The Effects of Fixed Versus Removable Orthodontic Retainers on Stability and Periodontal Health: 4-Year Follow-Up of a Randomized Controlled Trial.
Long-term or even indefinite retention is routinely prescribed after orthodontic treatment as a preventive safeguard against post-treatment changes induced by tooth movement, physiological healing, and the aging process. Though both fixed and removable versions of retainers may be equally effective in terms of results, sufficient research to support this assumption is missing at the moment. Long-term effects of fixed and removable retention on the periodontium, and the compliance level when used for an extended period of time. For 4 years participants were given a supply of canine-to-canine retainers and vacuum-formed canine-to-canine retainers. The inter-canine, as well as inter-molar widths, the length, and the extraction space opening of the mandibular anterior portion, were measured. Gingival inflammation, calculus, and plaque were observed, as well as the attachment of clinical and the case of bleeding during probing. 42 members had returned in the follow-up period, with 21 from each of the two groups. Measurements of the modified gingival index and plaque scoring were performed on the 10 intra-oral photographs that were taken at 4-week intervals in this study to investigate the intra-examiner reliability. After controlling for confounding variables, there was a 1.64 mm (95% confidence interval [CI], 0.30, 2.98 mm) median between-groups difference among patients who utilized vacuum-formed retainers (VFRs). The treatment groups did not vary in inter-canine and intermolar widths (P = 0.52; 95% CI, -1.07, 1.05), arch length (P = 0.99; 95% CI, -1.15, 1.14), or opening of extraction spaces (P = 0.84). A long-term study demonstrates that fixed retention can preserve the alignment of the mandibular anterior over time for the first time. Gingival discomfort and higher plaque scores were reported in both types of retainers.


Sexual stability in the nearly dioecious Pinus johannis (Pinaceae).
Even though dioecy is a dominant sexual system among gymnosperms, little is known about its evolutionary history. Pinus johannis may represent a model system because unisexual and monoecious individuals compose its populations. The presence of unisexual individuals in other Pinus species is a consequence of sexual lability. Here we determined whether P. johannis represents the first example of a dioecious or nearly dioecious reproductive system in conifers by evaluating its sexual stability. • To assess the stability of sexual expression, we quantified the proportion of male vs. female reproductive structures produced by trees over multiple years and tested for the presence of sexual dimorphism. Sexual lability hypotheses were also examined by looking at the relationship between environmental factors and sexual expression and by comparing the reproductive behavior of P. johannis with its closest labile relative, P. edulis. • Pinus johannis is nearly dioecious: ~99% of individuals are unisexual or express a low proportion of the opposite gender with few changes in sexual expression through time. We found sexual dimorphism consistent with sexual stability. Sexual expression did not vary with tree size/age, abiotic environment, or herbivore removal, providing evidence against sexual lability. Individuals of P. johannis tended to produce only male or female strobili, whereas those of P. edulis were mainly monoecious with a gradient in the female to male strobili ratio. • This study represents the first report of a nearly stable dioecious Pinus species. The variety of sexual morphs coexisting in the same population makes P. johannis a model for studying the evolution of dioecy in gymnosperms.


Accuracy of voice-announcement pedometers for youth with visual impairment.
Thirty-five youth with visual impairments (13.5 +/- 2.1 yrs, 13 girls and 22 boys) walked four 100-meter distances while wearing two units (right and left placement) of three brands of voice-announcement (VA) pedometers (Centrios Talking Pedometer, TALKiNG Pedometer, and Sportline Talking Calorie Pedometer 343) and a reference pedometer (NL2000). Registered pedometer steps for each trial were recorded, compared to actual steps assessed via digital video. Inter-unit agreement between right and left VA pedometer placement was low (ICC range .37 to .76). A systematic error was observed for the VA pedometers on the left placement (error range 5.6% to 12.2%), while right placement VA pedometers were at or below +/- 3% from actual steps (range 2.1% to 3.3%). The reference pedometer was unaffected by placement (ICC .98, error approximately 1.4%). Overall, VA pedometers demonstrated acceptable accuracy for the right placement, suggesting this position is necessary for youth with visual impairments.


