N-Heterocyclic carbenes: versatile second cyclometalated ligands for neutral iridium(III) heteroleptic complexes.
With 2-(2,4-difluorophenyl)pyridine (dfppy) as the first cyclometalated ligand and different monoanionic N-heterocyclic carbenes (NHCs) as the second cyclometalated ligands, 16 blue or greenish-blue neutral iridium(III) phosphorescent complexes, (dfppy)2Ir(NHC), were synthesized efficiently. The obtained Ir(III) complexes display typical phosphorescence of 455-485 nm with quantum yields up to 0.73. By modifying the phenyl moiety in the NHCs with electron-withdrawing substituents (e.g., -F or -CF3) or replacing it with N-heteroaromatic rings (pyridine or pyrimidine), the HOMO-LUMO gaps are broadened, and the emissions shift to the more blue region accordingly. Furthermore, to extend the application scope of NHCs as the second cyclometalated ligands, five other Ir(III) complexes from blue to red were synthesized with different first cyclometalated ligands. Finally, the organic light-emitting diodes using one blue emitter exhibit a maximum current efficiency of 37.83 cd A(-1), an external quantum efficiency of 10.3%, and a maximum luminance of 8709 cd m(-2). Our results demonstrate that NHCs as the second cyclometalated ligands are good candidates for the achievement of efficient phosphorescent Ir(III) complexes and corresponding devices.


Lyssaviruses and rabies: current conundrums, concerns, contradictions and controversies.
Lyssaviruses are bullet-shaped, single-stranded, negative-sense RNA viruses and the causative agents of the ancient zoonosis rabies. Africa is the likely home to the ancestors of taxa residing within the Genus Lyssavirus, Family Rhabdoviridae. Diverse lyssaviruses are envisioned as co-evolving with bats, as the ultimate reservoirs, over seemingly millions of years. In terms of relative distribution, overt abundance, and resulting progeny, rabies virus is the most successful lyssavirus species today, but for unknown reasons. All mammals are believed to be susceptible to rabies virus infection. Besides reservoirs among the Chiroptera, meso-carnivores also serve as major historical hosts and are represented among the canids, raccoons, skunks, mongooses, and ferret badgers. Perpetuating as a disease of nature with the mammalian central nervous system as niche, host breadth alone precludes any candidacy for true eradication. Despite having the highest case fatality of any infectious disease and a burden in excess of or comparative to other major zoonoses, rabies remains neglected. Once illness appears, no treatment is proven to prevent death. Paradoxically, vaccines were developed more than a century ago, but the clear majority of human cases are unvaccinated. Tens of millions of people are exposed to suspect rabid animals and tens of thousands succumb annually, primarily children in developing countries, where canine rabies is enzootic. Rather than culling animal populations, one of the most cost-effective strategies to curbing human fatalities is the mass vaccination of dogs. Building on considerable progress to date, several complementary actions are needed in the near future, including a more harmonized approach to viral taxonomy, enhanced de-centralized laboratory-based surveillance, focal pathogen discovery and characterization, applied pathobiological research for therapeutics, improved estimates of canine populations at risk, actual production of required vaccines and related biologics, strategies to maximize prevention but minimize unnecessary human prophylaxis, and a long-term, realistic plan for sustained global program support to achieve success in disease control, prevention, and elimination.


Influence of Vitamin D on the Incidence of Metabolic Syndrome and Hormonal Balance in Patients with Polycystic Ovary Syndrome.
Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder that affects 8-13% of women of reproductive age. It is one of the most common causes of infertility and is associated with hyperandrogenism in the form of hirsutism and acne, non-ovulatory cycles, and characteristic ovarian morphology. The available research on serum vitamin D deficiency in patients with PCOS and the appropriateness of vitamin D supplementation in this group of women is inconclusive, so we decided to investigate the influence of vitamin D on the incidence of metabolic syndrome and hormonal balance in patients with polycystic ovary syndrome. The study comprised 120 women aged between 18 and 42 years, who were divided into two groups: a group with diagnosed polycystic ovary syndrome (PCOS) and a group of regularly menstruating women without features of androgenisation, in whom polycystic ovary syndrome was excluded. Each patient underwent a history and physical examination, including a gynecological examination, anthropometric measurements were taken, including height, weight, waist, and hip circumference, and blood pressure was measured using the Korotkow method. In the female patients, the following parameters were also determined from the blood: follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol, TSH, ft4, prolactin (PRL), total testosterone, DHEASO4, 17-hydroxyprogesterone (17-OHP), sex-hormone-binding globulin (SHBG), androstendione, 25(OH) vitamin D3 metabolite. The majority of the patients with polycystic ovary syndrome were found to have deficient or suboptimal serum vitamin D levels, and the effects of vitamin D on the SHBG levels and free-androgen indices in these patients was examined. The effects of vitamin D on the incidence of metabolic syndrome and BMI, waist-to-hip ratio, waist circumference, and blood pressure in patients with polycystic ovary syndrome were also found.


A pressure cell for nonresonant inelastic x-ray scattering studies of gas phases.
We report the design and performance of a gas-phase sample cell for measurements of momentum transfer (q) dependent nonresonant inelastic x-ray scattering (NRIXS). NRIXS measurements from He gas at 2 MPa (20 bars) readily demonstrate dipole-allowed and dipole-forbidden final states for two-electron excitations. Direct comparison of gas-phase NRIXS measurements with the corresponding nonresonant electron energy loss spectroscopy results (EELS) will be a valuable method for characterizing systematic errors in either technique for studies that require absolute normalization of the double differential cross section.


Conditions for the genesis of early afterdepolarization in a model of a ventricular myocyte.
Early afterdepolarization (EAD) is a major arrhythmogenic factor in the long QT syndrome (LQTS), whose conditions for genesis have puzzled people for several decades. Here, we employ the phase I Luo-Rudy ventricular myocyte model to investigate EAD using methods from nonlinear dynamics and provide valuable insights into EAD genesis from a physical perspective. Two major results are obtained: (i) Sufficient parametric conditions for EAD are analytically determined and then used to analyze in detail the effects of the physiological parameters. (ii) The normal form of the Hopf bifurcation that leads to EAD is derived and then used to determine whether the Hopf bifurcation is subcritical or supercritical for EAD genesis and the corresponding amplitude and period of the EAD oscillation. Our work here paves the way for further studies of more complicated multi-scale dynamics of EAD and may lead to effective treatments for LQTS arrhythmias.


Rapid systemic delivery of zolmitriptan using an adhesive dermally applied microarray.
Adhesive Dermally-Applied Microarray (ADAM) is a device for intracutaneous drug administration consisting of a 3 cm2 disposable array of drug-coated titanium microprojections on an adhesive backing. It is applied using a low cost, reusable, handheld applicator. Microprojections penetrate the stratum corneum, delivering drug proximal to capillaries with limited likelihood of pain. The pharmacokinetics of zolmitriptan delivery using ADAM was evaluated in 20 healthy volunteers. Median tmax was <20 min, comparable to subcutaneous sumatriptan. Absorption was faster than for oral zolmitriptan, with higher exposure in the first 2 h. Most adverse events were consistent with those seen in previous triptan trials. Application site reactions were generally mild and resolved within 24 h. ADAM zolmitriptan shows a promising pharmacokinetic profile for migraine treatment.


Cyclopia and proboscis - the extreme end of holoprosencephaly.
Holoprosencephaly (HPE), a major congenital abnormality in brain development is characterized by the absence or incomplete cleavage of prosencephalon into separate hemispheres, with cyclopia as the extreme manifestation of HPE, presenting as a failure of embryonic prosencephalon to properly divide the orbits of the eye in two cavities. We report the case of a 15-year-old pregnant patient, who delivered a 34-week living fetus with alobar HPE, cyclopia and proboscis. The patient did not have any routine scans during pregnancy; her first obstetrical exam was performed at 29 weeks of gestation (WG), when a prenatal ultrasound found a fetus with alobar HPE, cyclopia, proboscis, polydactyly and single umbilical artery. Despite adequate medical and genetic counseling, the patient and her legal representative refused further investigations - magnetic resonance imaging and genetic testing. She was admitted to the hospital at 34 WG for premature rupture of membranes, with clear amniotic fluid. Twenty-four hours later, she delivered vaginally a living male fetus, weighing 1995 g. Macroscopic examination revealed umbilical cord with two vessels, fetal proboscis, cyclopia, low implanted ears, bilateral polydactyly of the upper limbs, spina bifida occulta in the sacral region. The newborn lived for 40 minutes. Microscopy of the eyeball revealed choroid, ciliary body and conjunctiva structures, with no identification of the retina, and no evidence of the optic nerve in the fragments obtained from the optic chiasm region. This case underlines the importance of early obstetrical examinations during pregnancy and raises concerns about the ethics of allowing therapeutic termination of pregnancy after 24 WG in selected cases.


Electrothermally Driven Fluorescence Switching by Liquid Crystal Elastomers Based On Dimensional Photonic Crystals.
In this article, the fabrication of an active organic-inorganic one-dimensional photonic crystal structure to offer electrothermal fluorescence switching is described. The film is obtained by spin-coating of liquid crystal elastomers (LCEs) and TiO2 nanoparticles alternatively. By utilizing the property of LCEs that can change their size and shape reversibly under external thermal stimulations, the λmax of the photonic band gap of these films is tuned by voltage through electrothermal conversion. The shifted photonic band gap further changes the matching degree between the photonic band gap of the film and the emission spectrum of organic dye mounting on the film. With rhodamine B as an example, the enhancement factor of its fluorescence emission is controlled by varying the matching degree. Thus, the fluorescence intensity is actively switched by voltage applied on the system, in a fast, adjustable, and reversible manner. The control chain of using the electrothermal stimulus to adjust fluorescence intensity via controlling the photonic band gap is proved by a scanning electron microscope (SEM) and UV-vis reflectance. This mechanism also corresponded to the results from the finite-difference time-domain (FDTD) simulation. The comprehensive usage of photonic crystals and liquid crystal elastomers opened a new possibility for active optical devices.


Characterization of the groEL-like genes in Streptomyces albus.
Three GroEL-like heat shock proteins (HSP56, HSP58, and HSP18) have been observed in Streptomyces albus (G. Guglielmi, P. Mazodier, C. J. Thompson, and J. Davies, J. Bacteriol. 173:7374-7381, 1991). Here we report the cloning and complete nucleotide sequence of groEL1, which encodes HSP18 and HSP58, and groEL2, which encodes HSP56. Both nucleotide sequences predicted proteins of 56,680 Da that were 70% identical. The 5' nucleotide sequence of groEL1 coded for a protein corresponding to HSP18 that may be a processed gene product. At least two groEL-like genes were present in all 12 Streptomyces species tested; they were not closely linked in the genome. groEL1, but not groEL2, was adjacent to a groES-like gene.


