[Clinical drug profiles: an instrument to improve shared decision-making].
Doctors and patients are increasingly choosing treatment options by means of the shared decision-making process. However, human decisions are subject to cognitive bias, i.e. systematic and predictable errors in probability estimation and information synthesis. Decision-making may also be hampered by incomplete information. Clinical Drug Profiles (CDPs) aim to provide up-to-date, evidence-based and independent information about drug characteristics that are relevant to doctors and patients alike in the context of shared decision-making. They contain information about mechanisms of action, mode and frequency of administration, clinical efficacy, therapeutic effectiveness, side effects, persistence and adherence, and safety monitoring. CDPs are to be made freely available on the internet, thus enabling doctors and patients to obtain drug-specific information on potential benefits and risks, before or during the decision-making process. In addition, the patient can make a subjective appraisal of the chances of success and the risk of side effects. In all, CDPs increase the likelihood that two major conditions of successful shared decision-making are met: minimisation of cognitive bias and complete information.


Prenatal, perinatal, and early childhood risk factors and drug involvement in adolescence.
This study examined prenatal, perinatal, and early childhood risk factors in relation to the etiology of adolescent involvement in cigarettes, alcohol, marijuana, and other illicit drugs. Over a span of 10 years, data were collected on 638 mainly White mother-child pairs at three points in time: at T1, when the children were 1 to 10 years old; at T2, when they were 9 to 18, and again at T3, when they were 11 to 20. Results showed that the early risks of an unwanted pregnancy and major illness were linked to all of the drug categories except "other illicit drugs." Aspects of mutual attachment in the mother-adolescent relationship were negatively correlated with adolescent drug use. Data on the interrelationship of the domains (i.e., sets of variables) of early risk factors and mother-adolescent relations supported an independent model with respect to cigarette and marijuana involvement, a finding in keeping with results showing that early risk did not significantly affect mother-adolescent relations. However, mother-adolescent protective factors were able to mitigate the impact of early risk factors on adolescent drug involvement.


Dispersal biophysics and adaptive significance of dimorphic diaspores in the annual Aethionema arabicum (Brassicaceae).
Heteromorphic diaspores (fruits and seeds) are an adaptive bet-hedging strategy to cope with spatiotemporally variable environments, particularly fluctuations in favourable temperatures and unpredictable precipitation regimes in arid climates. We conducted comparative analyses of the biophysical and ecophysiological properties of the two distinct diaspores (mucilaginous seed (M+ ) vs indehiscent (IND) fruit) in the dimorphic annual Aethionema arabicum (Brassicaceae), linking fruit biomechanics, dispersal aerodynamics, pericarp-imposed dormancy, diaspore abscisic acid (ABA) concentration, and phenotypic plasticity of dimorphic diaspore production to its natural habitat and climate. Two very contrasting dispersal mechanisms of the A. arabicum dimorphic diaspores were revealed. Dehiscence of large fruits leads to the release of M+ seed diaspores, which adhere to substrata via seed coat mucilage, thereby preventing dispersal (antitelechory). IND fruit diaspores (containing nonmucilaginous seeds) disperse by wind or water currents, promoting dispersal (telechory) over a longer range. The pericarp properties confer enhanced dispersal ability and degree of dormancy on the IND fruit morph to support telechory, while the M+ seed morph supports antitelechory. Combined with the phenotypic plasticity to produce more IND fruit diaspores in colder temperatures, this constitutes a bet-hedging survival strategy to magnify the prevalence in response to selection pressures acting over hilly terrain.


The Stanniocalcin-PAPP-A-IGFBP-IGF Axis.
The pappalysin metalloproteinases, PAPP-A and PAPP-A2, have emerged as highly specific proteolytic enzymes involved in the regulation of insulin-like growth factor (IGF) signaling. The only known pappalysin substrates are a subset of the IGF binding proteins (IGFBPs), which bind IGF-I or IGF-II with high affinity to antagonize receptor binding. Thus, by cleaving IGFBPs, the pappalysins have the potential to increase IGF bioactivity and hence promote IGF signaling. This is relevant both in systemic and local IGF regulation, in normal and several pathophysiological conditions. Stanniocalcin-1 and -2 were recently found to be potent pappalysin inhibitors, thus comprising the missing components of a complete proteolytic system, the stanniocalcin-PAPP-A-IGFBP-IGF axis. Here, we provide the biological context necessary for understanding the properties of this molecular network, and we review biochemical data, animal experiments, clinical data, and genetic data supporting the physiological operation of this branch as an important part of the IGF system. However, although in vivo data clearly illustrate its power, it is a challenge to understand its subtle operation, for example, multiple equilibria and inhibitory kinetics may determine how, where, and when the IGF receptor is stimulated. In addition, literally all of the regulatory proteins have suspected or known activities that are not directly related to IGF signaling. How such activities may integrate with IGF signaling is also important to address in the future.


Fluoroquinolone Derivatives in the Treatment of Mycobacterium tuberculosis Infection.
Tuberculosis (TB) is currently one of the leading causes of death due to infective agents, and the growing rate of multidrug-resistant tuberculosis (MDR TB) cases poses an emergent public health threat. Fluoroquinolones are commonly used in the treatment of both MDR TB and drug-sensitive tuberculosis patients who are intolerant to first-line antitubercular agents. Unfortunately, these drugs have mild side effects, relevant to the prolonged treatment regimens and diminished bioavailability due to binding of metal ions. Moreover, the resistance to fluoroquinolones is also on the rise, a characteristic of extensively drug-resistant TB (XDR TB). Here, we developed esters as prodrugs of the fluoroquinolones levofloxacin and ciprofloxacin, with long-chain fatty alcohols. Both the alcohols and the quinolone have previously shown antimycobacterial activity and the aim was to develop esters with improved lipophilicity and capable of delivering the free acid inside mycobacterial cells. The carboxylic acid group of fluoroquinolones is essential to the mode of action but is also responsible for many of its side effects and metal-chelating properties. The synthesis, stability in biological media, and antibacterial activity were evaluated, the latter not only against Mycobacterium tuberculosis but also against other clinically relevant bacterial species, since the parent compounds display a broad spectrum of activity. The biological results show a reduction in the antitubercular activity of the synthesized derivatives, probably due to deficient activation of the ester prodrug. Despite this, it was found that the derivatives exhibit bioactivity against other fluoroquinolone-resistant bacteria, indicating a different mode of action and suggesting that it may be worthwhile to research further modifications to the carboxylic acid group. This might lead to new compounds that are efficient against resistant strains. This idea that the compounds may act by a different mechanism of action was further supported by a brief computer investigation that demonstrated the potential lack of selectivity of the esters to the fluoroquinolone target.


[Comparative metabolism of three amide alkaloids from Piper longum in five different species of liver microsomes].
Piperine, piperlonguminine and pellitorine are three major amide alkaloids from Piper longum, showing a variety of pharmacological activities. In order to investigate the different metabolism pathways of these compounds in five species of liver microsomes in vitro, the data of full mass spectrum, and MS2, MS3 spectra of these three alkaloids were collected and analyzed by using ultra-high-performance liquid chromatography coupled with a LTQ-orbitrap mass spectrometer (UHPLC-LTQ-Orbitrap MS); gragment ion information was collected and combined with fragmentation regularities of mass spectra and accurate mass spectrometry data of metabolites, to compare the metabolism difference of three amide alkaloids in liver microsomes of human, rhesus monkey, Beagle dogs, rats and mice. 3 metabolites of piperine, 2 metabolites of piperlonguminine and 1 metabolite of pellitorine were identified quickly. The results showed that the major metabolic pathways of these amide alkaloids in liver microsomes were methylenedioxy group demethylation and oxidation reaction, and metabolic rates were different between species. This study provides basis for further research on in vivo metabolism of piperine analogues from Piper longum.


Morphology and oxidative physiology of boron-deficient mulberry plants.
The aim of the study was to induce B deficiency symptoms and to relate the generation of reactive oxygen species (ROS) and altered cellular redox environment with the effects of B deficiency in mulberry (Morus alba L.) cv. Kanva-2 plants. Study was undertaken on antioxidant responses, malondialdehyde (MDA) content as an indicator of oxidative damage and ratio of dehydroascorbate (DHA) to ascorbic acid (AsA) as an index of cellular redox environment in B-deficient (0.0 microM) and B-supraoptimal (33 microM) mulberry plants. B deficiency symptoms appeared as upward cupping of the young emerging leaves. Later on, B-deficient plants developed lenticels like cracks on major vein, petiole and stem. B-deficient leaves had higher water potential (Psi) and relative water content (RWC), contained a lower concentration of B, less chloroplastic pigments and high tissue Fe, Mn and Zn concentrations compared to the controls. Hydrogen peroxide was accumulated in leaves of B-deficient and B-supraoptimal plants. B-supraoptimal plants also showed an increased DHA/AsA ratio. The activities of superoxide dismutase (SOD, EC 220.127.116.11), catalase (CAT, EC 188.8.131.52), peroxidase (POD, EC 188.8.131.52) and ascorbate peroxidase (APX, EC 22.214.171.124) were increased in B-deficient leaves. The activities of SOD and POD were decreased in B-supraoptimal plants. The results suggest that B deficiency aggravates oxidative stress through enhanced generation of ROS in mulberry plants.


Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation.
Recently, type H vessels were reported to couple angiogenesis and osteogenesis during osteoclastogenesis, and tartrate-resistant acid phosphatase (Trap)+ preosteoclasts were found to secrete increased PDGF-BB to promote type H vessel formation. Therefore, utilization of type H vessels may be a strategy to treat diseases involving bone loss. In the present study, we found that nuciferine, a natural bioactive compound, has various effects, including inhibiting osteoclastogenesis and promoting type H vessel formation. Nuciferine inhibited osteoclastogenesis and bone resorption but increased the relative number of Trap+ preosteoclasts. Nuciferine restrained the expression of osteoclast-specific genes and proteins, promoted PDGF-BB production and potentiated related angiogenic activities by inhibiting the MAPK and NF-κB signaling pathways in vitro. We confirmed the bone-protective effects of nuciferine in ovariectomized mice and found that nuciferine treatment increased the PDGF-BB concentration and the number of type H vessels in the femur. In conclusion, our results demonstrated that nuciferine can decrease multinucleated osteoclast formation and promote type H vessel formation through preservation of Trap+ preosteoclasts via inhibition of the MAPK and NF-κB signaling pathways and may be an excellent agent for the treatment of diseases involving bone loss.