Erythrocyte cholinesterase activity levels in desert farm workers.
In this study we have examined 532 migrant farm workers engaged mainly in the cultivation of vegetable crops, in both greenhouses and openfarms, and an equal number of controls. Erythrocyte acetylcholinesterase activity (AChE) was measured to determine the degree of toxicity due to exposure to organophosphate and carbamate pesticides in the farm workers employed either as foremen (41.5%) or farmers (58.5%). The mean ages of the farm workers and controls were 35.2 +/- 7.4 (mean +/- SD) years and 34.6 +/- 7.1 years. AChE activity of the farm workers and controls was 3.89 +/- 0.64 UI/ml (mean +/- SD) and 4.15 +/- 0.29 UI/ml. The haemoglobin adjusted erythrocyte cholinesterase activity (HAChE) was 29.96 +/- 4.14 (mean +/- SD) for farm workers and 32.10 +/- 2.26 for controls. AChE activity was very highly significantly lower for the foremen (3.76 +/- 0.69) compared to farmers (3.98 +/- 0.59) (Student's t-test = 4.13, p = 0.0001). HAChE was also very highly significantly lower for foremen (29.24 +/- 4.37) compared to farmers (30.46 +/- 3.88) (Student's t-test = 3.64, p = 0.0001). The poorly controlled used of pesticides in the farms appeared to have caused sub-clinical intoxication in the farm workers and indicated the need for training and implementation of hygiene practices.


[Glycoproteins and proteoglycans in the predentin and dentin matrix in the rat: an ultrastructural study].
The ultrastructural distribution of the protein-polysaccharides was studied in the predentinal and dentinal matrices of the rat. Used for the indentification of the glycoproteins, the chromic-phosphotungstic acid mixture (Rambourt, 1967) weakly contrasted the predentine, underlined the mineralization front and impregnated the dentinal matrix. Alcian blue (Goldberg et al., 1977) as well as bismuth nitrate (Serafini-Fracassini and Smith, 1966), cationic stains for the proteoglycans, produced a strong contrast in the predentine, whereas in the dentine, which appeared clear, only 100 to 150 A granules associated with the periodic collagen striations were stained. This inverse variation between non collagenous proteoglycans and glycoproteins is discussed in relation to the mineralization process.


Are root exudates more important than other sources of rhizodeposits in structuring rhizosphere bacterial communities?
This review evaluates the importance of root exudates in determining rhizosphere bacterial community structure. We present evidence that indicates that: (1) the direct influence of root exudates on rhizosphere bacterial communities is limited to small spatiotemporal windows related to root apices; (2) upon rapid assimilation by microorganisms, root exudates are modified, independent of plant influences, before rerelease into the rhizosphere by the microorganisms themselves--thus, at short distances from root apices, rhizosphere carbon pools are unlikely to be dominated by root exudates; and (3) many of the major compounds found in root exudates are ubiquitous in the rhizosphere as they are found in other pools of rhizodeposits and in microbial exudates. Following this argument, we suggest that the importance of root exudates in structuring rhizosphere bacterial communities needs to be considered in the context of the wider contribution of other rhizosphere carbon pools. Finally, we discuss the implications of rhizosphere bacterial distribution trends for the development of effective strategies to manage beneficial plant-microorganism interactions.