Clathrin-Dependent Uptake of Paraquat into SH-SY5Y Cells and Its Internalization into Different Subcellular Compartments.
The herbicide paraquat (PQ) is an exogenous toxin that allows the selective activation of dopaminergic neurons in the mesencephalon to induce injury and also causes its apoptosis in vitro. However, uptake mechanisms between PQ and neurons remain elusive. To address this issue, we undertook a study of PQ endocytosis in a dopaminergic SH-SY5Y cell line as well as explored the subsequent subcellular location and potential functional analysis of PQ. The PQ was found to bind the SH-SY5Y cell membrane and then became internalized via a clathrin-dependent pathway. PQ was internalized by many subcellular organelles in a time- and dose-dependent manner. Interestingly, the taken up PQ and secretogranin III (SCG3), which became dysregulated with PQ treatment that induced SH-SY5Y apoptosis in our previous study, colocalized in cytoplasmic vesicles. Taken together, our findings indicate that PQ is endocytosed by SH-SY5Y cells and that its multiple, subcellular localizations indicate PQ may potentially be involved in subcellular-level functions. More importantly, PQ distributing preferentially into SCG3-positive vesicles demonstrates its selective targeting which may affect SCG3 and cargoes carried by SCG3-positive vesicles. Therefore, it is reasonable to infer that PQ toxic insults may potentially interfere with neurotransmitter storage and transport associated with secretory granules.


Regulation of complement and modulation of its activity in monoclonal antibody therapy of cancer.
The complement system is a powerful tool of the innate immune system to eradicate pathogens. Both in vitro and in vivo evidence indicates that therapeutic anti-tumor monoclonal antibodies (mAbs) can activate the complement system by the classical pathway. However, the contribution of complement to the efficacy of mAbs is still debated, mainly due to the lack of convincing data in patients. A beneficial role for complement during mAb therapy is supported by the fact that cancer cells often upregulate complement-regulatory proteins (CRPs). Polymorphisms in various CRPs were previously associated with complement-mediated disorders. In this review the role of complement in anti-tumor mAb therapy will be discussed with special emphasis on strategies aiming at modifying complement activity. In the future, clinical efficacy of mAbs with enhanced effector functions together with comprehensive analysis of polymorphisms in CRPs in mAb-treated patients will further clarify the role of complement in mAb therapy.


Effectiveness of intra-operative Mitomycin-C in reducing the recurrence of pterygium in Irrua, Nigeria.
To evaluate the effectiveness of intra-operative Mitomycin-C application after pterygium surgery in Irrua, Nigeria. The medical records of all patients who had pterygium excision with intra-operative application of 0.4mg/ml Mitomycin C between June 2002 and May 2007 and followed up for at least a year were reviewed. Two hundred and forty three eyes (196 patients) had pterygium excision with intra-operative application of 0.4mg/ml Mitomycin C over this period. Male to female ratio was 2:1. The mean age of the patients was 47.1years (SD+ 15.4) Eleven eyes had recurrence after a minimum follow up period of one year. Six (54.5%) out of the eleven eyes that had recurrence had conjunctival granuloma and in such cases recurrence was early (between 2 to 3 months of surgery). Conjunctival granuloma was the main complication occurring in 35 eyes (14.4%). Occurrence of granuloma was significantly associated with recurrence (P =0.0006). Delayed wound healing occurred in 5 eyes (2.1%). There was no case of either scleral or corneal melting. Intra-operative application of 0.4mg/ml Mitomycin C is very effective in reduction of recurrence of pterygium after excision. Hence patients should be given the benefit of intra-operative use of Mitomycin C during pterygium surgery.


Improved Accuracy and Efficiency in Quantum Embedding through Absolute Localization.
Projection-based quantum embedding methodologies provide a framework for performing wave function-in-density functional theory (WF-in-DFT) calculations. The total WF-in-DFT energy is dependent on the partitioning of the total system and requires similar partitioning in each system for accurate energy differences. To achieve this, we enforce an absolute localization of the WF orbitals to basis functions only associated with the WF subsystem. This absolute localization, followed by iterative optimization of the subsystems' orbitals, provides improved energy differences for WF-in-DFT while simultaneously improving the computational efficiency.


Turkey breeder hen age affects growth and systemic and intestinal inflammatory responses in female poults examined at different ages posthatch.
This trial examined the effect of 2 turkey breeder hen ages (33 or 55 wk of age) on performance, intestinal histology, and inflammatory immune response of female turkey poults grown to market weight. Using a randomized design, female poults were separated by breeder flock age (n = 8 floor pens/breeder flock age; n = 26 poults/pen; 0.195 m(2)/bird), fed identical commercial diets (9 phases), and grown to market weight (approximately 11.4 kg/ bird). At young ages, poults from the older breeder flock tended to have higher BW (P < 0.01 for d 7, P < 0.09 for d 63), although feed consumed was not significantly different due to breeder flock age (P > 0.20 for all ages). After approximately 63 d posthatch, no difference in BW was observed, suggesting that poults from the younger breeder flock were eventually able to compensate for initial reductions in performance. In addition to growth measurements on d 10, 24, and 65 posthatch, poults were vaccinated with lipopolysaccharide (LPS, from Salmonella Typhimurium; 0.5 mg/kg of BW intraabdominally) or not vaccinated (control), and intestinal histology and plasma haptoglobin were assessed at 24 h postadministration. In control birds, intestinal villus length was greater for poults from the older breeder flock (P < 0.05), as was crypt depth (P < 0.05 for d 11 and 25). Plasma haptoglobin levels did not change in 11-d-old poults after LPS administration, but they increased with LPS at d 25 and 66 posthatch (P < 0.05 for each). At d 66 posthatch, poults from the younger flock had increased haptoglobin levels post-LPS compared with those from the older breeder flock (P < 0.05). In general, LPS administration increased villus width in the jejunum and ileum (P < 0.05 for each), increased lamina propria width in the duodenum and ileum (P < 0.05 for each), and decreased ileum crypt depth (P < 0.05). Overall, poults from the older breeder flock had reduced inflammatory responses, even at 9 to 10 wk posthatch, even though performance was similar in poults from the 2 flocks by this age.


Tissue-specific inhibition of urokinase-type plasminogen activator expression in the testes of mice by inducible lentiviral RNA interference causes male infertility.
Urokinase-type plasminogen activator (uPA) is involved in many physiological processes, including male infertility. To explore the effects of uPA in male reproduction, we constructed an inducible uPA short hairpin RNA (shRNA) system expressed by lentiviral vectors. After proving inhibition of uPA expression in the mouse Sertoli cell line TM4 by 1μgmL-1 doxycycline (Dox), two lentivirus (pLenti4-shRNA and pLenti6/TR) were co-microinjected into mouse testes to produce TetR&shuPA mice model. Though oral gavage by 0.75mgmL-1 Dox each day for 1 week, the Plau mRNA expression, uPA protein level and uPA enzyme activity in mice testis decreased significantly in TetR&shuPA mice model. After Dox induction of 1 week, the TetR&shuPA mice mated with female mice. Our results show that the pregnancy rate was reduced by approximately 40% and the sperm motility also decreased significantly. These data indicated that downregulation of uPA could decrease the fertility of male mice, which may be caused by a reduction in sperm motility. To investigate the reversible effect and safety of the inducible uPA shRNA system, we withdraw Dox and found the mating rate and sperm motility gradually recovered after 2 weeks. The histopathology structure of the testis, epididymis, and main organs was not altered significantly. The results of the present study indicating that uPA may be regarded as a novel target for the regulation of male fertility.


Quantitative Methods to Study Protein Arginine Methyltransferase 1-9 Activity in Cells.
Protein methyltransferases (PRMTs) catalyze the transfer of a methyl group to arginine residues of substrate proteins. The PRMT family consists of nine members that can monomethylate or symmetrically/asymmetrically dimethylate arginine residues. Several antibodies recognizing different types of arginine methylation of various proteins are available; thus, providing tools for the development of PRMT activity biomarker assays. PRMT antibody-based assays are challenging due to overlapping substrates and motif-based antibody specificities. These issues and the experimental setup to investigate the arginine methylation contributed by individual PRMTs are discussed. Through the careful selection of the representative substrates that are biomarkers for eight out of nine PRMTs, a panel of PRMT activity assays were designed. Here, the protocols for cellular assays quantitatively measuring the enzymatic activity of individual members of the PRMT family in cells are reported. The advantage of the described methods is their straightforward performance in any lab with cell culture and fluorescent western blot capabilities. The substrate specificity and chosen antibody reliability were fully validated with knockdown and overexpression approaches. In addition to detailed guidelines of the assay biomarkers and antibodies, information on the use of an inhibitor tool compound collection for PRMTs is also provided.


Maturation of the retina of the canine neonate as determined by electroretinography and histology.
Retinal potentials were obtained by electroretinography from birth to maturity of dogs. Amplitudes, time latency, and flicker fusion frequencies under scotopic conditions were compared to the histologic development of the retina. There was no electroretinogram (ERG) recorded during the 1st week of life, but in the 2nd week, a small negative wave (not exceeding 5 microV) was detected. Small ERG waveforms appeared in dogs at 3 weeks of age; these markedly increased in amplitude and latency between the 3rd and the 4th weeks of age. Additional changes in the ERG amplitudes were evident in the 5th to the 8th weeks of life approximating amplitudes of the adult dog. Similarly, the greatest changes in flicker fusion frequencies occurred between the 3rd and the 5th weeks and the 7th and the 8th weeks. Latency of the a-wave indicated little change in the age groups studied. The greatest decrease in latency occurred in the b- and c-waves between the 3rd and 5th weeks of age. The rod and cone inner and outer segments were first observed microscopically in the 3rd week after the dogs were born. Further differentiation of the rod and cone segments and other retinal layers occurred from the 5th to the 8th weeks.