Management of accidental extubation during oral surgery by nasotracheal intubation using the King vision video laryngoscope and a gum elastic bougie - a case report.
Accidental extubation during intra operative period especially during oral surgery is challenging for any anaesthesiologist. Securing the definitive airway during this period is not only crucial and life saving but also challenging to the anaesthesia provider. Here we report a case which got extubated during hemimandibulectomy and was successfully reintubated using King Vision video laryngoscope. This videolaryngoscope proved to be a good rescue device in managing an accidental extubation during oral surgery and could represent a useful tool for the management of such unfamiliar situations.


Dexamethasone - Cyclophosphamide pulse (DCP) therapy in Pemphigus.
Of the 37 patients enrolled for this treatment, 13 have been lost to follow up and 4 have died. Of the remaining 20, 8 are already in remission (40%), while 12 are still having active disease. Of the 8 patients who are now in remission, 1 is in phase II and taking monthly dexamethasone cyclophosphamide pulse and 50 mg cyclophosphamide daily while in 3 patients all the treatment has already been withdrawn (phase IV). All these patients are being followed up for any recurrence. The duration of remission has been more than 6 months in 7 patients (maximum 2 years). The chief side-effect observed was increased susceptibility to pyogenic and candidal infections of the skin and oral mucosa respectively. The other side-effects noted were generalized weakness and lethargy following DCP (1), irregular menstrual periods (1), amenorrhoea (1), general darkening of complexion (1), steroid psychosis (1), transient eosinophilia (1) and marked transient oligospermia.


Class discovery analysis of the lung cancer gene expression data.
Traditional histological classification of lung cancer subtypes is informative, but incomplete. Recent studies of gene expression suggest that molecular classification can be used for effective diagnostic and prediction of the treatment outcome. We attempt to build a molecular classification based on the public data available from a few independent sources. The data is reanalyzed with a new cluster analysis algorithm. This algorithm allows us to preserve the high dimensionality of data and produce the cluster structure without preliminary selection of significant genes or any other presumption about the relation between different cancer and normal tissue samples. The resulting clusters are generally consistent with the histological classification. However, our analysis reveals many additional details and subtypes of previously defined types of lung cancer. Large histological cancer types can be further divided into subclasses with different patterns of gene expression. These subtypes should be taken into account in diagnostics, drug testing, and treatment development for lung cancer patients.


A shared antigenic determinant between human B lymphocytes and carcinomas (BLCa).
We have raised a murine IgM monoclonal antibody (MA6) against immunoprecipitate obtained by reacting the serum of an NPC patient with extract of the Burkitt lymphoma cell line, Raji. It reacts against an antigen (BLCa) which is broadly represented on human B lymphoid tissues and cell lines but is different from the functional B-cell markers such as surface immunoglobulins, Ia products, Fc and complement receptors. BLCa was found to occur on lymphoid cell lines representing all stages of B-cell differentiation. These included the pre-B and null-cell lines, Nalm 6 and Reh, the EBV-transformed lymphoid cell lines and the myeloma cell line. MA6 was reactive against all the Burkitt lymphoma cell lines, whether or not these harbored the EBV genomes, with the exception of P3HR-I. The antibody was found to be selectively reactive against a proportion of peripheral blood B lymphocytes and to stain the B-cell-rich primary follicles and mantle zones of secondary follicles in the lymph node. However, MA6 was not reactive against cell lines of T-lymphocyte, myeloid, monocyte fibroblast or epithelial origin. It did, nevertheless selectively stain tumor cells from a variety of carcinoma tissues originating from different anatomical sites, including the nasopharynx.


Epigenetics in prostate cancer: biologic and clinical relevance.
Prostate cancer (PCa) is one of the most common human malignancies and arises through genetic and epigenetic alterations. Epigenetic modifications include DNA methylation, histone modifications, and microRNAs (miRNA) and produce heritable changes in gene expression without altering the DNA coding sequence. To review progress in the understanding of PCa epigenetics and to focus upon translational applications of this knowledge. PubMed was searched for publications regarding PCa and DNA methylation, histone modifications, and miRNAs. Reports were selected based on the detail of analysis, mechanistic support of data, novelty, and potential clinical applications. Aberrant DNA methylation (hypo- and hypermethylation) is the best-characterized alteration in PCa and leads to genomic instability and inappropriate gene expression. Global and locus-specific changes in chromatin remodeling are implicated in PCa, with evidence suggesting a causative dysfunction of histone-modifying enzymes. MicroRNA deregulation also contributes to prostate carcinogenesis, including interference with androgen receptor signaling and apoptosis. There are important connections between common genetic alterations (eg, E twenty-six fusion genes) and the altered epigenetic landscape. Owing to the ubiquitous nature of epigenetic alterations, they provide potential biomarkers for PCa detection, diagnosis, assessment of prognosis, and post-treatment surveillance. Altered epigenetic gene regulation is involved in the genesis and progression of PCa. Epigenetic alterations may provide valuable tools for the management of PCa patients and be targeted by pharmacologic compounds that reverse their nature. The potential for epigenetic changes in PCa requires further exploration and validation to enable translation to the clinic.


ID-Checker Technology for the Highly Selective Macroscale Delivery of Anticancer Agents to the Cancer Cells.
Cancer cells deploy several glucose transport protein (GLUT) channels on the cell membranes to increase glucose uptake. Cancer cells die within 24 h in the absence of glucose. Thus, preventing the deployment of GLUT channels can deprive them of glucose, resulting in apoptosis within 24 h. Herein, we developed the ID-Checker with a glucose tag that ensures its highly specific macroscale delivery of anticancer agents to the cancer cells through the GLUT channels. ID-Checker presented here showed IC50 values of 0.17-0.27 and 3.34 μM in cancer and normal cell lines, respectively. ID-Checker showed a selectivity index of 12.5-20.2, which is about 10-20 times higher than that of known anticancer agents such as colchicine. ID-Checker inhibits the microtubule formation, which results in the prevention of the deployment of GLUT channels in 6 h and kills the cancer cells within 24 h without any damage to normal cells.


High-speed, multicolor fluorescent two-dimensional gene scanning.
Two-dimensional gene scanning (TDGS) is a method for analyzing multiple DNA fragments in parallel for all possible sequence variations, using extensive multiplex PCR and two-dimensional electrophoretic separation on the basis of size and melting temperature. High throughput application of TDGS is limited by the prolonged time periods necessary to complete the second-dimension electrophoretic separation step--denaturing gradient gel electrophoresis--and the current need for gel staining. To address these problems, we constructed a high-voltage, automatic, two-dimensional electrophoresis system and used this in combination with thinner gels to reduce two-dimensional electrophoresis time about 80%. Instead of gel staining, we used three different fluorophores to simultaneously analyze three samples in the same gel. These improvements greatly increase TDGS speed and throughput and make the method highly suitable for large-scale single-nucleotide polymorphism discovery and genetic testing.


Polymyalgia Rheumatica (PMR) with Normal Values of Both Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP) Concentration at the Time of Diagnosis in a Centenarian Man: A Case Report.
The possibility that polymyalgia rheumatica (PMR) can be diagnosed when both ESR and CRP are normal at the time of diagnosis and before therapy with glucocorticoids, has been often discussed in the literature. We present a case report of a 100-year-old Caucasian man referred to our outpatient clinic, complaining of chronic pain in the shoulder and hip girdle associated with normal values of both ESR (21 mm/1st hour) and CRP (4 mg/dL). In the previous four months, several anti-inflammatory drugs and painkillers associated with physiotherapy treatments gave no significant improvement in pain and self-care. After an ultrasound (US) and an 18-fluorodeoxyglucose positron emission tomography associated with total body computed tomography (18-FDG PET/CT) examination, PMR was diagnosed and he started therapy with 17.5 mg prednisone, obtaining a fast improvement in pain and self-care. After 10 months of tapering, he stopped prednisone without relapse. During a 3-year follow-up, no alternative diagnosis was done. When a patient complains of chronic bilateral shoulder and hip girdle pain associated with normal inflammatory indices, it is reasonable to think in the first instance that this person is not suffering from PMR. Moreover, the possibility that PMR may onset in a centenarian person, is exceptional. In our patient, when we piece the puzzle together, the diagnosis of PMR was the most possible one.


Aging of human palatal salivary glands: a histomorphometric study.
The aim of the present study was to examine age-related changes in the parenchymal and stromal components of palatal salivary glands of healthy subjects. Palatal salivary gland biopsies were obtained from 120 autopsies and were divided into young, adult, and old age groups. Histomorphometric measurements were performed on hematoxylin and eosin (H&E) stained slides. Parenchymal components included acini and ducts, and stromal components included connective tissue, blood and lymphatic vessels, inflammatory infiltrate, and adipose tissue. The mean volume fraction of each component in each age group was calculated. Statistical analysis was performed by one-way ANOVA and Tamhane tests. The mean volume fraction of the acinar component demonstrated a significant age-related decrease of 48% (P < 0.001). The mean volume fractions of the ducts and of all the stromal components demonstrated a significant age-related increase (P < 0. 001). The inflammatory infiltrate component had the highest increase with aging (1471%), followed by the ducts (177%), blood and lymphatic vessels (138%), adipose tissue (130%), and connective tissue (60%). These age-related changes, the first to be reported in palatal salivary glands from healthy subjects, are different from those described in the labial salivary glands, especially in regard to the significant increase in the parenchymal ductal component, as well as in the stromal inflammatory infiltrate and adipose tissue components. It can be suggested that these changes could have important implications regarding the age-related function of these glands.


Photochemical reduction of oxygen adsorbed to nanocrystalline TiO(2) films: a transient absorption and oxygen scavenging study of different TiO(2) preparations.
Transient absorption spectroscopy (TAS) has been used to study the interfacial electron-transfer reaction between photogenerated electrons in nanocrystalline titanium dioxide (TiO(2)) films and molecular oxygen. TiO(2) films from three different starting materials (TiO(2) anatase colloidal paste and commercial anatase/rutile powders Degussa TiO(2) P25 and VP TiO(2) P90) have been investigated in the presence of ethanol as a hole scavenger. Separate investigations on the photocatalytic oxygen consumption by the films have also been performed with an oxygen membrane polarographic detector. Results show that a correlation exists between the electron dynamics of oxygen consumption observed by TAS and the rate of oxygen consumption through the photocatalytic process. The highest activity and the fastest oxygen reduction dynamics were observed with films fabricated from anatase TiO(2) colloidal paste. The use of TAS as a tool for the prediction of the photocatalytic activities of the materials is discussed. TAS studies indicate that the rate of reduction of molecular oxygen is limited by interfacial electron-transfer kinetics rather than by the electron trapping/detrapping dynamics within the TiO(2) particles.


