggests a new method of quantifying drug-induced protein-linked DNA breaks by graphically determining the apparent dissociation-inhibition constant (Kdi) for the inhibitors.


The critical interplay between bone resorbing and bone forming cells.
In this article, the interplay between bone resorbing and bone forming cells is reviewed. This review examines the comprehensive literature on the interaction between bone resorption and bone formation. Coupling between bone resorption and bone formation refers to the process within basic multicellular units, in which osteoclastic bone resorption is met by the differentiation of osteoblasts and their bone forming activity. There are many possible signalling molecules that contribute to coupling at the asynchronously working remodelling sites throughout our skeleton. These include growth factors released from the bone matrix during bone resorption, soluble and membrane products of the osteoclasts and their precursors and signals from osteocytes. In this review, we describe the potential roles of a number of these factors, whose interactions are essential for a tight control of coupling within individual remodelling units, in order to control skeletal mass. Both pre-clinical evidence and clinical evidence pinpoint that molecules in the WNT signalling pathway could be promising bone augmentation therapeutic targets. Regarding oral implications, there is support, from preclinical studies in rats, that anti-sclerostin antibodies can restore alveolar bone mass.


Using Complex Networks in the Hearing Sciences.
In this Point of View, we review a number of recent discoveries from the emerging, interdisciplinary field of Network Science, which uses graph theoretic techniques to understand complex systems. In the network science approach, nodes represent entities in a system, and connections are placed between nodes that are related to each other to form a web-like network. We discuss several studies that demonstrate how the micro-, meso-, and macro-level structure of a network of phonological word-forms influence spoken word recognition in listeners with normal hearing and in listeners with hearing loss. Given the discoveries made possible by this new approach and the influence of several complex network measures on spoken word recognition performance we argue that speech recognition measures-originally developed in the late 1940s and routinely used in clinical audiometry-should be revised to reflect our current understanding of spoken word recognition. We also discuss other ways in which the tools of network science can be used in Speech and Hearing Sciences and Audiology more broadly.


Does regional variation impact decision-making in the management and palliation of pancreatic head adenocarcinoma? Results from an international survey.
Management and palliation of pancreatic head adenocarcinoma is challenging. End-of-life decision-making is a variable process involving multiple factors. We conducted a qualitative, physician-based, 40-question international survey characterizing the impact of medical, religious, social, training and system factors on care. A total of 258 international clinicians completed the survey. Respondents were typically fellowship-trained (78%), with a mean of 16 years' experience in a university-affiliated (93%) hepato-pancreato-biliary group (96%) practice. Most (91%) believed resection is potentially curative. Most patients were discussed preoperatively by multidisciplinary teams (94%) and medical assessment clinics (68%), but rarely critical care (21%). Intraoperative surgical palliation included double bypass or no intervention for locally advanced nonresectable tumours (41% and 49% v. 14% and 85%, respectively, for patients with hepatic metastases). Postoperative admission to the intensive care unit was frequent (58%). Severe postoperative complications were often treated with aggressive cardiopulmonary resuscitation, intubation and critical care (96%), with no defined time points for futility (74%). Admitting surgeons guided most end-of-life decisions (97%). Formal medical futility laws were rarely available (26%). Insurance status did not alter treatment (97%) or palliation (95%) in non-universal care regions. Clinician experience, regional culture and training background impacted treatment (all p < 0.05). Despite remarkable overall agreement, geographic and training differences are evident in the treatment and palliation of pancreatic head adenocarcinoma.


Reaction Wood: Its Structure and Function: Lignification may generate the force active in restoring the trunks of leaning trees to the vertical.
The mechanism by which the stems of trees recover after being bent or tilted out of the vertical is considered. The mechanical consequences of the tendency for the main stem apex to reerect itself and grow vertically or to be replaced by a vertically growing lateral branch, and of the asymmetrical radial growth of displaced stems, are pointed out. The asymmetry usually develops on the upper side of a bent or tilted hardwood stem and on the under side of a softwood stem. Since such asymmetry can usually be accounted for on the basis of accentuated development of wood rather than bark, the question of the possible functional significance of the wood arises. Experiments are cited to demonstrate that the wood (reaction wood) is effective as a means for assisting displaced stems to recover, contracting longitudinally on the upper side of a hardwood stem and expanding on the under side of a softwood stem. Consideration is then given to the structure, differentiation, and chemical composition of the reaction wood formed by hardwoods and softwoods with a view to locating the force active in aiding recovery and determining its origin. The consequences of associating the support of a still-growing stem displaced from the vertical with the idiosyncracies of secondary wall formation of reaction wood cells, and the reerection of such a stem with lignification of these walls, are explored. On this basis, the hypothesis is advanced that the recovery force is located in the region of differentiating reaction wood cells undergoing lignification, the active force arising from the swelling of cell walls as a result of deposition in them of lignin. Objections to the hypothesis are mentioned.