Detection and characterization of ciRS-7: a potential promoter of the development of cancer.
Circular RNAs (circRNAs) are a class of newly-identified non-coding RNA molecules. CircRNAs are conserved across different species and display specific organization, sequence, and expression in disease. Moreover, circRNAs' closed ring structure, insensitivity to RNase, and stability are advantages over linear RNAs in terms of development and application as a new kind of clinical marker. In addition, according to recent studies, circular RNA-7 (ciRS-7) acts as a sponge of miR-7 and thus inhibits its activity. Numerous evidences have confirmed expression of miR-7 is dysregulated in cancer tissues, however, whether ciRS-7 invovled in oncogenesis by acting as sponge of miR-7 remains unclear. Most recently, a study reported ciRS-7 acted as an oncogene in hepatocellular carcinoma through targeting miR-7 expression. This suggest ciRS-7/ miR-7 axis affects oncogenesis, and it provides a new perspective on the mechanisms of decreased miR-7 expression in cancer tissues. Discovery of sponge role of circRNAs caused researchers to more closely explore the underlying mechanism of carcinogenesis and has significant clinical implications, and may open a new chapter in research on the pathology and treatment of cancers. This review summarizes the structure and function of circRNAs and provides evidence for the impact of ciRS-7 in promoting the development of cancer by acting as sponge of miR-7.


[Psychological Care for a High Risk Group of Refugees - Concept of Care for the Yazidi Women and Children of the Sonderkontingent Baden-Württemberg in Freiburg].
After the genocide of Shingal in August 2014 in Northern Iraq, the humanitarian admissions program Sonderkontingent Baden-Württemberg "Schutzbedürftiger Frauen und Kinder aus dem Nordirak" was implemented. 1100 persons, most of them Yazidis, were hosted by different municipalities in Germany. The target group is a particularly vulnerable group of persons with a high risk for developing post-traumatic stress disorder. We present the concept of care in Freiburg for 205 Yazidi women and children in Freiburg. A stepped-care approach was developed for the psychological care to introduce the Yazidi people to the daily life and to the health care system in Germany. An outreach of psychological services and an interdisciplinary and multidisciplinary cooperation of all services involved were crucial.


Laparoscopic sleeve gastrectomy: Effect on long-term remission for morbidly obese patients with type 2 diabetes at 5-year follow up.
In the short-term, laparoscopic sleeve gastrectomy has been shown to be effective for the treatment of the type 2 diabetes in patients with severe obesity. There are few data with greater follow-up. Our aim was to evaluate the results of laparoscopic sleeve gastrectomy on the control of type 2 diabetes in patients with severe obesity at 5 years at the University Hospital, France. From a total of 355 patients with severe obesity operated between January 2006 and June 2010, 52 (15%) had a diagnosis of type 2 diabetes before undergoing laparoscopic sleeve gastrectomy. There were 31 females (60%) and 21 males (40%), with a mean age of 51 ± 10 years (range 27-67) with a mean body mass index of 48 ± 10 kg/m2 (range 35-82). The mean duration of type 2 diabetes was 10.8 ± 10.8 years before bariatric operation. The preoperative glycated hemoglobin was 8 ± 2% (range 5.9-12.8) in 45 patients; 17 patients (38%) had levels of glycated hemoglobin ≥9%. Three patients (6%) required insulin alone, 4 (8%) were taking oral antidiabetic medicine and insulin, and the remaining 45 patients (87%) were taking only oral antidiabetic medicines. The complete data regarding weight loss at 5-year follow-up were obtained for 46 patients, yielding an overall follow-up rate of 89%. The prolonged remission of type 2 diabetes achieved at 1 year that persisted at 5 years of follow-up was present in 9 patients (17%). No patient with complete remission of their type 2 diabetes required insulin preoperatively. Improvement of type 2 diabetes was observed in 30 patients (58%) at 1 year, which was maintained for 27 patients (52%) at 5-year follow-up. Laparoscopic sleeve gastrectomy has demonstrated a moderate efficacy in the treatment morbidly obese patients with type 2 diabetes. Markedly increased preoperative glycated hemoglobin levels, older age, and preoperative need for insulin treatment may be the factors predicting failure of complete remission of type 2 diabetes after laparoscopic sleeve gastrectomy.


Macrophage immunometabolism in diabetes-associated atherosclerosis.
Macrophages play fundamental roles in atherosclerotic plaque formation, growth, and regression. These cells are extremely plastic and perform different immune functions depending on the stimuli they receive. Initial in vitro studies have identified specific metabolic pathways that are crucial for the proper function of pro-inflammatory and pro-resolving macrophages. However, the plaque microenvironment, especially in the context of insulin resistance and type 2 diabetes, constantly challenges macrophages with several simultaneous inflammatory and metabolic stimuli, which may explain why atherosclerosis is accelerated in diabetic patients. In this mini review, we discuss how macrophage mitochondrial function and metabolism of carbohydrates, lipids, and amino acids may be affected by this complex plaque microenvironment and how risk factors associated with type 2 diabetes alter the metabolic rewiring of macrophages and disease progression. We also briefly discuss current challenges in assessing macrophage metabolism and identify future tools and possible strategies to alter macrophage metabolism to improve treatment options for diabetes-associated atherosclerosis.


Identification of disease modules using higher-order network structure.
Higher-order interaction patterns among proteins have the potential to reveal mechanisms behind molecular processes and diseases. While clustering methods are used to identify functional groups within molecular interaction networks, these methods largely focus on edge density and do not explicitly take into consideration higher-order interactions. Disease genes in these networks have been shown to exhibit rich higher-order structure in their vicinity, and considering these higher-order interaction patterns in network clustering have the potential to reveal new disease-associated modules. We propose a higher-order community detection method which identifies community structure in networks with respect to specific higher-order connectivity patterns beyond edges. Higher-order community detection on four different protein-protein interaction networks identifies biologically significant modules and disease modules that conventional edge-based clustering methods fail to discover. Higher-order clusters also identify disease modules from genome-wide association study data, including new modules that were not discovered by top-performing approaches in a Disease Module DREAM Challenge. Our approach provides a more comprehensive view of community structure that enables us to predict new disease-gene associations. https://github.com/Reed-CompBio/graphlet-clustering.


[The possibility of drug design of quinolones effective for multiresistant gram-positive pathogens].
Recently rapid increase in the emergence of multiresistant Gram-positive pathogen such as MRSA, penicillin resistant Streptococcus pneumoniae (PRSP), and vancomycin resistant Enterococcus (VRE). Whether quinolone antibacterial agent (quinolone) come to a promising drug or not for the treatment of these infectious diseases, it depend on an appropriate drug design of quinolones which have good toxicological and pharmacokinetic profile along with excellent antibacterial activities against these Gram-positive pathogens. In this chapter, we examine the possibility by following the history of the advances in quinolone research.


Thigh Length as the Most Consistent Anthropometric Parameter in Predicting the Size of Hamstring Tendon Autografts in Patients Undergoing Anterior Cruciate Ligament Reconstruction: A Cross-Sectional Study.
Individual variability in the length and thickness of hamstring tendon autografts is a serious drawback in using these tendons for anterior cruciate ligament reconstruction (ACLR). In this study, we aimed to determine the correlation between the anthropometric parameters and the size of hamstring tendon autografts. In a cross-sectional study, 52 male ACLR candidates were included. The length of semitendinosus and gracilis tendons and the diameter of single, doubled, and quadrupled tendons were measured. A graft sizing block device with an incremental size change of 0.5 mm (range 4.5-12) was used to measure the tendon graft diameter. The evaluated anthropometric parameters included age, gender, height, weight, BMI, thigh length and diameter, calf length, thigh-to-calf ratio, wrist diameter, and ankle diameter. A Pearson's or Spearman's correlation coefficient test was used for evaluating the correlation of anthropometric factors with graft characteristics. The mean age of the patients was 27.1 ± 6.4 years. The semitendinosus length was significantly correlated with the patient's height (r = 0.373, P = 0.007), thigh length (r = 0.364, P = 0.009), and calf length (r = 0.340, P = 0.015). The gracilis length was significantly correlated with thigh length (r = 0.278, P = 0.049). The mean quadruple diameter was 8.56 ± 1.15 mm (range 6.5-11). The quadruple diameter was significantly correlated with the thigh length (r = 0.283, P = 0.044). No other significant correlation was found between the tendons' size and evaluated anthropometric parameters. Thigh length was correlated with the semitendinosus length, gracilis length, and quadruple diameter. Therefore, it could be regarded as the most consistent and promising anthropometric factor in the prediction of hamstring autograft size.


A micro-incubator for cell and tissue imaging.
A low-cost micro-incubator for imaging dynamic processes in living cells and tissues has been developed. This micro-incubator provides a tunable environment that can be altered to study responses of cell monolayers for several days as well as relatively thick tissue samples and tissue-engineered epithelial tissues in experiments lasting several hours. Samples are contained in a sterile cavity closed by a gas-permeable membrane. The incubator can be positioned in any direction and used on an inverted or upright microscope. Temperature is regulated using a Peltier module controlled by a sensor positioned close to the sample, enabling compensation for any changes in temperature. Rapid changes in a sample's surrounding environment can be achieved due to the fast response of the Peltier module. These features permit monitoring of sample adaptation to induced environmental changes.


Is there still a role for the intra-aortic balloon pump in the management of cardiogenic shock following acute coronary syndrome?
The intra-aortic balloon pump has been widely used in the management of cardiogenic shock. Reducing cardiac afterload and myocardial oxygen consumption, and improving coronary blood flow, this safe and simple mechanical circulatory support has been considered the cornerstone of cardiogenic shock management for decades. However, because it failed to provide any clinical benefit in recent randomized trials, the latest guidelines discourage its routine use in this clinical setting. Moreover, new percutaneous circulatory supports providing greater haemodynamic improvement have recently been developed. Thus, intra-aortic balloon pump use has declined considerably in this clinical setting. However, the device does retain a minor role in cardiogenic shock management - mainly in the setting of mechanical complication of acute coronary syndrome, and for left ventricular unloading in patients treated with extracorporeal life support.


Multiple time scale behaviors and network dynamics in liquid methanol.
Canonical ensemble molecular dynamics simulations of liquid methanol, modeled using a rigid-body, pair-additive potential, are used to compute static distributions and temporal correlations of tagged molecule potential energies as a means of characterizing the liquid state dynamics. The static distribution of tagged molecule potential energies shows a clear multimodal structure with three distinct peaks, similar to those observed previously in water and liquid silica. The multimodality is shown to originate from electrostatic effects, but not from local, hydrogen bond interactions. An interesting outcome of this study is the remarkable similarity in the tagged potential energy power spectra of methanol, water, and silica, despite the differences in the underlying interactions and the dimensionality of the network. All three liquids show a distinct multiple time scale (MTS) regime with a 1/ f (alpha) dependence with a clear positive correlation between the scaling exponent alpha and the diffusivity. The low-frequency limit of the MTS regime is determined by the frequency of crossover to white noise behavior which occurs at approximately 0.1 cm (-1) in the case of methanol under standard temperature and pressure conditions. The power spectral regime above 200 cm (-1) in all three systems is dominated by resonances due to localized vibrations, such as librations. The correlation between alpha and the diffusivity in all three liquids appears to be related to the strength of the coupling between the localized motions and the larger length/time scale network reorganizations. Thus, the time scales associated with network reorganization dynamics appear to be qualitatively similar in these systems, despite the fact that water and silica both display diffusional anomalies but methanol does not.