[Treatment of varicocele in pediatric age with retroperitoneoscopic ''one trochar'' technique. Long term follow-up].
The incidence of varicocele varies from 6% to 16.2% in male children and adolescents. Various techniques were proposed to treat it. In the last years there was an increasing interest in the use of laparoscopy in pediatric urology. The authors reports their experience in the treatment of varicocele by retroperitoneoscopy with one trocar technique and the long-term follow-up in pediatric patients. Fourty patients were treated for idiopathic Horner's degree III or less, but symptomatic, and type 1 according to Coolsaet varicocele. All patients underwent a clinical examination and echo-color Doppler before treatment and during the follow-up. The following parameters were evaluated: duration of the operation, intra and postoperative complications, duration of hospitalization and of antalgic therapy. Follow-up was at 6, 12, 24 and 36 months (mean 23.4 months). Testicles diameters, persistence/recurrence of varicocele and hydroceles were estimated. The retroperitoneoscopic approach in the treatment of varicocele is an effective technique because it implies a minor surgical trauma, a rapid postoperative recovery and a good cosmetic result.


Mid-term repair durability after MitraClip implantation in patients with functional mitral regurgitation.
The aim of this study was to identify variables that are associated with the durability of percutaneous repair of secondary mitral regurgitation at 6-month follow-up. Thirty-five consecutive patients with functional mitral regurgitation scheduled for MitraClip implant were enrolled. Left ventricular (LV) volumes and function and mitral valve characteristics were assessed before and immediately after MitraClip implantation using three-dimensional transesophageal echocardiography. Five patients with an unsuccessful procedure were excluded. The other patients were subdivided according to repair durability: group 1 with a durable repair (19 patients, 65%) and group 2 with significant mitral regurgitation recurrence (11 patients, 35%). At baseline, group 1 patients had smaller and more elliptical mitral valve annulus (1055 ± 241 vs. 1273 ± 359 mm, P = 0.02 and 125 ± 11 vs. 117 ± 16%, P = 0.02), a smaller left atrial volume (54.1 ± 26 vs. 71.5 ± 20 ml, P = 0.005) and lower systolic pulmonary artery pressure (38 ± 11 vs. 49 ± 12 mmHg, P = 0.03). Baseline LV end systolic volume had a linear correlation with the 3D annulus area (P = 0.048) and an inverse correlation with annulus ellipticity (P = 0.021). Group 1 patients showed an increase in annulus ellipticity after MitraClip (125 ± 17 vs. 141 ± 23%, P = 0.014). Percutaneous mitral valve repair leads to a significant and stable mitral regurgitation reduction in a large number of patients. Annulus dimensions and remodeling as well as left atrial area and pulmonary hypertension seem to be associated with durability of the procedure.


An Implantable Wireless System for Remote Hemodynamic Monitoring of Heart Failure Patients.
This article presents an implantable wireless system for remote hemodynamic monitoring, which enables direct, continuous (24/7), and simultaneous measurement of pulmonary arterial pressure (PAP) and cross-sectional area (CSA) of the artery. The implantable device, which measures 3.2 mm × 2 mm × 10 mm, comprises a piezoresistive pressure sensor, an ASIC implemented in 180-nm CMOS, a piezoelectric ultrasound (US) transducer, and a nitinol anchoring loop. An energy-efficient pressure monitoring system, which employs duty-cycling and spinning excitation technique, achieves 0.44 mmHg resolution in a pressure range from -135 mmHg to +135 mmHg and consumes 1.1 nJ conversion energy. The artery diameter monitoring system utilizes the inductive characteristic of the implant's anchoring loop and achieves 0.24 mm resolution within a diameter range of 20 mm to 30 mm, four times higher than echocardiography lateral resolution. The wireless US power and data platform enables simultaneous power and data transfer employing a single piezoelectric transducer in the implant. The system is characterized with an 8.5 cm tissue phantom and achieves a US link efficiency of 1.8%. The uplink data is transmitted by using an ASK modulation scheme parallel to the power transfer and achieves a modulation index of 26%. The implantable system is tested in an in-vitro experimental setup, which emulates the arterial blood flow, and accurately detects fast pressure peaks for systolic and diastolic pressure changes at both 1.28 MHz and 1.6 MHz US powering frequencies, with corresponding uplink data rates of 40 kbps and 50 kbps.


Communication, the centrosome and the immunological synapse.
Recent findings on the behaviour of the centrosome at the immunological synapse suggest a critical role for centrosome polarization in controlling the communication between immune cells required to generate an effective immune response. The features observed at the immunological synapse show parallels to centrosome (basal body) polarization seen in cilia and flagella, and the cellular communication that is now known to occur at all of these sites.


Longitudinal Relationship between Cognitive Function and Health-Related Quality of Life among Middle-Aged and Older Patients with Diabetes in China: Digital Usage Behavior Differences.
Cognitive function and health-related quality of life (HRQoL) are important issues in diabetes care. According to the China Association for Aging, it is estimated that by 2030, the number of elderly people with dementia in China will reach 22 million. The World Health Organization reports that by 2044, the number of people with diabetes in China is expected to reach 175 million. Cohort analyses were conducted based on 854 diabetic patients aged ≥45 years from the third (2015) and fourth (2018) survey of the China Health and Retirement Longitudinal Study (CHARLS). Correlation analysis, repeated-measures variance analysis, and cross-lagged panel models were used to measure the difference in digital usage behavior in the established relationship. The results show that the cognitive function of middle-aged and older diabetic patients is positively correlated with HRQoL. HRQoL at T1 could significantly predict cognitive function at T2 (PCS: B = 0.12, p < 0.01; MCS: B = 0.14, p < 0.01). This relationship is more associated with individual performance than digital usage behavior. Unidirectional associations may exist between cognitive function and HRQoL among middle-aged and older Chinese diabetes patients. In the future, doctors and nurses can recognize the lowering of self-perceived HRQoL of middle-aged and older diabetic patients, and thus draw more attention to their cognitive function, in turn strengthening the evaluation, detection, and intervention of their cognitive function.


Correlation between Forced Vital Capacity and the Severity of Frailty-Induced Dysphagia.
Introduction: Frailty syndrome is a complex condition characterized by the gradual deterioration of an individual's physical, mental, and social functions. Dysphagia is a dysfunction triggered by frailty. However, in patients with frailty syndrome, dysphagia is often undermined, and a proper evaluation is not performed. Therefore, we tried to identify the factors that can provide proper information regarding dysphagia in the frail population. Methods: Patients with dysphagia were divided into those with frailty-induced dysphagia and those with brain-lesion-induced dysphagia. Factors related to the participants' pulmonary function test (PFT) results were evaluated. The severity of dysphagia was evaluated by determining modified videofluoroscopic dysphagia scale (mVDS) and penetration−aspiration scale (PAS) scores based on videofluoroscopic swallowing studies. Statistical analysis was performed to determine the correlation between PFT results and the parameters indicating dysphagia severity. Results: Multivariate logistic regression analysis revealed that forced vital capacity (FVC) was significantly correlated with mVDS scores in frailty-induced dysphagia (p < 0.05). However, no such significance was detected in brain-lesion-induced dysphagia (p ≥ 0.05). Conclusion: FVC was correlated with the severity of dysphagia (mVDS scores) in patients with frailty-induced dysphagia. Thus, serial FVC-based follow-up can be helpful for understanding patients' dysphagia status. However, studies with a general population of patients with frailty-induced dysphagia are needed for definite generalization.


[An outbreak of SARS in Dongcheng District, Beijing during March to June 2003].
To describe epidemiological characteristics of an outbreak of severe acute respiratory syndrome (SRAS) in Dongcheng District, Beijing during March to June 2003. Data of SARS cases notified from Dongcheng District Center for Disease Control and Prevention (CDC) and supplemented by other channels were collected. All data were input into dataset files by Microsoft Excel-2000 software and analyzed with SPSS version 10.0 software. Totally, 572 cases notified were collected during this period in Dongcheng District, Beijing, and 99 of them were excluded from SARS, because of diagnosis of common cold, pneumonia, measles, or rubella, etc. Actually, 473 SARS cases were analyzed. Attack rate of SARS in permanent residents of Dongcheng was 28.3 per 100,000. Forty-one of them died, with a case-fatality ratio of 8.7%. Outbreak of SARS in Dongcheng District started on March 14, with a peak during mid- and late April, and dropped from May 5, 2003. Persons were all susceptible to SARS, with the highest proportion at ages of 20-50 years, which accounted for 68.7% of the total cases. Average age of the patients at their onset was 40.7 years. No gender difference in SARS cases was found. Number of SARS cases in health care workers (HCWs) accounted for 18.0% and that in the retired persons accounted for 15.4% of the total cases. Cases occurred in all 10 sub-districts of Dongcheng. Totally, 230 of the 572 notified cases (40.2%) hospitalized at local hospitals under the jurisdiction of Dongcheng District. Eighteen of 85 cases of SARS occurred in health care workers of local hospitals, accounting for 4.5% of the total number of health care workers working at the wards caring for SARS patients or at fever clinics. There were 34.7% of SARS cases without any contact histories before their onset. Familial aggregation phenomena were observed in 41.8% of the cases and 18.1% of households. And, 7.4% (attack rate) in those exposed to SARS cases suffered the illness during the periods of quarantine. SARS appeared outbreak in Dongcheng District, Beijing during March to June 2003. People were all susceptible to SARS, which mainly threatened the young adults and the middle-aged, as well as health care workers and the retired workers. Main mode of transmission was exposure to SARS patients in a near distance at hospitals or families. Prevention and control of SARS should be focused on early isolation of patients and quarantine for the contacts. Current available measures to prevent and control SARS proved effective.