Critical appraisal of therapeutic interventions in the intensive care unit: human monoclonal antibody treatment in sepsis. Journal Club of the Hamilton Regional Critical Care Group.
Using the medical literature to solve patient problems is challenging and rewarding. For intensive care physicians, this evidence-based medicine approach is more compelling when basic critical appraisal skills are developed. We highlight the important methodological points for interpreting the literature on treatment, using a cogent example from the critical care literature--monoclonal antibody therapy in sepsis. It is likely that as we move into the 1990s, growth in the number of articles on immunotherapy in the sepsis syndrome will parallel the growth of the general biomedical literature.


Factor structure and factorial invariance of the Multidimensional Acculturative Stress Inventory.
Using a national data set, this study examined the factor structure and factorial invariance of the Multidimensional Acculturative Stress Inventory (MASI) across Latino and Asian Americans, gender, and nativity (U.S.- vs. foreign-born). Results showed that a 4-factor model of acculturative stress provided good fit to the data. Tests of factorial invariance provided evidence of measurement equivalence across all of the groupings tested. These findings suggest that the MASI operationalizes acculturative stress in an equivalent manner across Latino and Asian American students, gender, and nativity.


Effect of dehydration during pregnancy on birth weight and length in West Jakarta.
Nutrition and maternal behavior are critical factors in fetal development. Maternal water intake is necessary to regulate metabolism and may influence fetal growth. This study aims to determine the effect of dehydration during pregnancy on birth weight and length. This cohort-prospective study took place in the area of Kebon Jeruk District Health Centre. A total of 38 subjects of pregnant women in their second trimester were examined. Subject characteristics were collected through direct measurements and interviews. Urine and blood samples were collected at the sixth trimester (32-34 and 35-37 weeks) to determine hydration status. Nutritional status was collected through food recall, while birth weight and length were obtained from the anthropometric measurements 30 min after birth. From a total of 38 subjects, 20 were dehydrated, and 18 were well hydrated. There was a significant relationship between hydration status and water intake, birth weight and length, head circumference, and chest circumference. After being corrected to the level of water intake, the difference in birth weight and length between the two groups were 500⋅6 g and 0⋅4 cm, and 0⋅8 cm and 1⋅4 cm for the head circumference and chest circumference (P < 0⋅05). It is recommended for mothers to monitor their weight and ensure fluid intake of 3⋅0 l per day. Further research requires more subjects to observe the effects of chronic maternal dehydration on pregnancy output and a cohort study that monitors infant development in the first six months of life.


Absolute bioavailability and metabolic disposition of valaciclovir, the L-valyl ester of acyclovir, following oral administration to humans.
Valaciclovir (Valtrex), the L-valyl ester of acyclovir, is undergoing clinical development for the treatment and suppression of herpesviral diseases. The absolute bioavailability of acyclovir from valaciclovir and the metabolic disposition of valaciclovir were investigated with healthy volunteers in two separate studies. In a randomized, crossover study, 12 fasting healthy volunteers each received 1,000 mg of oral valaciclovir and a 1-h intravenous infusion of 350 mg of acyclovir. The mean absolute bioavailability of acyclovir was 54.2%, a value three to five times that obtained previously with oral acyclovir. A similar estimate of 51.3% was made from urinary recovery of acyclovir. In the second study, four fasting volunteers received a single oral dose of 1,000 mg of [14C]valaciclovir. The majority of plasma radioactivity was accounted for by acyclovir, with very low plasma valaciclovir concentrations (mean maximum concentration of drug in plasma = 0.19 microM), which were undetectable after 3 h postdose. By 168 h, more than 90% of the administered radioactive dose was recovered, with approximately 45% in urine and 475 in feces. More than 99% of the radioactivity recovered in urine corresponded to acyclovir and its known metabolites, 9-(carboxymethoxymethyl)guanine and 8-hydroxy-9- [(2-hydroxyethoxy)methyl]guanine, with valaciclovir accounting for less than 0.5% of the dose. Acyclovir, but no valaciclovir, was detected in fecal samples. These studies show that after oral administration to humans, valaciclovir is rapidly and virtually completely converted to acyclovir to provide a high level of acyclovir bioavailability in comparison with that following oral administration of acyclovir. The plasma acyclovir exposure obtained following oral administration of valaciclovir is similar to that achieved with doses of intravenous acyclovir, which are effective in the treatment and suppression of the less susceptible herpesviral diseases.