[Adolescents' physical activity].
The paper defines the parameters reflecting the physical activity of adolescents and their correlation with health and a risk of behavioral disorders, bad habits, and cravings. A total of 9499 Georgian adolescents aged 14-18 years, the senior (9th-llth-form) pupils, selected through two-step cluster sampling were surveyed. The pupils anonymously filled in special questionnaires. This yielded the parameters reflecting the intensity of physical activity of the adolescents and the latter's going in for sports. The parameters were shown to have a beneficial effect on health, including mental health, and on the magnitude of unhealthy behavior.


[Treatment efficiency evaluation of left cardiac sympathetic denervation for patients with inherited arrhythmia by exercise-stress test].
Objective: To evaluate the efficiency of left cardiac sympathetic denervation (LCSD) in inherited arrhythmia patients with adrenergic activity-induced malignant ventricular arrhythmia, and observe exercise-stress test features before and after LCSD. Methods: This retrospective observational study included catecholaminergic polymorphic ventricular tachycardia(CPVT) and long QT syndromes(LQTS) patients who underwent video-assisted LCSD at Beijing Tsinghua Changgung Hospital and Peking University People's Hospital from September 2006 to May 2020. The indications for LCSD surgery were intolerant or refractory to beta-blocker medication. Clinical and exercise-stress tests data of included patients were collected before and 1 month after LCSD. Heart rate, exercise tolerance, atrial and ventricular arrhythmia, QTc interval and predictors for sudden cardiac death were analyzed. Patents were regularly followed up at 1, 3, 6, and 12 months after LCSD and then once every year thereafter. Cardiac events and medication adjustment records were collected. Results: Five patients (2 CPVT, 1 LQT1, and 2 LQT2)were included in the study. All patients experienced syncope as first symptom at the median age of 12(10, 16)years, and underwent LCSD at the median age of 21(16, 26)years, Baseline heart rate was similar before and after LCSD ((65.6±6.5) beats/min vs. (68.0±11.1) beats/min, P=0.57); while maximum workload tended to be lower after LCSD ((12.1±2.8) metabolic equivalents (METS) before surgery vs. (10.5±2.4) METS after surgery, P=0.07). Incidence of atrial and ventricular arrhythmia were significantly reduced post LCSD, and the ventricular arrhythmia score was decreased after LCSD in CPVT patients (4 points before LCSD vs. 3 points after LCSD in case 1;5 points before LCSD vs. 3 points after LCSD in case 2). QTc interval was shortened significantly in three LQTs patients (QTc interval at baseline heart rate: (546.6±72.3) ms before surgery vs. (493±61.1) ms after LCSD, P=0.047; QTc interval at maximal exercise heart rate: (516.3±73.7) ms before surgery vs. (486.7±64.2)ms after LCSD, P=0.035). Additionally, sudden cardiac death risk indicator ΔHRR1 (heart rate decreasing value within the first 1 min during recovery phase) decreased from (51.5±21.1) beats/min before surgery to (32.0±13.9) beats/min after surgery (P=0.035). During a median follow-up of 1(1, 4) year, all five patients were on low dosage of propranolol (37.0±21.7) mg/d. Cardiac events free survival was achieved in four out of 5 patients (80%) after sympathectomy, while 1 case suffered from sudden cardiac death after emotional stress. Conclusion: LCSD surgery can be safely and effectively performed in most hereditary arrhythmia patients with adrenergic activity-induced life-threatening cardiac events. Exercise stress test results show that LCSD could reduce malignant arrhythmias and improve sudden cardiac death risk indicators without decreasing heart rate.


Physician resource planning: quest for answers.
The average annual rate of physician growth in Canada, just over 4% prior to 1989, has fallen to about 2% since 1990, approximating the average annual growth rate of the Canadian population. The growth rate is not uniform for all specialties, with surgical specialties experiencing the smallest increases. Sub-specialist growth in the past 5 y has occurred preferentially in disciplines identified as areas of need and those identified as emerging specialties. Assessment of average workloads of physicians derived from full-time equivalent measurements, reported by the National Physician Data Base, indicates increasing workloads in the specialist group, which is most marked in the surgical specialties. Among a number of factors influencing workload measures, which might explain differences noted among specialty groups, are age, gender, lifestyle choices, technology changes, physician growth rates, and saturation of the market place balancing physician availability with "demand" for services. All such factors, along with the impact of current health care reform initiatives, must be considered when forecasting and managing physician resources.


Genetics teaching for non-geneticist health care professionals in the UK.
It was the aim of this study to describe the structure and content of training in genetics for non-genetics specialist health care professionals in the UK. Data were collected by assessment of published syllabi and curricula and through contact with educational leads at responsible organisations. Twenty-six universities, 7 Royal Colleges and various intercollegiate boards and committees are involved in the provision of medical education at various levels, in addition to institutions offering nursing and/or midwifery training. Genetics is taught in variable formats, quantities and contents, and although some institutions are moving to adopt minimum competencies in genetics, this is by no means widespread. Given the wide number of stakeholders in the field, consensus competencies seem most likely to advance practice, and thus, phase II of the GenEd project will survey professionals to ascertain their priorities for genetic education.


The oncogenic potential of hepatitis B virus rtA181T/ surface truncation mutant.
Previously, a less prevalent lamivudine-resistant mutant (rtA181T) was discovered in Taiwanese patients, in which a stop codon in the surface gene concomitantly occurred, leading to impaired secretion of hepatitis B virus (HBV) surface antigen. The rtA181T mutant also conferred drug resistance to adefovir. We discovered a 39-year-old patient with advanced hepatocellular carcionoma, who was seropositive for HBV e antigen but seronegative for HBV surface antigen. Nucleotide sequence analysis revealed the presence of polymerase rtA1 81T/surface truncation mutant in both the serum and hepatoma samples. Surprisingly, this patient has never received lamivudine or adefovir antiviral therapy. Here, we aimed to evaluate the oncogenic potential of HBV rtA181T/surface truncation mutant. Site-directed mutagenesis experiments followed by transactivation assays were performed in HepG2 cells to evaluate the transactivation activities of the corresponding pre-S/S truncation mutant for c-Mye, c-Fos and Simian virus 40 promoters. NIH3T3 cells stably expressing the mutant were used to assess the tumourigenicity in nude mice. Transactivation experiments revealed that the corresponding pre-S/S truncation mutant was capable of transactivating the Simian virus 40 and human c-Mye promoters but not the c-Fos promoter. NIH3T3 cells stably expressing this mutant were tumourigenic in four of the five nude mice tested. Our data indicate that an HBV polymerase rtA181T/surface truncation mutant could emerge spontaneously without previous antiviral treatment. The presence of this mutant in a patient with advanced hepatocellular carcinoma as well as its oncogenic potential warrants careful re-evaluation of the current strategy of prolonged antiviral therapy.


EFFECT OF MENSTRUAL CYCLE PHASE ON THE GLUCOSE-INSULIN RELATIONSHIP AT REST AND DURING EXERCISE.
The purpose of this study was to investigate the effect of menstrual cycle phase on the insulin/glucose relationship at rest and response to sub-maximal exercise. Eight eumenorrheic women completed exercise sessions (60 min, 70% V̇O2max) in the follicular (day 7±2) and luteal (day 20±2) phases of their cycles. At 45 min before each exercise session the subject consumend an oral glucose load (OGL) of 1 gkg-1 body weight in a 400 ml solution. Blood samples were obtained before the OGL (-45 min) immediately before exercise, and at 15 min intervals until the end of exercise (60 min). Results indicated that serum glucose and insulin increased (P<0.01) due to the OGL and decreased (P<0.01) due to exercise. No significant phase differences were observed for the glucose responses: however, insulin levels were greater immediately before exercise in the luteal than follicular phase (47.2±5.8 vs. 39.3±5.1 U·ml-1, respectively). The insulin-to-glucose ratio (I/G) was calculated and also showed significant changes. The I/G ratio was greater in the luteal than in the follicular phase at 0 min (6.5±0.4 vs. 5.3±0.6 mU·mmol-1, respectively). These data would suggest that in eumenorrheic women the menstrual cycle impacts the insulin/glucose relationship at rest, but has no effect during exercise. Whether the mechanism of the resting effect is due to changes in pancreatic and/or target tissue functions in unclear.


Dose-dependence of changes in cortical protein expression induced with repeated transcranial magnetic theta-burst stimulation in the rat.
Theta Burst stimulation (TBS) applied via transcranial magnetic stimulation (TMS) effectively modulates human neocortical excitability but repeated applications of the same TBS protocol at short intervals may be not simply accumulative. Our aim was to investigate the impact of multiple blocks of either intermittent (iTBS) or continuous TBS (cTBS) on the expression of neuronal activity marker proteins in rat cortex. Up to four iTBS- or cTBS-blocks of 600 stimuli were applied to urethane-anesthetized rats followed by immunohistochemical and Western blot analyses. The effects of iTBS and cTBS were similar but slightly differed with regard to the number of stimuli applied. The expression of the 65-kD isoform of glutamic acid decarboxylase (GAD65) increased with each stimulation block, while that of the 67-kD isoform (GAD67), and that of the calcium-binding proteins (CaBP) Parvalbumin (PV) and Calbindin (CB) and that of the immediate early gene c-Fos progressively decreased. Both TBS protocols increased the expression of the vesicular glutamate transporter 1 (VGLUT1) with 1200-1800 stimuli but then decreased them after the 4th block. Our findings indicate that repeated TBS elicits no simple accumulative dose-dependent effect for all activity-markers but distinct profiles with threshold characteristics and a waxing-and-waning effect especially for the markers of inhibitory activity CB and GAD67. Interestingly, somatic activity markers, such as c-Fos for mainly excitatory and GAD67, CB and PV for inhibitory neurons, decreased with repeated stimulation while synaptic activity markers mainly increased which could be a result of the artificial stimulation of axons.