Premenopausal women have increased risk of hypertensive target organ damage compared with men of similar age.
The impact of high blood pressure (BP) on target organs (TO) in premenopausal women is not well known. The purpose of this study was to describe gender differences in TO involvement in a cohort of young-to-middle-aged subjects screened for stage 1 hypertension and followed for 8.2 years. Participants were 175 women and 451 men with similar age (range 18-45 years). Ambulatory BP at entry was 127.5±12.5/83.7±7.2 mm Hg in women and 131.9±10.3/81.0±7.9 mm Hg in men. Ambulatory BP, albumin excretion rate (AER), and echocardiographic data (n=489) were obtained at entry, every 5 years, and before starting antihypertensive treatment. Female gender was an independent predictor of final AER (p=0.01) and left ventricular mass index (LVMI) (p<0.001). At follow-up end, both microalbuminuria (13.7% vs. 6.2%, p=0.002) and left ventricular hypertrophy (LVH) (26.4% vs. 8.8%, p<0.0001) were more common among women than men. In a multivariable Cox analysis, after adjusting for age, lifestyle factors, body mass, ambulatory BP, heart rate, and parental hypertension, female gender was a significant predictor of time to development of microalbuminuria (p=0.002), with a hazard ratio (HR) of 3.06, (95% confidence interval [CI] 1.48-6.34) and of LVH (p=0.004), with an HR of 2.50 (1.33-4.70). Inclusion of systolic and diastolic BP changes over time in the models only marginally affected these associations, with HRs of 3.13 (1.50-6.55) and 3.43 (1.75-6.70), respectively. These data indicate that premenopausal women have an increased risk of hypertensive TO damage (TOD) and raise the question about whether early antihypertensive treatment should be considered in these patients.


Dendronized DNA Chimeras Harness Scavenger Receptors To Degrade Cell Membrane Proteins.
Bispecific chimeras bridging cell membrane proteins with lysosome-trafficking receptors (LTRs) provide an effective therapeutic approach through lysosomal degradation of disease-relevant targets. Here, we report a novel dendronized DNA chimera (DENTAC) strategy that uses a dendritic DNA to engage cell surface scavenger receptors (SRs) as LTR. Using bioorthogonal strain-promoted alkyne-azide cycloaddition to conjugate the dendritic DNA with protein binder, the resulting DENTAC is able to traffic the protein target into the lysosome for elimination. We demonstrated the utility of DENTAC by degrading oncogenic membrane nucleolin (NCL) and epidermal growth factor receptor (EGFR). The anti-cancer application of NCL-targeting DENTAC was validated in a mouse xenograft model of lung cancer. This work thus presents a new avenue for rapid development of potent degraders against membrane proteins, with also broad research and therapeutic prospects.


Improvement of the pilocarpine epilepsy model in rat using bone marrow stromal cell therapy.
Temporal lobe epilepsy is one of the most common types of epilepsy. Cytotherapy was tried for several neurological disorders. In this investigation, bone marrow stromal cells (BMSCs) were used in order to evaluate the recovery of epileptic rats induced by pilocarpine. The rats were divided into four groups: a negative control, treated groups, and epileptic rats treated with the vehicle only. The animals in the chronic phase were monitored for three weeks using Racine scale. BMSCs were labeled with BrdU and injected intravenously. After 6 weeks, the rats were killed and processed in paraffin as well as immunohistochemical techniques. The results of the behavioral test showed that the number of seizures significantly decreased in treatment groups. Histopathology of the tissues from the untreated rats showed cell death and neurophagia. The numerical density of neurons per area was significantly higher in the treated groups than in the untreated ones. BMSCs localized in the hippocampus of the treated animals. The results showed that there is structural and functional improvement in the epileptic rats treated with BMSCs.


A training agenda in adolescent medicine and health.
The complexity of health issues facing young people, an appreciation that problems arising in adolescence may have long term implications for health, and greater confidence about the value of clinical intervention are key factors underpinning current efforts in Australia to build an education agenda for health professionals working with young people. This paper outlines a series of education initiatives in both undergraduate and postgraduate settings and discusses the growing support for more strategic and coherent approaches to education nationally. In particular, efforts to improve the capacity of health professionals to work with young people are described, together with the opportunity for more focused subspeciality training in Adolescent Medicine. Within our region and beyond, Australia is increasingly being turned to as a model of academic leadership in adolescent medicine, including professional education and training. In Australia, this has been best achieved by centres of excellence in adolescent health.


Quality of life and mental health in caregivers of outpatients with advanced cancer.
This study evaluates the quality of life (QOL) and mental health (MH) of caregivers of patients with advanced cancer who are receiving ambulatory oncology care and associations with patient, caregiver and care-related characteristics. Patients with advanced gastrointestinal, genitourinary, breast, lung or gynaecologic cancer, and their caregivers, were recruited from 24 medical oncology clinics for a cluster-randomized trial of early palliative care. Caregivers completed the Caregiver QOL--Cancer scale and the Medical Outcomes Study Short Form, version 2, and a questionnaire including care-related factors such as hours/day providing care and change in work situation. Patients completed a demographic questionnaire and measures of their QOL and symptom severity. Associations of these factors with caregiver QOL and MH were examined using linear regression analyses. Of the 191 caregivers, 84% were spouses/partners, 90% cohabited with the patient, half were working and 25% had a change in work situation since the patient's diagnosis. On multiple regression analysis, better caregiver QOL was associated with better caregiver MH and patient physical well-being and with not providing care for other dependents. Worse caregiver MH was associated with female caregiver sex, worse patient emotional well-being, more hours spent caregiving and change in the caregiver's work situation. Caregivers of ambulatory patients with advanced cancer may have compromised QOL and MH associated with worse patient physical and emotional well-being and with simultaneously caring for others and working outside the home. Early palliative care interventions directed at patient symptoms and caregiver support may improve QOL in this population.


Anemia and Associated Factors among Pregnant Women Attending Prenatal Care in Rural Dembia District, North West Ethiopia: A cross-Sectional Study.
Introduction: About 22% of pregnant women are anemic in Ethiopia, but there is a large variation across the country. Hence, the aim of this study identifies the prevalence of anemia and associated factors among pregnant women attending prenatal appointments in Dembia District, northwest Ethiopia.Methods and materials: A facility-based, cross-sectional study was conducted among 713 pregnant women. A multi-stage, stratified sampling technique was used to select the study participants. A structured and pretested questionnaire, laboratory data, and chart review were used to collect data. Bivariate and multivariate logistic regression analyses were used to identify factors associated with anemia in pregnant women.Results: Prevalence of anemia was 32.4% with a majority of these having moderate anemia. Type of health center being rural/urban health center, water sources, days since fasting, 4 weeks of iron supplementation, craving unusual foods, mid-upper arm circumference scores, and decision power were significant predictors of anemia.Conclusion: The present study suggests anemia among pregnant women attending prenatal in Dembia district was high. Working to enhance adherence to iron supplementation and partner involvement for joint decision-making is recommended to avert prenatal anemia. Health-care providers and programmers are advised to pay special attention to rural and fasting pregnant mothers.Abbreviations: AOR: Adjusted Odd Ratio; CMHS: College of medicine and health sciences; CI: Confidence Interval; HFIAS: Household Food Insecurity Access Scale; RCSI: Reduced Coping Strategies Index; Hgb: Hemoglobin; MCMC: Marco Chain Monte Carlo; EPV: Events per variable; BMI: Body Mass Index; PPS: Population proportionate to size sampling; SRS: simple random sampling; DALYS: Disability-adjusted life years; MUAC: Mid-upper-arm-circumference; WHO: World Health Organization; EDHS: Ethiopian Demographic and Health Survey; SPSS: Statistical package for social science; ANC: Ante natal care; PCA: Principal component analysis; MASL: Meter above sea level; g/dl: gram per decilitre HALE: Health Action Leicester Ethiopia; WDDS: Women's Dietary Diversity Scale.


Culture-independent phylogenetic analysis of the faecal flora of the rat.
The dominant faecal flora of the rat was determined using randomly cloned 16S rDNA comparative sequence analysis. A total of 109 near full-length 16S rDNA clones were sequenced, representing 69 unique 16S rRNA phylotypes or operational taxonomic units (OTUs). Estimates of species richness indicated that approximately 338 species were present in the faeces, suggesting that only 20% of species were identified. Only two of 39 Gram-negative clones aligned with previously cultured species, the remainder fell into a separate lineage within the Bacteroides-Cytophaga phylum. Several clones within this new group were related to 16S rDNA sequences previously identified from mouse faeces. Lactobacilli were the most abundant Gram-positive species, representing 23% of the total clones but only 7% of OTUs. The remaining Gram-positive clones were distributed among the Clostridium coccoides group (9%), the Clostridium leptum subgroup (18%), and throughout the low GC Gram-positive bacteria (13%). The majority of OTUs (63/69 or 91%) were less than 97% homologous to previously cultured bacteria. Faecal samples were also cultured using a variety of anaerobic media. With the exception of the lactobacilli, the cultured isolates demonstrated low species diversity and poorly reflected the population, as defined through comparative sequence analysis.


The Genome-Wide Analysis of RALF-Like Genes in Strawberry (Wild and Cultivated) and Five Other Plant Species (Rosaceae).
The rapid alkalinization factor (RALF) gene family is essential for the plant growth and development. However, there is little known about these genes among Rosaceae species. Here, we identify 124 RALF-like genes from seven Rosaceae species, and 39 genes from Arabidopsis, totally 163 genes, divided into four clades according to the phylogenetic analysis, which includes 45 mature RALF genes from Rosaceae species. The YISY motif and RRXL cleavage site are typical features of true RALF genes, but some variants were detected in our study, such as YISP, YIST, NISY, YINY, YIGY, YVGY, FIGY, YIAY, and RRVM. Motif1 is widely distributed among all the clades. According to screening of cis-regulatory elements, GO annotation, expression sequence tags (EST), RNA-seq, and RT-qPCR, we reported that 24 RALF genes coding mature proteins related to tissue development, fungal infection, and hormone response. Purifying selection may play an important role in the evolutionary process of RALF-like genes among Rosaceae species according to the result from ka/ks. The tandem duplication event just occurs in four gene pairs (Fv-RALF9 and Fv-RALF10, Md-RALF7 and Md-RALF8, Pm-RALF2 and Pm-RALF8, and Pp-RALF11 and Pp-RALF14) from four Rosaceae species. Our research provides a wide overview of RALF-like genes in seven Rosaceae species involved in identification, classification, structure, expression, and evolution analysis.


Diagnosis and cause of death in a neonatal intensive care unit--how important is autopsy?
To characterize mortality in a tertiary referral Neonatal Intensive Care Unit (NICU) in Portugal and evaluate the concordance between ante-mortem and post-mortem diagnoses. Retrospective review of the clinical and pathological records of infants who died in five consecutive years was done. Pathological findings and clinical diagnoses were compared and classified according to general concordance and to modified Goldman classification. During the referred period, 1938 patients were admitted to the NICU, with a mortality rate of 5.7% (110 patients). The median of age at death was 10.5 days and the most frequent causes of death were congenital malformations and prematurity with its complications. Autopsy was performed in 53 patients resulting in a 48.2% overall autopsy rate. There was complete agreement between pathological and clinical diagnoses in 18 cases (34%) and additional findings were identified in 22 cases; in 13 cases (24.5%), the diagnosis was revised or established by pathology. Five autopsies revealed information relevant for genetic counseling. Despite the high agreement rate between clinical and pathological diagnoses, autopsy frequently added important data, including several cases in which it established the diagnosis or provided information relevant for parental counseling regarding future pregnancies.