Memory Impairing Effect of Propranolol on Consolidation and Reconsolidation for Various Learning Tasks.
Newly acquired memory traces have been thought to become stable and resistant to interruption after they are stored in long-term memory. However, according to a recent research drugs such as beta-adrenergic receptor antagonists enable memories to be updated and rewritten when administered during consolidation and reconsolidation. Propranolol is a widely used beta-adrenergic receptor antagonist that disrupts the consolidation and reconsolidation processes of memory formation as it inhibits protein synthesis in the central nervous system. This review aims to discuss the memory impairing effect of the systemic and intracerebral administration of propranolol during the consolidation and reconsolidation processes associated with different learning tasks. In doing so, this review will help elucidate the effects of propranolol on different stages of memory formation. Since learning and maladaptive memories underpin some of the most common psychological disorders, such as phobias, post-traumatic stress disorder, addiction, drug-seeking behavior, and so on, a thorough understanding of propranolol's memory-impairing effect has significant clinical value and the potential to help people suffering from these disorders.


Resiliency factors protecting against teenage alcohol use and smoking: influences of religion, religious involvement and values, and ethnicity in the Missouri Adolescent Female Twin Study.
The objective of this study was to investigate the contribution of ethnicity (African American vs European/other ancestry), family religious affiliation, religious involvement, and religious values, to risk of alcohol and cigarette use in adolescent girls; and to estimate genetic and shared environmental effects on religious involvement and values. Telephone interviews were conducted with a sample of female like-sex twin pairs, aged 13-20 (n = 1687 pairs, including 220 minority pairs), as well as with one or both parents of twins aged 11-20 (n = 2111 families). These data, together with one-year follow-up twin questionnaire data, and two-year follow-up parent interview data, were used to compare ethnic differences. Proportional hazards regression models and genetic variance component models were fitted to the data. Despite higher levels of exposure to family, school and neighborhood environmental adversities, African American adolescents were less likely to become teenage drinkers or smokers. They showed greater religious involvement (frequency of attendance at religious services) and stronger religious values (eg belief in relying upon their religious beliefs to guide day-to-day living). Controlling for religious affiliation, involvement and values removed the ethnic difference in alcohol use, but had no effect on the difference in rates of smoking. Religious involvement and values exhibited high heritability in African Americans, but only modest heritability in EOAs. The strong protective effect of adolescent religious involvement and values, and its contribution to lower rates of African American alcohol use, was confirmed. We speculate about the possible association between high heritability of African American religious behavior and an accelerated maturation of religious values during adolescence.


Mutations in DYT1: extension of the phenotypic and mutational spectrum.
Most cases of early-onset primary torsion dystonia (PTD) are caused by the same three-base pair (bp) (GAG) deletion in the DYT1 gene. Exon rearrangements are a common mutation type in other genes and have not yet been tested for in DYT1. Several lines of evidence suggest a relationship of the DYT1 gene with Parkinson disease (PD). To investigate the frequency and type of DYT1 mutations and explore the associated phenotypes in a mixed movement disorders patient cohort and in controls. The authors screened 197 patients with dystonia (generalized: n = 5; focal/segmental: n = 126; myoclonus-dystonia: n = 34; neuroleptic-induced: n = 32), 435 with PD, and 42 with various other movement disorders, along with 812 healthy controls, for small deletions in exon 5 of DYT1 and tested for exon rearrangements by quantitative, duplex PCR in 51 GAG deletion-negative dystonia cases. The GAG deletion was detected in five patients: three with early-onset PTD, one with generalized jerky or clonic dystonia, and one with generalized dystonia and additional features (developmental delay, pyramidal syndrome). A novel out-of-frame four-bp deletion (934_937delAGAG) in exon 5 of the DYT1 gene was found in a putatively healthy blood donor. No exon rearrangements were identified in DYT1. In this mixed patient sample, the GAG deletion was rare and in two out of five cases associated with an unusual phenotype. In addition, a novel DYT1 truncating mutation of unknown clinical relevance was found in a putatively unaffected individual. DYT1 exon rearrangements, however, do not seem to be associated with PTD.