PPARγ gene expression is autoregulated in primary adipocytes: ligand, sumoylation, and isoform specificity.
Being a key-factor in glucose homeostasis, PPARγ transcriptional activity (TA) is of high importance. However, its mediation by ligands and post-translational modifications in insulin target tissues are unclear. We investigated effects of rosiglitazone (Rg) and sumoylation on PPARγ-TA by overexpressing expression vectors and promoter-reporters for PPARγ1 and PPARγ2 in primary rat adipocytes. Wild type (WT) PPARγ1 and PPARγ2 dose-dependently repressed transcription from their promoters to a maximum of 40-50%. PPARγ2 mutants defective in either MAP-kinase phosphorylation (S112A) or the ligand-binding domain (LBD; P495L, L496A/E499A) exhibited decreased repression of PPARγ2 promoter. Rg enhanced repression by S112A, but not by LBD-defective mutants. Sumoylation-defective PPARγ1 mutants K77R and K365R repressed PPARγ2 promoter activity similar to WT, while Rg enhanced repression by K77R but not by K365R. Sumoylation-defective PPARγ2 mutants K107R and K395R exhibited impaired TA and impaired responsiveness to Rg. GLUT4 promoter, previously shown by us to be repressed by WT-PPARγ1 and WT-PPARγ2, was similarly repressed by both sumoylation-defective PPARγ1 mutants, while both sumoylation-defective PPARγ2 mutants exerted reduced repression. Surprisingly, Rg alleviated only WT-PPARγ2-induced repression, while augmenting that induced by WT-PPARγ1 and all sumoylation-defective mutants. Promoter and chromatin immunoprecipitation analyses revealed that PPARγ2 autorepression involves its direct binding to its promoter. In concert with effects at promoter level, Rg decreased endogenous level of PPARγ2 mRNA, while increasing that of GLUT4. We suggest a hypothetical model for PPARγ gene regulation in primary adipocytes that is isoform-specific and Rg/sumoylation-dependent. These findings are important due to the role of PPARγ and Rg in insulin sensitivity.


Reconstruction of large cranial defects with poly-methyl-methacrylate (PMMA) using a rapid prototyping model and a new technique for intraoperative implant modeling.
Reconstruction of large cranial defects after craniectomy can be accomplished by free-hand poly-methyl-methacrylate (PMMA) or industrially manufactured implants. The free-hand technique often does not achieve satisfactory cosmetic results but is inexpensive. In an attempt to combine the accuracy of specifically manufactured implants with low cost of PMMA. Forty-six consecutive patients with large skull defects after trauma or infection were retrospectively analyzed. The defects were reconstructed using computer-aided design/computer-aided manufacturing (CAD/CAM) techniques. The computer file was imported into a rapid prototyping (RP) machine to produce an acrylonitrile-butadiene-styrene model (ABS) of the patient's bony head. The gas-sterilized model was used as a template for the intraoperative modeling of the PMMA cranioplasty. Thus, not the PMMA implant was generated by CAD/CAM technique but the model of the patients head to easily form a well-fitting implant. Cosmetic outcome was rated on a six-tiered scale by the patients after a minimum follow-up of three months. The mean size of the defect was 74.36cm2. The implants fitted well in all patients. Seven patients had a postoperative complication and underwent reoperation. Mean follow-up period was 41 months (range 2-91 months). Results were excellent in 42, good in three and not satisfactory in one patient. Costs per implant were approximately 550 Euros. PMMA implants fabricated in-house by direct molding using a bio-model of the patients bony head are easily produced, fit properly and are inexpensive compared to cranial implants fabricated with other RP or milling techniques.


Childhood and adolescent obesity: Primary Health Care Physicians' perspectives from Riyadh, Saudi Arabia.
Primary health care (PHC) physicians are foremost to confront childhood and adolescent obesity. Our objective was to evaluate PHC Physicians perspectives for managing overweight/obesity in children and adolescents. PHC services from eight public hospitals in Riyadh participated. A self-administered tool maintaining anonymity evaluated facilitators and barriers for managing overweight/obese children and adolescent patients. Physicians who 'always' recommended weight management for an overweight / obese patient during past year, by involving patient, parents, and others were classified as having positive and appropriate practice. Of the 58 respondents, 51.7% had appropriate practices. Lack of patient motivation (82.2%), and parental involvement (70.7%) were the major barriers. Physicians with appropriate practices differed in perspectives from those with less appropriate practices by attending continued education forums (p<0.026), referring patients to sub-specialty (p< 0.041), clinical knowledge (p<0.039), convinced on interventions (p<0.017), low concern for precipitating eating disorders (p<0.019), comfortable in examining obese patients (p<0.020), and considered patient's readiness for weight change (p< 0.007). Efforts are needed to equip PHC physicians in managing overweight and obesity in Saudi children and adolescents.


Microsomal activation of chlordane isomers to derivatives that irreversibly interact with cellular macromolecules.
Incubation of 14C-labeled cis and trans isomers of chlordane with cofactor-fortified mouse hepatic microsomes resulted in binding of insecticide-derived material to endogenous protein and RNA and to added DNA. The microsomes were prepared from male C57BL/6J mice. Chlordane is known to cause hepatocellular carcinoma in a similar strain. The highest concentrations of radioactive material bound to protein, followed by RNA and DNA. The cis isomer produced greater amounts of bound radioactivity, while binding from trans-chlordane was slight and, in the case of DNA, not detectable. Investigation of the effect of microsomal enzyme induction by chlordane isomers and phenobarbital on the yield of bound, chlordane-derived material gave mixed results. Generally, use of induced microsomes increased binding to protein and DNA and had no effect on binding to RNA. The inducers caused increased mixed-function oxidase activity, cytochrome P-450 content, and epoxide hydratase activity in experimental microsomes. Omission of the NADPH generating system from microsomal preparations had a variable effect on binding. Inhibition of epoxide hydratase reduced cis-chlordane-related binding to DNA to unmeasurable levels.


Enhanced detection of sphingoid bases via divalent ruthenium bipyridine complex derivatization and electrospray ionization tandem mass spectrometry.
Sphingoid bases, such as unsaturated sphingosine (So) and its corresponding dihydro-saturated species sphinganine (Sa), are present in cell samples in low abundance. This fact combined with their low-to-moderate electrospray ionization (ESI) potential, compared to other sphingolipids such as sphingomyelins, limits their detection and quantitation by liquid chromatography-tandem mass spectrometry (LC-MS(2)). To enhance the ESI efficiency of sphingoid bases, a novel procedure to generate stably derivatized analytes that enhance the LC-MS(2) detection of sphingoid bases when analyzed using LC-MS(2) was developed. In this method, a ruthenium complex, [4-(N-succimidyloxycarbonyl propyl)-4'-methyl-2,2'-bipyridine] bis(2,2'-bipyridine) Ru(II) dihexafluorophosphate, is added directly to a cell extract. This complex reacts with and covalently binds to an amino group within the sphingoid bases. The dicationic nature of the ruthenium ion enhances the compound's ionization efficiency resulting in increased LC-MS(2) signals for the derivatized sphingoid bases. Consequently, the detection and quantitation of sphingoid bases are greatly improved.


IMRAS-Immunization with radiation-attenuated Plasmodium falciparum sporozoites by mosquito bite: Cellular immunity to sporozoites, CSP, AMA1, TRAP and CelTOS.
Immunization with radiation-attenuated sporozoites (RAS) by mosquito bites provides >90% sterile protection against Plasmodium falciparum malaria in humans. We conducted a clinical trial based on data from previous RAS clinical trials that suggested that 800-1200 infected bites should induce ~50% protective vaccine efficacy (VE) against controlled human malaria infection (CHMI) administered three weeks after the final immunization. Two cohorts were immunized separately. VE was 55% in Cohort 1 but 90% in Cohort 2, the cohort that received a higher first dose and a reduced (fractional) fifth dose. Immune responses were better boosted by the fractional fifth dose in Cohort 2 and suggested the importance of the fractional fifth dose for increased protection in Cohort 2 responses. Three protected subjects were later boosted and were protected suggesting that protection could be extended to at least 67 weeks. The ex vivo FluoroSpot assay was used to measure peripheral IFN-γ, IL2, and IFN-γ+IL2 responses to PfNF54 sporozoites and malaria antigens CSP, AMA1, TRAP, and CelTOS using pools of synthetic overlapping 15mer peptides spanning each antigen. There was no correlation between IFN-γ, IL2, and IFN-γ+IL2 responses to sporozoites and protection, but fold-increases between post-4th and post-5th responses greater than 1.0 occurred mostly in protected subjects. IFN-γ and IL2 responses to TRAP, CelTOS and CSP occurred only in protected subjects. Peripheral IFN-γ, IL2, and IFN-γ+IL2 responses were short-lived and low by 27 weeks post-CHMI but were restored by boosting. These studies highlight the importance of vaccine dose and schedule for vaccine efficacy, and suggest that CSP, TRAP, AMA1 and CelTOS may be targets of protective immunity. The correlation between fold-increases in responses and protection should be explored in other vaccine trials. ClinicalTrials.gov NCT01994525.


Critical-point analysis for three-variable cancer angiogenesis models.
We perform critical-point analysis for three-variable systems that represent essential processes of the growth of the angiogenic tumor, namely, tumor growth, vascularization, and generation of angiogenic factor (protein) as a function of effective vessel density. Two models that describe tumor growth depending on vascular mass and regulation of new vessel formation through a key angiogenic factor are explored. The first model is formulated in terms of ODEs, while the second assumes delays in this regulation, thus leading to a system of DDEs. In both models, the only nontrivial critical point is always unstable, while one of the trivial critical points is always stable. The models predict unlimited growth, if the initial condition is close enough to the nontrivial critical point, and this growth may be characterized by oscillations in tumor and vascular mass. We suggest that angiogenesis per se does not suffice for explaining the observed stabilization of vascular tumor size.