Fatty acid composition and arachidonic acid intake of selected Saudi foods.
Twenty-eight Saudi Arabian common foods were analyzed for their fatty acid contents by gas-liquid chromatography using capillary column. The predominant fatty acids were oleic, palmitic, linoleic and stearic acids. The polyunsaturated to saturated fats ratio (P:S) as well as the n-3:n-6 ratio were generally not compatible with recommended values. Assessment of C20:4 (n-6) content in those foods showed a noticeable variation ranging from 9 mg/100 gm in beef sirloin to 256 mg/100 g in kannad fish. Eicosapentaenoic acid (C20:5) n-3 content was highest in kannad (925 mg/100 g). Applying C20:4 (n-6) values determined in this work to Saudi Balanced Sheet, the mean C20:4 (n-6) intake for a Saudian was estimated as approximately 115 mg/day.


Achieving the Sustainable Development Goal 06 in Brazil: the universal access to sanitation as a possible mission.
Sanitation (which includes national public policies for drinking water, sewage services and waste management) is precarious in Brazil and therefore poses a challenge to a range of actors. Poor sanitation impacts public health, education, the environment, and daily life. Globally, it emits increasing greenhouse gases. Universalization of any major public service appears difficult, if not impossible; however, Brazil's program to universalize access to electricity proves the opposite, as will be shown in this paper. By describing the successful implementation of electricity for everyone, we show that planned public efforts, coordinated with private initiatives and local communities, have worked, and the same can be achieved for the sanitation sector. An overview of all sectors that touch on sanitation and emissions is also provided, highlighting the challenges and possibilities for infrastructure projects.


Factors determining choice of complementary and alternative medicine in acute and chronic diseases.
Background Systematic analysis of the determinants of choice of a treatment modality aids to the understanding of decision process of healthcare utilization. The revealed preference of a single modality may differ according to the nature of disease. Existing studies have not integrated possible causal factors in a model with respect to diseases. This study identifies major determinants and formulates their integral effect on choice of a particular modality on acute and chronic diseases in accordance to socio-behavioural model. Methodology A cross-sectional study on 300 samples using a 30-point questionnaire, developed in Likert scale and dichotomous scale. Possible determinants are tested on choice of CAM in case of acute disease and of chronic disease separately. Results Revealed single modality treatment preference (of CAM) varies widely between acute disease (13%) and chronic disease (58.67%). Bivariate associations are significant for gender (For, overall CAM preference, p=0.001, acute disease, p<0.001, chronic disease, p=0.024), Disease burden (overall and chronic: p<0.001, acute: p=0.008) and previous CAM usage (overall and chronic: p<0.001, acute: p=0.016). Social factor individually has significant influence on choosing CAM both acute (OR=1.096, p<0.001) and chronic disease (OR=1.036, p<0.001). Ideation of philosophical need factor, guided by philosophical congruence with CAM (OR=1.047, p<0.001) is a novel finding of this study. While with multiple logistic regression male gender (p=0.03), social factor (p<0.001), perception of CAM efficacy (p=0.02) and negative ideation about CAM cost-effectiveness (p=0.002) are found to be important in Acute disease; choosing CAM in chronic disease is guided by female gender (p=0.001), making decision in-group (p=0.001), low disease burden (p<0.001), philosophical need factor (p=0.001), and perception of CAM efficacy (p<0.001). Conclusion Demographic, social, cognitive and philosophical factors are important determinants of choosing CAM as a treatment modality over conventional medicine, but they act differently on CAM preference in acute and chronic diseases.


An improved diagnostic method for chronic hepatic disorder: analyses of metallothionein isoforms and trace metals in the liver of patients with hepatocellular carcinoma as determined by capillary zone electrophoresis and inductively coupled plasma-mass spectrometry.
It is desirable to diagnose hepatocellular carcinoma (HCC) in the early stages during its development since its treatment is usually difficult. We previously proposed a new diagnostic method that made use of the total metallothionein (MT), zinc (Zn), and copper (Cu) concentrations in the liver of the HCC patients. We recently found that MT-1 is involved in the metabolism or detoxification of toxic metals, such as cadmium; on the other hand, MT-2 is responsible for the homeostasis of essential metals such as copper, in experimental models such as Long Evans Cinnamon (LEC) rats. In order to device a better diagnostic method than the one we proposed previously, in this study, we newly propose an improved method that includes the discriminative determination data regarding the MT isomers, namely, MT-1 and MT-2, in the liver of patients with or without HCC as compared with the total MT level. The total MT and Zn concentrations in the HCC patients were confirmed to be significantly lower than those in patients without hepatic disorders (Ctrl). In contrast, Cu concentrations of the HCC patients were higher than those of the Ctrl patients. In addition, in the juxta-tumor portion with HCC, MT-1 concentrations were significantly higher than those of MT-2. In contrast, the MT-1 concentrations in the tumor portion were significantly lower than that in the juxta-tumor portion. In addition, MT-1/MT-2 ratio in the tumor portion was significantly lower than that of the juxta-tumor portion. By using parameters such as concentrations of Cu, Zn, total MT, and MT isomers, we performed the multivariate discriminative analysis (MDA). The results suggest that the concentrations of MT isomers change depending on the progress of the tumor, and information on MT isomers and trace elements is very useful in determining the stage of the chronic hepatic disorder.


The inactivation of the fragile X chromosome in female carriers of the Martin Bell syndrome as studied by two different methods.
Female heterozygotes for the fragile X syndrome show variable levels of mental handicap from normal to severely retarded. The degree to which they are affected may depend upon whether the fragile or the normal X chromosome is preferentially inactivated, but one of the problems with the use of BUdR for the study of Lyonisation in fragile-X heterozygotes is that it reduces the level of expression of the fragile site. Results obtained by this method will be biased if the suppression occurs preferentially in either the active or the inactive X chromosome. To confirm that BUdR does not preferentially cause repair of the fragile site on either the late or the early replicating X chromosome, a comparison was made between the percentage of active or early fragile-X obtained using BUdR, and that obtained using tritiated thymidine in cells from the same heterozygote.


The effectiveness of active head restraint in preventing whiplash.
Whiplash injury claims have increased for two decades and manual head restraints are often incorrectly adjusted. A Self-Aligning Head Restraint (SAHR) was designed to move upward and forward by occupant motion in a rear crash providing earlier neck support, even when the head restraint is positioned low. This study determines its field effectiveness. Insurance records were analyzed for consecutive Saab rear crashes in Sweden over 18 months. The Saab 9000/900 had standard head restraints and Saab 9-5/9-3 had SAHR. A questionnaire was mailed to the occupants, insurance and medical records were reviewed, and phone interviews were conducted. SAHR reduced whiplash injury risks by 75 +/- 11% from an 18 +/- 5% incidence in 85 occupants with standard head restraints to 4 +/- 3% in 92 occupants with SAHR. No SAHR seat required repair or replacement after the crashes. SAHR is effective in reducing whiplash injury in rear crashes and is a passive public-health approach that works irrespective of manual head-restraint adjustment.


Tazarotene 0.045% Lotion for Moderate-to-Severe Acne Patients: Pooled Phase 3 Analysis by Age and Sex.
Two identical phase 3 trials (NCT03168321 and NCT03168334) and pooled post hoc analyses have established efficacy and safety of a polymeric tazarotene 0.045% lotion formulation in patients with moderate-to-severe acne. Presented here are post hoc analyses that further examine efficacy and safety of tazarotene 0.045% lotion by age and sex. Patients aged ≥ 9 years with moderate-to-severe acne (score 3 or 4 on the Evaluator's Global Severity Score [EGSS]) were equally randomized to once-daily tazarotene 0.045% lotion or vehicle lotion for 12 weeks. Efficacy outcomes included inflammatory/noninflammatory lesion counts and treatment success (proportion of participants achieving ≥ 2-grade reduction from baseline in EGSS and score of 0 [clear] or 1 [almost clear]). Adolescent and adult females (n=1,013) and males (n=529) were subdivided into 3 age groups: 13–19, 20–29, and ≥30 years. At week 12, large least-squares mean percent reductions in inflammatory and noninflammatory lesions were observed across all 3 tazarotene-treated age groups in males and females (range, -50.2% to -64.8%). Treatment success rates ranged from 23.6% to 38.4%. Across all efficacy assessments, significant differences between tazarotene and vehicle (P<0.05) were generally observed in the younger male and female participants (13–19 and 20–29). No notable age-related patterns were found for safety outcomes, though tazarotene-treated males of all age groups reported fewer adverse events than females. Tazarotene 0.045% lotion is efficacious and well tolerated in female and male adolescents and adults with moderate-to-severe acne. J Drugs Dermatol. 2021;20(6):608-615. doi:10.36849/JDD.6070.


The mammalian guanine nucleotide exchange factor mSec12 is essential for activation of the Sar1 GTPase directing endoplasmic reticulum export.
The Sar1 GTPase is an essential component of COPII vesicle coats involved in export of cargo from the endoplasmic reticulum of mammalian cells. To begin to elucidate its mechanism of action, we now report the identity of the mammalian homolog to the yeast Sec12 guanine nucleotide exchange factor (18% identity) that promotes Sar1 activation. Mammalian Sec12 (mSec12) is a type II transmembrane protein with a large cytosolic domain, a fragment of which has previously been reported as the transcription factor prolactin regulatory element binding protein (PREB). mSec12 promotes efficient guanine nucleotide exchange on Sar1, but not Arf1 or Rab GTPases. mSec12 is localized to the endoplasmic reticulum and an antibody to the cytosolic domain of mSec12 potently inhibits Sar1 recruitment and the formation of COPII vesicles in vitro. The dominant negative GDP-restricted mutant Sar1[T39N] is shown to be a potent inhibitor of mSec12 activity, consistent with its role in preventing COPII vesicle formation in vitro and during transient expression in vivo. We propose that mSec12 is an evolutionarily distant guanine nucleotide exchange factor directing Sar1 GTPase activation in mammalian cells. Its divergence from yeast Sec12p may reflect the specialized needs of the mammalian endoplasmic reticulum involving the formation of Sar1-dependent transitional elements (Aridor M, et al. J Cell Biol 2001;152:213-229) and selection of cargo into prebudding complexes.