'One-trial sensitization' to the anxiolytic-like effects of cannabinoid receptor antagonist SR141716A in the mouse elevated plus-maze.
Significant variability in the effects of cannabinoid CB1 receptor ligands on emotional reactivity in animals and humans suggests that the endocannabinoid system may selectively modulate certain types of anxiety. In view of substantial evidence for qualitative differences in the nature of anxiety elicited on initial and subsequent exposures to the elevated plus-maze, the present studies contrasted the behavioural effects of the selective CB1 receptor antagonist SR141716A (0.1-10.0 mg/kg) and the reference benzodiazepine chlordiazepoxide (CDP, 15 mg/kg) both in maze-naive mice (trial 1) and in mice that had been given a single undrugged exposure to the maze 24 h prior to testing (trial 2). Results confirmed the anxioselective effect of CDP on trial 1 but a complete absence of such activity on trial 2 (i.e. one trial tolerance). In marked contrast, SR141716A had no behavioural effects in maze-naive mice but, at doses of 1.0-3.0 mg/kg (effect maximal at 1.0 mg/kg), significantly reduced anxiety-like responses in maze-experienced animals. Like the effect of CDP on trial 1, the antianxiety profile of SR141716A on plus-maze trial 2 was observed in the absence of any change in general activity levels. The apparent experientially induced 'sensitization' to the anxiolytic-like effects of SR141716A in the plus-maze contrasts markedly with the widely reported loss of benzodiazepine efficacy in test-experienced animals. Data are discussed in relation to the recently described phenotypes of CB1 receptor knockout mice and, in particular, to mounting evidence for the existence of a novel SR141716A-sensitive neuronal cannabinoid receptor.


The inhibitor protein of the cyclic AMP-dependent protein kinase-catalytic subunit interaction. Composition of multiple complexes.
It has been previously demonstrated that the combination of pure preparations of the inhibitor protein of the cyclic AMP-dependent protein kinase and the catalytic subunit of this enzyme resulted in the formation of multiple complexes [Van Patten, Fletcher & Walsh (1986) J. Biol. Chem. 261, 5514-5523]. In the present study it is demonstrated that these multiple species occur because the bovine heart protein kinase preparation contains multiple forms of catalytic subunit [Kinzel, Hotz, König, Gagelmann, Pyerin, Reed, Köbler, Hofmann, Obst, Gensheimer, Goldblatt & Shaltiel (1987) Arch. Biochem. Biophys. 253, 341-349].


Development and testing of implanted carbon electrodes for electromagnetic field mapping during neuromodulation.
Deep brain stimulation electrodes composed of carbon fibers were tested as a means of administering and imaging magnetic resonance electrical impedance tomography (MREIT) currents. Artifacts and heating properties of custom carbon-fiber deep brain stimulation (DBS) electrodes were compared with those produced with standard DBS electrodes. Electrodes were constructed from multiple strands of 7-μm carbon-fiber stock. The insulated carbon electrodes were matched to DBS electrode diameter and contact areas. Images of DBS and carbon electrodes were collected with and without current flow and were compared in terms of artifact and thermal effects in phantoms or tissue samples in 7T imaging conditions. Effects on magnetic flux density and current density distributions were also assessed. Carbon electrodes produced magnitude artifacts with smaller FWHM values compared to the magnitude artifacts around DBS electrodes in spin echo and gradient echo imaging protocols. DBS electrodes appeared 269% larger than actual size in gradient echo images, in sharp contrast to the negligible artifact observed in diameter-matched carbon electrodes. As expected, larger temperature changes were observed near DBS electrodes during extended RF excitations compared with carbon electrodes in the same phantom. Magnitudes and distribution of magnetic flux density and current density reconstructions were comparable for carbon and DBS electrodes. Carbon electrodes may offer a safer, MR-compatible method for administering neuromodulation currents. Use of carbon-fiber electrodes should allow imaging of structures close to electrodes, potentially allowing better targeting, electrode position revision, and the facilitation of functional imaging near electrodes during neuromodulation.


Imaging gastric pennies in children.
Pennies are among the most common foreign objects ingested by children. This occurrence has traditionally been managed conservatively. However, more recent studies indicate that the higher zinc composition of pennies produced after 1982 may be more dangerous than previously believed. We reported earlier the in situ reaction of such pennies following immersion in hydrochloric acid at gastric pH. The present study examines the utility of radiographic examination of such pennies.


The detection of verocytotoxins in bacterial cultures from human diarrhoeal samples with monoclonal antibody-based ELISAs.
Bacterial cultures from 1801 human diarrhoeal faecal specimens were examined for verocytotoxins I and II by monoclonal antibody-based sandwich ELISAs. Of the 68 ELISA-positive cultures selected from initial screening, 32 were positive by ELISA on repeat or from freshly grown cultures. ELISA-positive pure cultures were obtained from 13 of these, of which seven were confirmed as verocytotoxin positive by cytotoxicity assay. These seven strains were typed as O26 (5) and O146 (2). The six false positive results were from isolates of Enterobacter sp. (1), Citrobacter Freundii (1) and Escherichia coli (4), one each of types O1, O18ac and O98 and an untypable strain. Despite the occurrence of false positive reactions, sandwich ELISA was a useful method for the rapid screening of samples, and detected verocytotoxin-positive E. coli strains, other than O157, from patients with clinical conditions in which they could be implicated.