Studies in asymptomatic primary hyperlipidaemia, III. Physical working capacity.
One-hundred-and-sixty male and 123 female subjects with asymptomatic primary hyperlipidaemia (HLP) selected from a health control centre have been studied with a heart rate (HR) controlled exercise test. Ther serum cholesterol and/or TG at screening were above 350 mg/100 ml and 3.5 mmol/l, respectively. As a reference group 49 male and 60 female age-matched subjects from the same centre with serum cholesterol below 300 mg/100 ml and TG below 2.00 mmol/l were investigated using the same technique. Quantitative lipoprotein (LP) analyses and typing were performed on all HLP and control subjects. The subjects were divided into two age groups, 36-50 and above 50 years of age. Men with all types of HLP had lower working capacity, expressed in W170 or W150, than controls, most pronounced in the younger age group. Younger women with type II A had lower working capacity than their controls. After correction for variation in body weight and age there remained a significantly lower W150, in male types II A (11%) and IV (21%) and female type II A (11%). There was no difference in systolic BP during exercise between controls and HLP. The total exercise time and final HR did not differ in control and HLP subjects. Dynamic spirometry was performed im 102 of the male subjects and a significantly lower vital capacity was found in HLP subjects compared with controls after correction for variation in age, weight and height. No differences were found in the maximal flow values. The observed differences in working capacity between controls and HLP subjects are explained by a difference in stroke volume. The lower stroke volumes in male types II A and IV and female type II A could be explained by a lower degree of physical fitness, by a common genetic factor resulting in HLP and decreased stroke volume or by a less effective myocardial function in HLP subjects.


Primary structure of the cytochrome P450 lanosterol 14 alpha-demethylase gene from Candida tropicalis.
We report the nucleotide sequence of the gene and flanking DNA for the cytochrome P450 lanosterol 14 alpha-demethylase (14DM) from the yeast Candida tropicalis ATCC750. An open reading frame (ORF) of 528 codons encoding a 60.9-kD protein is identified. This ORF includes a characteristic heme-binding domain, HR2, common to all P450 proteins. This protein and the 14DM from Saccharomyces cerevisiae share 66.5% identical and 23.1% conservatively replaced amino acids in a 516-amino-acid alignment, and thus are orthologous forms of the P450LIA1 gene. Conversely, C. tropicalis 14DM shares relatively little sequence similarity with P450alk, the predominant P450 protein present when this organism is grown on n-alkanes. Sequence information of these three yeast P450s will be useful for structure-function analyses in the future.


Unilateral grip fatigue reduces short interval intracortical inhibition in ipsilateral primary motor cortex.
This study was designed to examine whether exhaustive grip exercise of the left hand affected intracortical excitability in ipsilateral motor cortex. Ten healthy male subjects (aged 21-24 years) participated in experiment 1 in which paired-pulse transcranial magnetic stimulation (TMS) was used to test corticospinal and corticocortical excitability in right (relaxed) first dorsal interosseous (FDI) muscle during the recovery period after exhaustive forceful grip exercise of the left hand. Seven of the same subjects participated in experiment 2, in which the intensity of the test stimulus was adjusted so that the amplitude of motor evoked potential (MEP(TEST)) was kept constant throughout the measurement. In experiment 1, MEP(TEST) was slightly reduced from 5 to 15min after exercise whilst short interval intracortical inhibition (SICI) at interstimulus interval (ISI) of 2 and 3ms became less effective. Intracortical facilitation (ICF) was unchanged. In experiment 2 when the MEP(TEST) was maintained at a constant size there was again no change in ICF, and the reduction in SICI was still present at the same intervals. We conclude that unilateral exhaustive grip exercise reduced the excitability of the corticospinal output of the ipsilateral motor cortex whilst simultaneously reducing the excitability of SICI. These results would be compatible with the idea that fatigue increases the tonic level of interhemispheric inhibition from the fatigued to the non-fatigued cortex. Muscle fatigue to the point of exhaustion has lasting effects on the excitability of intracortical circuits in the non-exercised hemisphere, perhaps via changes in the tonic levels of activity in transcallosal pathways.


Chondrosarcoma of the skull base: long-term follow-up.
Chondrosarcoma of the skull base is an uncommon neoplasm comprising 0.15% of all intracranial tumors and 6% of skull base neoplasms. The outcome of treatment is difficult to assess because the slow growth rate means that there is a long interval before detecting the recurrence. We describe the use of lateral skull base techniques for these lesions and examine the long-term outcomes. The pathological features, radiological findings, and radiotherapy options are also discussed. Retrospective case review with current follow-up where possible. Tertiary referral neurotologic private practice. Eight patients with histologically confirmed skull base chondrosarcoma operated on since 1979. At the time of the surgery, the five women and three men ranged in age from 31 to 63 years, with a mean of 42.9 years. The follow-up ranged from 9 months to 25 years and 5 months. All patients underwent surgical removal; the earliest patient underwent surgical removal via transcochlear and retrosigmoid approaches, and seven via an infratemporal fossa approach, with or without exenteration of the otic capsule. Number of patients with residual and recurrent tumors. In the patient who underwent surgery via the transcochlear approach, recurrence was noted within 3 months, and new exploration using the retrosigmoid approach was performed for the removal of the recurrent lesion. This patient showed no signs of recurrence for 25 years since last surgery. Of the seven patients who underwent surgery via the infratemporal fossa approach, one had residual tumor found at 1 year, but remained alive and well for 21 years after the surgery. The other six had gross total resection and showed no signs of recurrence at the last known follow-up. One patient died as a result of an unrelated cause 18 years after surgery for the chondrosarcoma. The gross total resection of these lesions is possible because of the evolution of lateral skull base techniques and can be routinely accomplished with the infratemporal fossa approach. The improved exposure afforded by this approach seems to have resulted in more complete extirpation of the tumor and a decrease in the recurrence rate.


Doping-Free High-Performance Photovoltaic Effect in a WSe2 Lateral p-n Homojunction Formed by Contact Engineering.
Two-dimensional transition metal dichalcogenides (TMDs) are promising materials for semiconductor nanodevices owing to their flexibility, transparency, and appropriate band gaps. A variety of optoelectronic and electronic devices based on TMDs p-n diodes have been extensively investigated due to their unique advantages. However, improving their performance is challenging for commercial applications. In this study, we propose a facile and doping-free approach based on the contact engineering of a few-layer tungsten di-selenide to form a lateral p-n homojunction photovoltaic. By combining surface and edge contacts for p-n diode fabrication, the photovoltaic effect is achieved with a high fill factor of ≈0.64, a power conversion efficiency of up to ≈4.5%, and the highest external quantum efficiency with a value of ≈67.6%. The photoresponsivity reaches 283 mA/W, indicating excellent photodiode performance. These results demonstrate that our technique has great potential for application in next-generation optoelectronic devices.


Mass spectrometry-based proteomics in neurodegenerative lysosomal storage disorders.
The major function of the lysosome is to degrade unwanted materials such as lipids, proteins, and nucleic acids; therefore, deficits of the lysosomal system can result in improper degradation and trafficking of these biomolecules. Diseases associated with lysosomal failure can be lethal and are termed lysosomal storage disorders (LSDs), which affect 1 in 5000 live births collectively. LSDs are inherited metabolic diseases caused by mutations in single lysosomal and non-lysosomal proteins and resulting in the subsequent accumulation of macromolecules within. Most LSD patients present with neurodegenerative clinical symptoms, as well as damage in other organs. The discovery of new biomarkers is necessary to understand and monitor these diseases and to track therapeutic progress. Over the past ten years, mass spectrometry (MS)-based proteomics has flourished in the biomarker studies in many diseases, including neurodegenerative, and more specifically, LSDs. In this review, biomarkers of disease pathophysiology and monitoring of LSDs revealed by MS-based proteomics are discussed, including examples from Niemann-Pick disease type C, Fabry disease, neuronal ceroid-lipofuscinoses, mucopolysaccharidosis, Krabbe disease, mucolipidosis, and Gaucher disease.


Differential RNA fingerprinting as a tool in the analysis of spermatozoal gene expression.
The apparent decline in human male fertility and the concomitant increase in testicular pathology have prompted discussion of the underlying molecular mechanisms which may underpin these observations. While monitoring the expression of protamine-2 genes in the human ejaculate, we found a representative complement of sperm mRNAs following sequence-independent amplification of reverse-transcribed cDNAs with the polymerase chain reaction (RT-PCR). The revelation of unique sperm-derived PCR products using this method suggests that it should now be possible to investigate gene expression in human spermatogenesis by differential RNA fingerprinting of ejaculate spermatozoa. The identification of molecular markers and the corresponding genes associated with male infertility will be considerably enhanced by these investigations while obviating the requirement for invasive biopsy.


Long-acting beta-2 agonists. An attempted response to various questions which can be posed by pneumonologists.
The use of long acting beta 2 agonists is an undeniable improvement in the treatment of certain types of asthma. It enables better control of unstable asthma, improves and gives a superior quality of life. Current work confirms however that when used in the long term they ought to be associated with anti-inflammatory treatment. If they do not produce any important secondary effects, even when used for a long period, it is not currently possible to confirm that their prolonged use does not change the intensity of their bronchodilator effect and/or the intensity of the bronchodilator effect of the short acting beta 2 stimulants. Some studies have shown that their addition to basic treatment with inhaled steroids is more effective than increasing the inhaled steroids. Other studies are necessary to know if they may enable the reduction in inhaled corticosteroids and how far.


Asymptomatic cholelithiasis in children with sickle cell disease: early or delayed cholecystectomy?
Our study aimed to evaluate the role of elective laparoscopic cholecystectomy (LC) in children with sickle cell disease (SCD) and asymptomatic cholelithiasis and, furthermore, to determine whether the outcome is related to the operation timing. The records of 30 children with SCD diagnosed with cholelithiasis from June 1995 to September 2005 were retraspectively reviewed. All 30 children were asymptomatic at the time of the first visit, and an elective LC was proposed to all of them. The operation was accepted in the period of study by 16 children and refused by 14. During medical observation, 10 of the 14 children who refused surgery were admitted for severe biliary colics. Acute cholecystitis was diagnosed by abdominal ultrasound in 3 cases and in 1 case choledocholithiasis, ultrasonographically suspected, was confirmed by magnetic resonance cholangiopancreatography (MRCP) and treated during endoscopic retrograde cholangiopancreatography (ERCP). All children, emergency admitted, underwent LC after the onset of symptoms. The patients were divided up into 2 groups (A: asymptomatic; B: symptomatic) depending on clinical presentation and operation timing and the respective outcomes were compared. Elective LC in asymptomatic children (group A) is safe with no major complications reported. During medical observation in children who refused elective surgery (group B), 6 biliary colics, 3 acute cholecystitis, and 1 choledocholithiasis were observed. Three sickle cell crises occurred in symptomatic children during biliary colics. The correlation between cholecystectomy performed in asymptomatic children (group A) and cholecystectomy performed in symptomatic children (group B) showed significant differences in the outcome. Morbidity rate and postoperative stay increased when children with SCD underwent emergency LC. Elective LC should be the gold standard in children with SCD and asymptomatic cholelithiasis to prevent the potential complications of biliary colics, acute cholecystitis, and choledocholithiasis, which lead to major risks, discomfort, and longer hospital stay.