Dynamics of elongation factor 2 kinase regulation in cortical neurons in response to synaptic activity.
The rapid regulation of cell signaling in response to calcium in neurons is essential for real-time processing of large amounts of information in the brain. A vital regulatory component, and one of the most energy-intensive biochemical processes in cells, is the elongation phase of mRNA translation, which is controlled by the Ca(2+)/CaM-dependent elongation factor 2 kinase (eEF2K). However, little is known about the dynamics of eEF2K regulation in neurons despite its established role in learning and synaptic plasticity. To explore eEF2K dynamics in depth, we stimulated synaptic activity in mouse primary cortical neurons. We find that synaptic activity results in a rapid, but transient, increase in eEF2K activity that is regulated by a combination of AMPA and NMDA-type glutamate receptors and the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) and mammalian target of rapamycin complex 1 (mTORC1) pathways. We then used computational modeling to test the hypothesis that considering Ca(2+)-coordinated MEK/ERK, mTORC1, and eEF2k activation is sufficient to describe the observed eEF2K dynamics. Although such a model could partially fit the empirical findings, it also suggested that a crucial positive regulator of eEF2K was also necessary. Through additional modeling and empirical evidence, we demonstrate that AMP kinase (AMPK) is also an important regulator of synaptic activity-driven eEF2K dynamics in neurons. Our combined modeling and experimental findings provide the first evidence that it is necessary to consider the combined interactions of Ca(2+) with MEK/ERK, mTORC1, and AMPK to adequately explain eEF2K regulation in neurons.


Experimental African trypanosomiasis: lack of effective CD1d-restricted antigen presentation.
BALB/c mice are highly susceptible to African trypanosomiasis, whereas C57BL/6 mice are relatively resistant. Other investigators have reported that the synthesis of IgG antibodies to purified membrane form of variant surface glycoprotein (mfVSG) of Trypanosoma brucei is CD1 restricted. In this study, we examine the role of the CD1d/NKT cell pathway in susceptibility and resistance of mice to infection by African trypanosomes. Administration of anti-CD1d antibodies to Trypanosoma congolense-infected BALB/c mice neither affects the parasitemia nor the survival time. Correspondingly, CD1d(-/-) and CD1d(+/+) BALB/c mice infected with T. congolense or T. brucei show no differences in either parasitaemia or survival time. The course of disease in relative resistant C57BL/6 mice infected with T. congolense is also not affected by the absence of CD1d. Parasitaemia, survival time, and plasma levels of IgG2a and IgG3 parasite-specific antibodies in infected CD1d(-/-) C57BL/6 are not different from those of infected CD1d(+/+) C57BL/6 mice. We conclude that CD1d-restricted immune responses do not play an important role in susceptibility/resistance of mice infected with virulent African trypanosomes. We speculate that virulent trypanosomes have an evasion mechanism that prevents the induction of a parasite-specific, CD1d-restricted immune response by the host.


Understanding the Diagnosis and Treatment of COPD and Asthma to Better Inform Site Selection and Patient Recruitment Planning.
There is an increasing worldwide population of people with chronic obstructive pulmonary disease (COPD) and asthma. Mortality from COPD is expected to double over the next 3 decades, making it the third leading cause of death worldwide. It is estimated that as many as 300 million people of all ages and all ethnic backgrounds worldwide suffer from asthma. Devising and implementing a successful strategy for the execution of COPD and asthma trials requires a multifaceted approach, coupled with an understanding of the factors that drive patient recruitment. However, little has been written about recruitment and the comparative success of different recruitment strategies. This paper focuses on results obtained from various assessments of treatment guidelines compliance, patient diagnosis and treatment, approved therapies, and patient profiles that have helped provide insight into critical factors to help drive country, site, and patient recruitment strategies.


Alcohol abuse and superego conflicts.
This paper reports the author's experiences with alcohol abusers in their initial or premorbid phase. The emphasis is on their superego conflicts and how these conflicts relate to their alcohol abuse. The adaptational function of their heavy drinking pattern is to neutralize an archaic persecutive superego through an oral-sadistic counterattack. The drinking is an attempt to reach inner structural change, which is successful during the first moments of intoxication, but often backfires when the ego strength is lessened under the influence of alcohol.


Control of Macrophage Inflammation by P2Y Purinergic Receptors.
Macrophages comprise a phenotypically and functionally diverse group of hematopoietic cells. Versatile macrophage subsets engage to ensure maintenance of tissue integrity. To perform tissue stress surveillance, macrophages express many different stress-sensing receptors, including purinergic P2X and P2Y receptors that respond to extracellular nucleotides and their sugar derivatives. Activation of G protein-coupled P2Y receptors can be both pro- and anti-inflammatory. Current examples include the observation that P2Y14 receptor promotes STAT1-mediated inflammation in pro-inflammatory M1 macrophages as well as the demonstration that P2Y11 receptor suppresses the secretion of tumor necrosis factor (TNF)-α and concomitantly promotes the release of soluble TNF receptors from anti-inflammatory M2 macrophages. Here, we review macrophage regulation by P2Y purinergic receptors, both in physiological and disease-associated inflammation. Therapeutic targeting of anti-inflammatory P2Y receptor signaling is desirable to attenuate excessive inflammation in infectious diseases such as COVID-19. Conversely, anti-inflammatory P2Y receptor signaling must be suppressed during cancer therapy to preserve its efficacy.


Proteomics Approach To Trace Site-Specific Damage in Aquatic Extracellular Enzymes During Photoinactivation.
Extracellular enzymes are major drivers of biogeochemical nutrient and carbon cycling in surface water. While photoinactivation is regarded as a major inactivation process of these enzymes, the underlying molecular changes have received little attention. This study demonstrates how light exposure leads to a rapid loss of phosphatase, aminopeptidase, and glucosidase activities of biofilm samples and model enzymes. Here, an optimized proteomics approach allowed simultaneous observation of inactivation and molecular changes. Site-specific fingerprints of degradation kinetics have been generated and visualized in the three-dimensional proteins. Oxidation of tryptophan, the chromophoric target, initiated secondary reactions. Evidence was obtained that tyrosine residues act as intramolecular antioxidants, reflected in decelerated decay of tryptophan-containing peptides and enhanced decay of tyrosine-containing peptides. In addition, subsequent methionine oxidation and disulfide reduction contribute to heterogeneous photodamage. The proximity to tryptophan residues explains >95% of the photodamage across the protein structures. The presence of redox active organic matter or a model antioxidant in solution quenched not only photoinactivation and tryptophan oxidation but also all subsequent damage. The developed analytical approach can be applied to other research questions in environmental sciences where site-specific damage in a protein is essential.


Determinants of Sports Injury in Young Female Swedish Competitive Figure Skaters.
Introduction: Although figure skating attracts several hundred thousand participants worldwide, there is little knowledge about physical health and sports injuries among young skaters. The present study aimed to describe the health status of a geographically defined Swedish population of licensed competitive figure skaters and to examine injury determinants. Methods: All licensed competitive skaters in the southeastern region of Sweden were in April 2019 invited to participate in a cross-sectional study using an online questionnaire. Multiple binary logistic regression was used for the examination of injury determinants. The primary outcome measure was the 1-year prevalence of a severe sports injury episode (time loss >21 days). The secondary outcome measure was the point prevalence of an ongoing injury. The determinants analyzed were age, skating level, relative energy deficiency indicators, and training habits. Results: In total, 142 (36%) skaters participated, 137 (96%) girls [mean (SD) age: 12.9 (SD 3.0) years]. Participating boys (n = 5) were excluded from further analysis. The 1-year prevalence of a severe sports injury episode was 31%. The most common injury locations for these injuries were the knee (25%), ankle (20%), and hip/groin (15%). In the multiple model, having sustained a severe injury episode was associated with older age (OR 1.2, 95% CI 1.1-1.4; p = 0.002) and an increased number of skipped meals per week (OR 1.1, 95% CI 1.0-1.3; p = 0.014). The point prevalence of an ongoing injury episode was 19%. The most common locations were the knee (24%), ankle (24%), and foot (24%). Having an ongoing injury episode was associated with older age (OR 1.4, 95% CI 1.2-1.7; p < 0.001) and an increased number of skipped meals per week (OR 1.1, 95% CI 1.0-1.3; p = 0.049). Conclusion: One-third of young female Swedish competitive figure skaters had sustained a severe injury episode during the past year, and a fifth reported an ongoing episode. Older age and an increased number of skipped meals per week were associated with a sports injury episode. Long-term monotonous physical loads with increasing intensity and insufficient energy intake appear to predispose for injury in young female figure skaters. Further examination of injury determinants among competitive figure skaters is highly warranted.


The Role of Social Support in Cardiovascular Clinical Trial Participation among Black Men: Black Impact.
Attainment of the American Heart Association's Life's Simple 7 (LS7) metrics reduces cardiovascular disease (CVD) risk; yet, Black Americans have the lowest LS7 attainment among all communities, the highest rate of CVD mortality, and low clinical trial participation. Social support is positively correlated with chronic disease self-management. Here, we describe the role of social support in a single-arm pilot clinical trial of a community-based lifestyle intervention among Black American men. The 24-week intervention featured weekly team-based physical activity and LS7-themed education. Seventy-four Black men participated in the intervention; twenty agreed to participate in exit surveys via one of three semi-structured focus groups. Data were transcribed verbatim and analyzed using content analysis framed by House's social support framework. Participants reported support from both peers and health coaches. The sub-themes of social support among peers were: (1) acknowledgement, understanding, and validation, (2) inspiration, (3) sense of community, (4) fear of disappointing fellow participants, and (5) group synergy. The sub-themes of social support from the health coaches and study team staff included: (1) contemplation of current health status, (2) racial concordance of health coaches and study team staff, (3) investment of the research team, (4) incentives, (5) access to healthcare providers, and (6) the COVID-19 pandemic. Emotional support was the most frequently discussed theme. Social support, especially emotional support, from peers and health coaches was a driver of clinical trial participation among participants. The intervention created a positive social environment and decreased medical mistrust. This intervention may provide a framework by which to facilitate clinical trial participation among Black men.