Volatile organic compounds from leaf litter decomposition alter soil microbial communities and carbon dynamics.
Investigations into the transfer of carbon from plant litter to underlying soil horizons have primarily focused on the leaching of soluble carbon from litter belowground or the mixing of litter directly into soil. However, previous work has largely ignored the role of volatile organic compounds (VOCs) released during litter decomposition. Unlike most leaf carbon, these litter-derived VOCs are able to diffuse directly into the soil matrix. Here, we used a 99-d microcosm experiment to track VOCs produced during microbial decomposition of 13 C-labeled leaf litter into soil carbon fractions where the decomposing litters were only sharing headspace with the soil samples, thus preventing direct contact and aqueous movement of litter carbon. We also determined the effects of these litter-derived VOCs on soil microbial community structure. We demonstrated that the litter VOCs contributed to all measured soil carbon pools. Specifically, VOC-derived carbon accounted for 2.0, 0.61, 0.18, and 0.08% of carbon in the microbial biomass, dissolved organic matter, mineral-associated organic matter, and particulate organic matter pools, respectively. We also show that litter-derived VOCs can affect soil bacterial and fungal community diversity and composition. These findings highlight the importance of an underappreciated pathway where VOCs alter soil microbial communities and carbon dynamics.


Topological, geometric, and chemical order in materials: insights from solid-state NMR.
Unlike the long-range order of ideal crystalline structures, local order is an intrinsic characteristic of real materials and often serves as the key to the tuning of their properties and their final applications. Although researchers can easily assess local ordering using two-dimensional imaging techniques with resolution that approaches the atomic level, the diagnosis, description, and qualification of local order in three dimensions is much more challenging. Solid-state nuclear magnetic resonance (NMR) and its panel of continually developing instruments and methods enable the local, atom-selective characterization of structures and assemblies ranging from the atomic to the nanometer length scales. By making use of the indirect J-coupling that distinguishes chemical bonds, researchers can use solid-state NMR to characterize a variety of materials, ranging from crystalline compounds to amorphous or glassy materials. In crystalline compounds showing some disorder, we describe and distinguish the contributions of topology, geometry, and local chemistry in ways that are consistent with X-ray diffraction and computational approaches. We give examples of materials featuring either chemical disorder in a topological order or topological disorder with local chemical order. For glasses, we show that we can separate geometric and chemical contributions to the local order by identifying structural motifs with a viewpoint that extends from the atomic scale up to the nanoscale. As identified by solid state NMR, the local structure of amorphous materials or glasses consists of well-identified structural entities up to at least the nanometer scale. Instead of speaking of disorder, we propose a new description for these structures as a continuous assembly of locally defined structures, an idea that draws on the concept of locally favored structures (LFS) introduced by Tanaka and coworkers. This idea provides a comprehensive picture of amorphous structures based on fluctuations of chemical composition and structure over different length scales. We hope that these local or molecular insights will allow researchers to consider key questions related to nucleation and crystallization, as well as chemically (spinodal decomposition) or density-driven (polyamorphism) phase separation, which could lead to future applications in a variety of materials.


Understanding attitudes towards tissue donation.
Nurses discussing organ or tissue donation with patients and their relatives need to be well informed. Tissue donation is not being optimised. The attitude of health professionals towards organ and tissue donation can influence the relatives' decision.


Serum Neuron-Specific Enolase Level as Predictor of Neurologic Outcome after Aortic Surgery.
This study aimed to evaluate the significance of serum neuron-specific enolase (NSE) level as a predictor of neurologic injury in thoracic aortic surgery. We neurologically assessed 60 consecutive patients who underwent thoracic aortic surgery for thoracic aortic aneurysm (n = 26) and aortic dissection (n = 34). Using moderate hypothermic circulatory arrest with antegrade cerebral perfusion, total arch replacement and hemiarch replacement were performed in 37 and 23 patients, respectively. Serum NSE levels in venous blood samples drawn before surgery and at 1 day after surgery were measured. Severity of neurologic injury was categorized as either uncomplicated (n = 48), temporary neurologic dysfunction (TND, n = 5), or permanent neurologic dysfunction (PND, n = 7). The extent of stroke was estimated on computed tomography or magnetic resonance imaging. The NSE level significantly differed among the three groups (PND > TND > uncomplicated) on the first postoperative day. Receiver-operating characteristic curve analysis showed that the cutoff value of NSE level was 34.14 ng/mL for neurologic injury (sensitivity, 0.769; specificity, 0.851) and 43.56 ng/mL for PND (sensitivity, 1.000; specificity, 0.963). The NSE level significantly correlated with the extent of stroke (r = 0.61, p < 0.001). Serum NSE level is a significant predictor of adverse neurologic outcomes and extent of stroke after thoracic aortic surgery.


Characterization of invasion plasmid antigen genes (ipaBCD) from Shigella flexneri.
The large invasion plasmid of Shigella flexneri M9OT-W was used to generate recombinant plasmids carrying the ipaA, -B, -C, and -D genes, whose products are associated with the entry of the bacteria into colonic epithelial cells. Complete DNA sequences of ipaB, -C, and -D were determined. The proteins predicted (62, 42, and 37 kDa, respectively) from the nucleotide sequences lack a signal-peptide sequence. Hydrophilic segments of the IpaB and IpaC proteins were found to overlap known epitopic domains of these membrane antigens. Analysis of total RNA demonstrated that temperature control of ipa gene expression occurs at the level of transcription. Multiple mRNA bands were detected by using ipa gene fragments as hybridization probes, and a putative transcript map for the ipa genes was constructed. Comparison of this map with the DNA sequence reveals a complex system of ipa gene regulation.


The Head Down Generation: Musculoskeletal Symptoms and the Use of Smartphones Among Young University Students.
Background: Smartphones offer a variety of mobile applications for diverse purposes and access to services that contribute to an increased time of interaction with the device, influencing the users' health and behavior.Introduction: The time of interaction with smartphones is more intense with the younger generation, and physical, psychological, and social complications are reported. This research aims at identifying the factors associated with musculoskeletal symptoms due to the use of smartphones in university students in Brazil.Materials and Methods: The study has a quantitative transversal type approach, with 522 college students between the ages 18 and 26. A structured questionnaire was applied in 2017, to characterize the sociodemographic profile, composed of information regarding the use of smartphones added to the Nordic questionnaire of musculoskeletal symptoms.Results: One of the main results found was a tendency for participants to have symptoms of musculoskeletal pain with regards to their typing methods on smartphones. When asked about the cases when such symptoms were considered to be related to the use of the device, most cited the cervical region (43.87% of cases). It was also found that those who type on their phones with the head at 45° and 60° angles are about twice as likely to have higher scores of severe symptoms than those typing with their neck at 0° (anatomical position).Conclusion: Within the university student population the typing position on a smartphone and time of use are associated with the presence of pain in the cervical region.


Determination of protein phosphorylation sites by mass spectrometry: a novel electrospray-based method.
Several methods are used to identify protein phosphorylation sites. We report a novel electrospray-based method for the determination of phosphorylation sites by mass spectrometry, using two different declustering potential values. This method allows one to obtain, with a single liquid chromatography/mass spectrometry (LC/MS) run, the pattern with either the phosphorylated or the unphosphorylated species of a protein tryptic digest, that can be further analyzed by tracing back the origin of each HPO3-deprived form using the capabilities of tandem mass spectrometers.


Sensitivity to interaural intensitive disparities: listeners' use of potential cues.
Thresholds for interaural intensitive disparities (IIDs) for a 500-Hz tone were measured in several stimulus conditions including those in which the use of intracranial position as a cue was effectively eliminated by roving the interaural temporal disparity of the stimuli. Removing position as a cue resulted in substantial degradation of sensitivity to IID. The overall patterning of the data suggests that threshold-IIDs measured in standard binaural paradigms that yield fused intracranial images reflect the use of changes in intracranial position. That is, comparisons among the data suggest that listeners' judgments depend upon binaural spatial cues and not on comparisons of the concomitant monaural increments and decrements in level, per se, that inevitably result from the imposition of IIDs.


General, regional or local anesthesia for successful radial cephalic arteriovenous fistula.
Autogenous fistulas and in particular radiocephalic fistulas are recommended as the first vascular access for hemodialysis. Unfortunately, the rates of early failure and non-maturation are very high. For more than a decade, brachial plexus block has been proposed as the anesthesia of choice for fistula creation due to its beneficial sympathectomy-like effect, causing vasodilation and attenuation of spasm. Until recently, there was not a single randomized clinical study supporting this proposition. Because performing regional anesthesia is time-consuming and requires expertise, many surgeons prefer local or general anesthesia for vascular access surgery. However, in August 2016 a randomized clinical trial was published showing that regional anesthesia significantly reduces early failure and improves primary and functional patency at 3 months compared to local anesthesia. The aging of the dialysis population, with their attendant morbidity and increased risk for general anesthesia, makes it clear that regional anesthesia is the recommended approach for fistula creation. The excess time required for this approach will decrease with increasing expertise along the learning curve, and will be compensated by a reduction in time that would otherwise be needed for new access construction due to failure of fistulas constructed under local anesthesia.


An annotated checklist of the leaf beetles (Coleoptera, Chrysomelidae) from El Salvador, with additions from the Bechyné collection in the Royal Belgian Institute of Natural Sciences.
A checklist of the species of leaf beetles (Coleoptera: Chrysomelidae) of El Salvador is presented based on data from literature and a digitization project of the Bechyné collection of the Royal Belgian Institute of Natural Sciences (RBINS). The RBINS collections contain a total of 2797 individual chrysomelid specimens from El Salvador, sorted into 89 species and 132 genera. In total, the current checklist contains 420 species, of which 33 are new records for El Slavador from the Bechyné collection. In these collections, there are also ten nomina nuda named by Bechyné, which need further study. The leaf beetle diversity in El Salvador, partly due to the country's unstable political history, remains poorly studied, and many (new) species await discovery. This checklist provides a baseline for further study in El Salvador and nearby region.