Recombinant human erythropoietin in the treatment of cancer-related anaemia.
The aim of this study was to investigate the effects of recombinant human erythropoietin (rh-EPO) in patients with cancer-related anaemia. Thirty-six ambulatory patients who had malignant neoplasms and haemoglobin (Hb) values of < 11 g/dl (Pretoria is 1,310 m above sea level) entered the study. Patients with renal insufficiency or anaemia caused by bleeding or haemolysis, and patients with iron deficiency or megaloblastic anaemia, were not entered in the study. 22 IU/kg rh-EPO was given subcutaneously 3 times/week. The dose was escalated if Hb values did not rise after 4 weeks. All 36 patients were evaluable for toxicity. Side effects ascribed to rh-EPO were pain or discomfort at the site of injection (12 patients), heart palpitations (3 patients), skin rash (2 patients) and hypertension, deep vein thrombosis, and myalgia in 1 patient each. Thirty of the 36 patients who entered the study were evaluable for response. There were 16 females and 14 males among the evaluable patients. Median age was 64.5 years. Response, defined as an increase of Hb of at least 2 g/dl or to 12.5 g/dl, for at least 1 month, was documented in 12 patients. This was accompanied by an improvement in performance status and occurred within 1 month in 5 of the 12 patients who responded. rh-EPO has a limited but measurable therapeutic value for patients with cancer-associated anaemia.


Structure-controlled solventless thermolytic synthesis of uniform silver nanodisks.
Monodisperse silver nanodisks are synthesized on the gram scale from a well-characterized layered silver thiolate precursor via thermolysis at 180-225 degrees C under a N(2) atmosphere. XRD, TEM, HRTEM, and AFM analyses indicate that the nanodisks generated at 180 degrees C over 2 h have an average diameter of about 16.1 nm (sigma = +/-12%) and a thickness of 2.3 nm (sigma = +/-14%), and they lie on their (111) faces. The disk shape is considered to be predestined by the crystal structure of the precursor. Important aspects regarding the stability of the precursor, the thermolysis temperature, and the annealing time, as well as a possible conversion mechanism, are discussed.


Dental dams: the secret tool for infection control.
Dental dams, although in existence for over 100 years, are the most widely underused tool of infection control. This article addresses the many benefits of using dental dams and discusses simplified methods of incorporating dams into the dental practice.


Quinazoline-2-Carboxamides as Selective PET Radiotracers for Matrix Metalloproteinase-13 Imaging in Atherosclerosis.
Matrix metalloproteinase-13 (MMP-13) plays a critical role in the progression of unstable atherosclerosis. A series of highly potent and selective MMP-13 inhibitors were synthesized around a quinazoline-2-carboxamide scaffold to facilitate radiolabeling with fluorine-18 or carbon-11 positron-emitting nuclides and visualization of atherosclerotic plaques. In vitro enzyme inhibition assays identified three compounds as promising radiotracer candidates. Efficient automated radiosyntheses provided [11C]5b, [11C]5f, and [18F]5j and enabled pharmacokinetic characterization in atherosclerotic mice. The radiotracers displayed substantial differences in their distribution and excretion. Most favorably for vascular imaging, [18F]5j exhibited low uptake in metabolic organs with minimal retention of myocardial radioactivity, substantial renal clearance, and high metabolic stability in plasma. Ex vivo aortic autoradiography and competition studies revealed that [18F]5j specifically binds to MMP-13 within atherosclerotic plaques and localizes to lipid-rich regions. This study demonstrates the utility of the quinazoline-2-carboxamide scaffold for MMP-13 selective positron emission tomography (PET) radiotracer development and identifies [18F]5j for imaging atherosclerosis.


Impact and barriers of an HIV rapid test program implementation at an oncological referral center in Mexico.
The aim of this study was to evaluate the implementation of human immunodeficiency virus (HIV) screening with rapid tests in an oncologic center in Mexico City, report the HIV prevalence, and describe contacts screening and linkage to HIV care while identifying barriers to the performance of the program. In 2014, an HIV rapid test program was implemented in four departments of the hospital "Instituto Nacional de Cancerología". From 2014 to 2016, 3032 HIV rapid tests were performed in the hospital. The overall HIV prevalence was 0.8%, with the highest prevalence in the Hematology Department (2.4%). In the Gynecology Department, prevalence was 0.05%. Only 25 and 22 tests were performed in the lung cancer and germ cell tumor clinic, respectively, with one positive test. The health staff not offering the test was the main limitation to the full implementation of the program in those departments. The contacts screening led to three positive cases. The acceptance of the test was 99%. Patients who tested positive were seen by an infectious diseases physician on the same day the test was performed. Rapid HIV tests are a useful tool to expand HIV diagnosis in patients with cancer and to establish a rapid linkage to HIV care. Staff education needs to be improved to raise awareness of the health staff for a successful scale up of the program.


The effects of high-load strength training with protein- or nonprotein-containing nutritional supplementation in patients undergoing dialysis.
The aim of this study was to investigate the effects of high-load strength training and protein intake in patients undergoing dialysis with a focus on muscle strength, physical performance, and muscle morphology. This was a randomized controlled study conducted in three dialysis centers. Subjects for the study included 29 patients undergoing dialysis. The participants went through a control period of 16 weeks before completing 16 weeks of strength training. Before the training period, the participants were randomly assigned to receive a protein or a nonprotein drink after every training session. Muscle strength and power were tested using the good strength equipment and the leg extensor power rig. Physical performance and function were assessed using a chair stand test and the Short Form 36 questionnaire. Muscle fiber type size and composition were analyzed in biopsies obtained from the m. vastus lateralis. All variables remained unchanged during the control period. After training, muscle strength and power, physical performance, and physical function increased significantly. Muscle fiber composition was changed by a relative decrease in type 2x muscle fiber number whereas muscle size at the fiber level was unchanged. There were no effects of combining the training with protein intake. High-load strength training is associated with improvements in muscle strength and power, physical performance, and quality of life. The effects were surprisingly not associated with muscle hypertrophy, and the results did not reveal any additional benefit of combining the training with protein intake. The positive results in muscle strength and physical performance have clinically relevant implications in the treatment of patients undergoing dialysis.


Advent of Imidazo[1,2-a]pyridine-3-carboxamides with Potent Multi- and Extended Drug Resistant Antituberculosis Activity.
A set of nine 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides and one 2,6-dimethylimidazo[1,2-a]pyrimidine-3-carboxamide were synthesized. The compounds were evaluated for their in vitro anti-tuberculosis activity versus replicating, non-replicating, multi- and extensive drug resistant Mtb strains. The MIC(90) values of seven of these agents were ≤ 1 μM against the various tuberculosis strains tested. A representative compound of this class (1) was screened against seven non-tubercular strains as well as other non-mycobacteria organisms and demonstrated remarkable microbe selectivity. A transcriptional profiling experiment of Mtb treated with compound 1 was performed to give a preliminary indication of the mode of action. Lastly, the in vivo ADME properties of compounds 1, 3, 4, and 6 were assessed. The 2,7-dimethylimidazo[1,2-a]pyridine-3-carboxamides are a drug-like and synthetically accessible class of anti-TB agents that have excellent selective potency against multi- and extensive drug resistant TB and encouraging pharmacokinetics.


Towards a patient-centred approach in therapeutic patient education. A qualitative study exploring health care professionals' practices and related representations.
This study aimed to explore the practice-representation links among Health Care Professionals (HCP)s practising Therapeutic Patient Education (TPE). Understanding these links might actually help to address the challenges of TPE implementation, particularly the patient-centred dimension. A qualitative study using individual interviews was conducted with HCPs practising in French-speaking Belgium or in France. Data analysis was carried out in two steps: to draw up a typology of educational practices (including variations) and, in line with the Social Representation Theory, to identify possible related social representations. The typology, based on HCP-Patient power distribution, was built from 26 interviews. Four types and nine subtypes were identified. Besides the power distribution, practice (sub)types were also specific regarding communication modes, consideration for patients' representations, motivational approach, personalization, complexity of methods and learning contents, and practice reflexivity. Practices were seldom constant. Three variations were highlighted: within a subtype, between different subtypes, and between education and technical care. Both practice subtypes and variations were related to specific decisive representations. Representations related to practices and those related to practices variations offer new perspectives for TPE implementation. There is no panacea for achieving more patient-centred approaches; tailored strategies based on practice subtypes are needed.


[Haemagglutinins and adhesins of Escherichia coli strains isolated from urine: inhibitory effect of sub-inhibitory concentrations of tetracycline, doxycycline and minocycline. Preliminary results ].
The present work concerned the study of the sub-minimal inhibitory doses of tetracyclin, doxycyclin and minocyclin on both hemagglutinating activity and adhesion capacity demonstrated in three E. coli strains isolated from urine. Two different types of hemagglutinins, mannose-resistant (HAMR) and mannose-sensitive (HAMS), were associated in two strains; HAMR was present in the third strain. Adhesion capacity was detected, in vitro, with uroepithelial cells spontaneously eliminated in urine. Whatever the antibiotic used, HAMR titers clearly decreased. In contrast, the effect of these antibiotics on the HAMS titers was inconstant, according to the bacterial strain or the antibiotic used. Adhesion capacity was inhibited particularly in the presence of tetracyclin and doxycyclin. Minocyclin was not a very good inhibitor molecule. The analysis of coefficient of correlation showed that the ability of adhering to uroepithelial cells was related to the HA titers. But it is impossible to say if the same bacterial structure migt be considered as mediator for both HA and adhesion capacity.


Effects of intrathecal sufentanil on plasma oxytocin and cortisol concentrations in women during the first stage of labor.
Intrathecal sufentanil provides analgesia comparable to epidural bupivacaine for the first stage of labor. Both epidural local anesthetics and intrathecal opioid reduce some parameters of the neuroendocrine response to labor pain and the reflex release of oxytocin in animals. In humans, epidural local anesthetics only reduce the spurt release of oxytocin. This study compared the effect of intrathecal sufentanil and epidural bupivacaine administration on the plasma concentration of oxytocin and cortisol in women with labor pain during the first stage of labor. Thirty healthy parturients requesting analgesia were enrolled in this randomized and open-label study. Each patient was in spontaneous labor at greater than 5 cm cervical dilatation. Using a combined spinal and epidural technique, patients received either intrathecal sufentanil 10 microg (SUF = intrathecal sufentanil group) or epidural plain bupivacaine 0.25%, 12 mL (BUPIV = epidural bupivacaine group). Analgesia was assessed using a visual analog scale, and blood samples for oxytocin and cortisol plasma concentration measurements were collected immediately before analgesia and 15, 30, 60, and 90 minutes after induction of the analgesia. Plasma cortisol and oxytocin concentrations were determined by specific radioimmunoassay. The values were expressed as mean +/- SEM. Intrathecal sufentanil provided faster and more complete analgesia within 15 and 30 minutes of its administration, compared with epidural bupivacaine. Plasma oxytocin concentrations were similar in the 2 groups before analgesia (7.24 +/- 2.1 and 6.6 +/- 3.1 pg/mL SUF and BUPIV, respectively). It decreased significantly in the SUF and increased in the BUPIV after analgesic administration. Cortisol concentrations were elevated in both groups before analgesia (51.6 +/- 5.3 and 54.2 +/- 4.8 microg/dL SUF and BUPIV, respectively). Both analgesic treatments significantly decreased the plasma cortisol levels. Intrathecal sufentanil analgesia decreases plasma concentrations of oxytocin and cortisol in women with labor pain during the first stage of labor, but epidural bupivacaine only reduced the cortisol concentration.


Microtensile bond strength and interfacial properties of self-etching and self-adhesive resin cements used to lute composite onlays under different seating forces.
To evaluate strength and morphology of the interface created on enamel and dentin by Panavia F 2.0 (P, Kuraray), RelyX Unicem (RU, 3M ESPE), and Maxcem (M, Sybron-Kerr), applied under two standardized clinically realistic seating pressures. Composite overlays (Paradigm MZ100, 3M ESPE) were luted on flat enamel or dentin surfaces of 48 extracted molars. During the initial 5-min self-curing period, a pressure of either 20 or 40 g/mm(2) was maintained on the overlay. Curing was completed by light irradiation from the top of the overlay for 20 s. Microtensile sticks and specimens for SEM observations were obtained from the luted teeth. Bond strength data from enamel and dentin (MPa) were analyzed with separate two-way ANOVAs in order to assess the effect of cement type, luting pressure, and their interactions. Tukey's test was used for post-hoc comparisons (alpha = 0.05). The bond strengths (MPa) to dentin were: P 20 g/mm(2) 7.5 +/- 3.7, 40 g/mm(2) 10.9 +/- 4.5; RU 20 g/mm(2) 6.8 +/- 2.6, 40 g/mm(2) 14.5 +/- 5.3; M 20 g/mm(2) 4.1 +/- 1.8, 40 g/mm(2) 5.2 +/- 1.6. The bond strengths (MPa) to enamel were: P 20 g/mm(2) 25.2 +/- 9.0, 40 g/mm(2) 30.7 +/- 8.6; RU 20 g/mm(2) 10.7 +/- 4.9, 40 g/mm(2) 11.1 +/- 5; M 20 g/mm(2) 7.3 +/- 3.1, 40 g/mm(2) 7.9 +/- .2. Cement type, luting pressure, and the interaction of these two factors had significant influences on dentin bond strength, with RU and P outperforming M. RU and P significantly benefited from the increase in luting pressure. In enamel, the type of cement was a significant factor for adhesion, with P yielding the highest and M the lowest strength. The measured bond strengths corresponded with the morphological results. Interfacial strength and adaptation of self-etching and self-adhesive dual-curing cements are enhanced if a seating force greater than finger pressure is maintained throughout the initial self-curing period.


Selective synthesis of poly-substituted fluorine-containing pyridines and dihydropyrimidines via cascade C-F bond cleavage protocol.
Fluorinated azaheterocycles are frequently found in pharmaceuticals, drug candidates, ligands for transition metal catalysts, and other molecular functional materials, so efficient methods for the synthesis of these compounds are of significant value. We herein describe a selective strategy for the synthesis of poly-substituted pyridines and fluoroalkyl dihydropyrimidines based on C-F bond breaking of the anionically activated fluoroalkyl group. An array of pyridines and dihydropyrimidines were prepared through this domino process in high yields under noble metal catalyst-free conditions, making this method a valuable supplement to azaheterocycle synthesis.


DNA cross-link repair protein SNM1A interacts with PIAS1 in nuclear focus formation.
The yeast SNM1/PSO2 gene specifically functions in DNA interstrand cross-link (ICL) repair, and its role has been suggested to be separate from other DNA repair pathways. In vertebrates, there are three homologs of SNM1 (SNM1A, SNM1B, and SNM1C/Artemis; SNM1 family proteins) whose functions are largely unknown. We disrupted each of the SNM1 family genes in the chicken B-cell line DT40. Both SNM1A- and SNM1B-deficient cells were sensitive to cisplatin but not to X-rays, whereas SNM1C/Artemis-deficient cells exhibited sensitivity to X-rays but not to cisplatin. SNM1A was nonepistatic with XRCC3 (homologous recombination), RAD18 (translesion synthesis), FANCC (Fanconi anemia), and SNM1B in ICL repair. SNM1A protein formed punctate nuclear foci depending on the conserved SNM1 (metallo-beta-lactamase) domain. PIAS1 was found to physically interact with SNM1A, and they colocalized at nuclear foci. Point mutations in the SNM1 domain, which disrupted the interaction with PIAS1, led to mislocalization of SNM1A in the nucleus and loss of complementation of snm1a cells. These results suggest that interaction between SNM1A and PIAS1 is required for ICL repair.


Chemopreventive targeted treatment of head and neck precancer by Wee1 inhibition.
HPV-negative head and neck squamous cell carcinomas (HNSCCs) develop in precancerous changes in the mucosal lining of the upper-aerodigestive tract. These precancerous cells contain cancer-associated genomic changes and cause primary tumors and local relapses. Therapeutic strategies to eradicate these precancerous cells are very limited. Using functional genomic screens, we identified the therapeutic vulnerabilities of premalignant mucosal cells, which are shared with fully malignant HNSCC cells. We screened 319 previously identified tumor-lethal siRNAs on a panel of cancer and precancerous cell lines as well as primary fibroblasts. In total we identified 147 tumor-essential genes including 34 druggable candidates. Of these 34, 13 were also essential in premalignant cells. We investigated the variable molecular basis of the vulnerabilities in tumor and premalignant cell lines and found indications of collateral lethality. Wee1-like kinase (WEE1) was amongst the most promising targets for both tumor and precancerous cells. All four precancerous cell lines were highly sensitive to Wee1 inhibition by Adavosertib (AZD1775), while primary keratinocytes tolerated this inhibitor. Wee1 inhibition caused induction of DNA damage during S-phase followed by mitotic failure in (pre)cancer cells. In conclusion, we uncovered Wee1 inhibition as a promising chemopreventive strategy for precancerous cells, with comparable responses as fully transformed HNSCC cells.


Some physiological and metabolic effects of sodium nitroprusside and cyanide in the dog.
The cardiovascular and acid-base changes following equivalent i.v. bolus doses of sodium nitroprusside (SNP) and potassium cyanide (KCN) have been studied in two groups of anaesthetized dogs. In a third group, the metabolic changes produced by i.v. infusion of SNP 1.5 mg kg-1 at a constant rate over 1 h have been studied. In contrast to a decrease in arterial pressure following SNP, hypertension and tachycardia occurred after the administration of KCN, with hyperventilation and an increase in packed cell volume. During infusion of SNP, increases in plasma cyanide concentrations were associated with an increase in arterial base deficit, plasma lactate and excess lactate and a decrease in oxygen consumption. The occurrence of lactic acidosis with SNP 1.5 mg kg-1 suggests that this may be the maximum safe dose for short term infusion. However, all these changes reversed spontaneously following discontinuation of SNP, indicating that base deficit is an adequate metabolic monitor during administration of SNP.


The microvascular thrombi of colonic tissue in ulcerative colitis.
Mucosal microvascular thrombi in rectal biopsies were observed in some ulcerative colitis (UC). Heparin may be effective in steroid resistant UC in some studies, however, the new results of meta-analysis demonstrated a non-significant effect of heparin in controlled clinical trials, differing markedly from observational studies. The objective of this study was to identify colonic microvascular thrombi in larger cases with UC, and analyse its possible risk factors: age, gender, histologic score, extent of lesions and operation or biopsy specimens, and assess the significance of microvascular thrombosis in patients with UC. The microvascular thrombi were identified by immunohistochemical staining with anti-CD61 monoclonal antibody and Martius scarlet blue (MSB) staining in 40 colonic tissue samples of UC (31 biopsy specimens and nine operated cases) and 12 cases of normal colon tissue from operated colonic carcinoma. Logistic regression analysis was used to assess the relationship of age, gender, degree of histology, origin of the specimens, extent of lesions and microvascular thrombi examined. Microvascular thrombi were positive in 14 of 40 UC cases, and none in the controls. The presence of microvascular thrombi was related to operation specimens with odds ratio 11.667, P=0.0179, it might be also related to histologic score (OR=1.350) and extent of lesions (OR=1.619). These results suggest that microvascular thrombosis may be one of the important pathogenesis in some UC, and that the effect of anticoagulant treatment still needs to be assessed.


Surface Ordering in Molecular Clusters by Interactions of Well-Defined Parity Multipoles.
The spontaneous alignment of dipoles in patterns tangential or transversal to the interface of molecular clusters is studied by molecular dynamics simulations throughout the entire aggregation process. Tangential ordering (TANGO) is found to rely on dispersion forces driven by dipolar fluctuations. Transversal ordering (TRANSO) results from the interplay of two conditions: the broken translational invariance at the cluster interface and the interactions of multipoles of opposite parity. In this case, the orientational order parameter at the interface follows a universal scaling law behavior. In the limiting case of strongly interacting particles, a sharp structural transition from a disordered into an ordered state is observed at a critical distance inside the cluster and at a critical magnitude of the dipole moment.


Clinical features of corrosive ingestion.
To study the clinical presentation after corrosive ingestion. A University Hospital. Prospective descriptive study. Corrosive ingestion patients were studied, from July 2000 to December 2002. Reasons for ingestion, symptoms, physical findings and routine investigations were recorded in a standard form. Data analysed using the descriptive statistical method. There were 73 patients, 55 women and 18 men, median age 22 years, 48 (65.8%) of whom had ingested strong acid, 3 (4.1%) ingested strong alkali. Suicidal gesture was the most common reason for ingestion (89.2%). The amount of ingestion was less in accidental cases. Symptoms of nausea/vomiting, drooling and abdominal tenderness were associated with the amount of ingestion, while severity of lips, buccal mucosa and palate injuries was significantly related with strong corrosive agents (p < 0.05). Leucocytosis was found in patients who had symptoms of drooling, hoarseness, stridor and signs of mucosal slough or superficial ulcers (p < 0.05). Four required surgery. Two of them had esophago-gastrectomy. Twenty-one patients were followed-up, with the median follow-up time of 11 (1-28) months. One patient died from HIV infection. The rest were normal. Drooling and oral mucosal slough or ulcers were significant findings and were related to the amount and strength of the corrosive substance ingested, respectively. To meet the goal of a holistic approach, attention must also be given to psychiatric management, and surgeons should provide a supportive role.