Quantifying potential health impacts of cadmium in cigarettes on smoker risk of lung cancer: a portfolio-of-mechanisms approach.
This article introduces an approach to estimating the uncertain potential effects on lung cancer risk of removing a particular constituent, cadmium (Cd), from cigarette smoke, given the useful but incomplete scientific information available about its modes of action. The approach considers normal cell proliferation; DNA repair inhibition in normal cells affected by initiating events; proliferation, promotion, and progression of initiated cells; and death or sparing of initiated and malignant cells as they are further transformed to become fully tumorigenic. Rather than estimating unmeasured model parameters by curve fitting to epidemiological or animal experimental tumor data, we attempt rough estimates of parameters based on their biological interpretations and comparison to corresponding genetic polymorphism data. The resulting parameter estimates are admittedly uncertain and approximate, but they suggest a portfolio approach to estimating impacts of removing Cd that gives usefully robust conclusions. This approach views Cd as creating a portfolio of uncertain health impacts that can be expressed as biologically independent relative risk factors having clear mechanistic interpretations. Because Cd can act through many distinct biological mechanisms, it appears likely (subjective probability greater than 40%) that removing Cd from cigarette smoke would reduce smoker risks of lung cancer by at least 10%, although it is possible (consistent with what is known) that the true effect could be much larger or smaller. Conservative estimates and assumptions made in this calculation suggest that the true impact could be greater for some smokers. This conclusion appears to be robust to many scientific uncertainties about Cd and smoking effects.


Adaptation of the clinical trials directive: recommendations on the contents of a dossier for the request for authorisation of the first trials in human subjects.
The European Directive on clinical trials of medicinal products will fall within the scope of the legislation of Member States on 1 May 2004. In France, this adaptation will be carried out by a public health bill concerning, among other things, the reform of the current Huriet-Sérusclat law, and by means of regulations. For trials concerning the initial administration of a product to human subjects, the group suggested the following recommendations: In French texts, to include a deadline of 30 days for the initial authorisation by the competent authority (Afssaps [Agence française de sécurité sanitaire des produits de santé]). To maintain an observed deadline of 20 days (35 official days) for the decision of the Ethics Committee (EC) [Committee for the Protection of Persons (CPP)]. To obtain a more specific evaluation of the pharmaceutical dossier of the investigational medicinal product (IMP) from the competent authority. To provide both bodies with nonclinical and possibly clinical data concerning the IMP information of the participants and their consent. To follow the recommendations posted on the Afssaps website for the entire IMP dossier. To submit a protocol under the International Committee on Harmonisation (ICH) E6 format adapted for phase I and, possibly as a separate document, justification of a certain number of points (a total of ten) that are more specific to this trial phase to facilitate and improve the document review while also providing the expected guarantees. To limit the 'substantial' amendments to those provided for in the European guidelines. To break the blind for every serious event reported to the sponsor by the investigator, and report to the competent authority any serious adverse event related to the IMP or to the trial or without documented cause, while keeping ECs and investigators informed. Furthermore, certain points concerning the authorisations for packaging, labelling and dispensing of the batches of medicinal products for clinical trials will need to be specified for these early studies. All these recommendations are intended to help promote the development of studies involving the initial administration of medicinal products in France.


Effect of captopril at two different dosage regimens in hypertensive non-insulin dependent patients.
Thirty patients (21 F, 9 M) of mean age 55.3 years with non-insulin dependent diabetes mellitus of mean duration 10.8 years and hypertension (blood pressure 160/95 mm Hg) of 0.3 to 4.0 years were randomly allocated to either a twice daily regimen of captopril (50 mg twice daily, Group A) or a once daily captopril schedule (50 mg once daily, Group B). Good glycaemic control (HbA1c, mean 7.63%) had been achieved with sulphonylureas in 22 patients and insulin in 8 patients. There were no statistical differences in baseline values between the two groups. For the 15 patients in Group A, blood pressure fell significantly from a baseline of 177 +/- 13.2/106 +/- 7.8 mm Hg to 161 +/- 14.3/91 +/- 6.9 after one month (P less than 0.05) and continued to decrease at 3 and 6 months. In Group B the blood pressure changed from 179 +/- 19.0/110 +/- 15.6 to 169 +/- 21.0/98 +/- 7.2 at 1 month (P less than 0.05) with further reductions again seen at 3 and 6 months. Nine patients had poorer response than the other 21 but there were no demographic differences between these subgroups nor were there any differences in plasma renin activity or aldosterone responses. There were no statistically significant changes in haematological or biochemical values in either group during treatment. In particular, HbA1c and fasting glucose were unaffected by captopril treatment. No side effects were encountered during the 6 months of follow-up. In conclusion, captopril is an effective antihypertensive in non-insulin dependent diabetes mellitus with mild to moderate hypertension and a once daily regimen could improve compliance.


Quantitative proteomics reveals new insights into calcium-mediated resistance mechanisms in Aspergillus flavus against the antifungal protein PgAFP in cheese.
The ability of Aspergillus flavus to produce aflatoxins in dairy products presents a potential hazard. The antifungal protein PgAFP from Penicillium chrysogenum inhibits various foodborne toxigenic fungi, including Aspergillus flavus. However, PgAFP did not inhibit A. flavus growth in cheese, which was related to the associated cation content. CaCl2 increased A. flavus permeability and prevented PgAFP-mediated inhibition in potato dextrose broth (PDB). PgAFP did not elicit any additional increase in permeability of CaCl2-incubated A. flavus. Furthermore, PgAFP did not alter metabolic capability, chitin deposition, or hyphal viability of A. flavus grown with CaCl2. Comparative proteomic analysis after PgAFP treatment of A. flavus in calcium-enriched PDB revealed increased abundance of 125 proteins, including oxidative stress-related proteins, as determined by label-free mass spectrometry (MS)-based proteomics. Seventy proteins were found at lower abundance, with most involved in metabolic pathways and biosynthesis of secondary metabolites. These changes do not support the blockage of potential PgAFP receptors in A. flavus by calcium as the main cause of the protective role. A. flavus resistance appears to be mediated by calcineurin, G-protein, and γ-glutamyltranspeptidase that combat oxidative stress and impede apoptosis. These findings could serve to design strategies to improve PgAFP activity against aflatoxigenic moulds in dairy products.


Ultrahigh activity and broad temperature resistance of amine-imine cobalt precatalysts for butadiene polymerization.
A series of amine-imine cobalt complexes (Co1-Co7) has been prepared and characterized. The complexes Co3, Co4, and Co6 have a distorted tetrahedral geometry, as determined by single crystal X-ray diffraction. In the presence of ethylaluminum sesquichloride (EASC), Co3 exhibited ultra-high activity toward butadiene (Bd) polymerization (up to 7813 kgpolymer mol-1 h-1). The activity is higher than any yet recorded for which yield high cis-1,4 polybutadiene by the well-defined late-transition metal catalytic system. The catalyst also exhibited excellent tolerance towards the ratio of Co/Bd and broad temperature stability. At a ratio of Bd/Co3 = 50 000, the complexes Co1-3 can afford polybutadiene with yields higher than 96% within 2 hours. At -20 °C to 100 °C, the complex Co3 afforded relatively high polymer yields at low catalyst concentrations (Bd/Co3 = 25 000). In addition, all polymers showed a relatively high molecular weight (up to 1.06 × 106 g mol-1).


[Carbon storage of forest stands in Shandong Province estimated by forestry inventory data].
Based on the 7th forestry inventory data of Shandong Province, this paper estimated the carbon storage and carbon density of forest stands, and analyzed their distribution characteristics according to dominant tree species, age groups and forest category using the volume-derived biomass method and average-biomass method. In 2007, the total carbon storage of the forest stands was 25. 27 Tg, of which the coniferous forests, mixed conifer broad-leaved forests, and broad-leaved forests accounted for 8.6%, 2.0% and 89.4%, respectively. The carbon storage of forest age groups followed the sequence of young forests > middle-aged forests > mature forests > near-mature forests > over-mature forests. The carbon storage of young forests and middle-aged forests accounted for 69.3% of the total carbon storage. Timber forest, non-timber product forest and protection forests accounted for 37.1%, 36.3% and 24.8% of the total carbon storage, respectively. The average carbon density of forest stands in Shandong Province was 10.59 t x hm(-2), which was lower than the national average level. This phenomenon was attributed to the imperfect structure of forest types and age groups, i. e., the notably higher percentage of timber forests and non-timber product forest and the excessively higher percentage of young forests and middle-aged forest than mature forests.


Preconditioning: the mitochondrial connection.
Over the past decade there has been considerable progress in elucidating the signaling pathways involved in cardioprotection. Considerable recent data suggest that many of these signaling pathways converge on the mitochondria, where such pathways alter the activity of key mitochondrial proteins, leading to reduced apoptosis and necrosis. Inhibition of the mitochondrial permeability transition pore is emerging as a central mechanism in cardioprotection. This review focuses on mechanisms by which cardioprotection alters mitochondrial proteins and channels that regulate cell death and survival.


Modeling and experiments of O-band transmission over G.654.C optical fiber.
We address the potential application of G.654.C optical fiber for O-band transmission in the wavelength range of 1270 nm to 1330 nm. Fiber samples at the extreme upper end of the cable cutoff manufacturing distribution are chosen for modeling and experimentation. Modeling of multipath interference (MPI) generation in bend conditions representative of cable deployment suggests minimal to negligible penalty and transmission experiments at 100 Gb/s and 400 Gb/s with commercial IMDD transceivers demonstrate longer transmission with increased power margin compared to standard G.652 fiber due to lower O-band attenuation and no adverse impacts from MPI.


Improvement of the Process Stability of Arylmalonate Decarboxylase by Immobilization for Biocatalytic Profen Synthesis.
The enzyme arylmalonate decarboxylase (AMDase) enables the selective synthesis of enantiopure (S)-arylpropinates in a simple single-step decarboxylation of dicarboxylic acid precursors. However, the poor enzyme stability with a half-life time of about 1.2 h under process conditions is a serious limitation of the productivity, which results in a need for high catalyst loads. By immobilization on an amino C2 acrylate carrier the operational stability of the (S)-selective AMDase variant G74C/M159L/C188G/V43I/A125P/V156L was increased to a half-life of about 8.6 days, which represents a 158-fold improvement. Further optimization was achieved by simple immobilization of the cell lysate to eliminate the cost- and time intensive enzyme purification step.


A Case of Isolated Congenital Stapedial Suprastructure Fixation.
We report a case of conductive hearing loss caused by isolated congenital stapedial suprastructure fixation with normal footplate mobility. A 60-year-old woman visited the clinic for right-sided mixed hearing loss. Exploratory tympanotomy revealed a bony synostosis between the stapedial suprastructure and promontory, while all the ossicles were present and normally shaped. As the bony synostosis was separated, the stapes became mobile. This is the first report in the medical literature of this congenital ear anomaly. This case also illustrates that stapedial fixation can occur in the suprastructure as well as in the footplate; thus, one must be mindful of this when performing exploratory tympanotomy for stapes fixation.