Biophysical properties of novel 1-deoxy-(dihydro)ceramides occurring in mammalian cells.
Ceramides and dihydroceramides are N-acyl derivatives of sphingosine and sphinganine, respectively, which are the major sphingoid-base backbones of mammals. Recent studies have found that mammals, like certain other organisms, also produce 1-deoxy-(dihydro)ceramides (1-deoxyDHCers) that contain sphingoid bases lacking the 1-hydroxyl- or 1-hydroxymethyl- groups. The amounts of these compounds can be substantial-indeed, we have found comparable levels of 1-deoxyDHCers and ceramides in RAW 264.7 cells maintained in culture. The biophysical properties of 1-deoxyDHCers have not yet been reported, although these lipids might play important roles in normal cell regulation and in the pathology of diseases in which they are elevated, such as hereditary sensory autonomic neuropathies or diabetes. This study uses several approaches, including surface-pressure measurements, differential scanning calorimetry, and confocal microscopy, to study the behavior of 1-deoxyDHCers of different N-acyl-chain lengths and their interaction with sphingomyelin (SM). The thermotropic behaviors of 1-deoxyDHCers alone and in mixtures with SM are described, together with their interactions in monolayers and giant unilamellar vesicles. The gel-fluid transition temperatures of the pure compounds increase in the order 1-deoxyceramide < ceramide ≈ 1-deoxyDHCer < 1-(deoxymethyl)DHCer. In general, canonical ceramides are more miscible with SM in bilayers than are 1-deoxyceramides, and 1-(deoxymethyl)DHCers are the most hydrophobic among them, not even capable of forming monolayers at the air-water interface. Thus, these properties suggest that 1-deoxyDHCer can influence the properties of cellular membranes in ways that might affect biological function/malfunction.


Reduced urine kallikrein excretion and antikaliuresis by chlorazanil in rats.
In normal conscious female Sprague-Dawley rats chlorazanil (3 mg/kg intraperitoneally) reduced urine kallikrein excretion by approximately 80%. Thus, urine kininogenase activity decreased from 54 +/- 5 U/kg/3 hrs to 10 +/- 2 U/kg/3 hrs and urine TAMe-esterase activity decreased from 34 +/- 1.5 mEU/kg/3 hrs to 7.4 +/- 1.0 mEU/kg/3 hrs. In addition kidney kallikrein content decreased by approximately 50% from 0.76 +/- 0.03 U/kidney to 0.40 +/- 0.07 U/kidney at three hours post treatment. Chlorazanil (3 mg/kg intraperitoneally) increased urine sodium excretion from 0.48 +/- 0.04 mmol/kg/3 hrs to 2.48 +/- 0.98 mmol/kg/3 hrs and decreased the potassium excretion from 1.06 +/- 0.45 mmol/kg/3 hrs to 0.29 +/- 0.09 mmol/kg/3 hrs. Comparable antikaliuretic doses of amiloride (5 mg/kg intraperitoneally) or triamterene (10 mg/kg orally) did not change urine kallikrein excretion It is suggested that chlorazanil inhibits kidney kallikrein synthesis perhaps by an innate antimineralocorticoid-like effect.


Establishing the global working group on Reproductive and Developmental Environmental Health (RDEH): practicum of a global resource.
Advocacy, training, and research for the prevention of adverse health effects from environmental exposure are the major foci of the International Federation of Gynecology and Obstetrics (FIGO) Reproductive and Developmental Environmental Health (RDEH) Working Group. A critical need for a consistent global effort to address these threats to human reproductive and developmental health was identified after the publication of influential committee opinions (ACOG, Obstet Gynecol, 2013; FIGO, Int J Gynaecol Obstet, 2015) and the assembling of the FIGO 2015 Pre-Congress Workshop, "Summit on Shaping Our Planetary Legacy: Setting an Agenda for Environmental Reproductive Health." RDEH's goals are to convene experts of diverse backgrounds to generate evidence-based knowledge and propose solutions to the increasing threats of harmful environmental chemicals to global human reproduction and development by prevention of harm through education, research, and advocacy. This practicum is a guide for establishing a global task force, such as FIGO RDEH, for developing collaboration among experts across disciplines and time zones, and for building accessible and vital databases.


Engeletin Protects Against TNF-α-Induced Apoptosis and Reactive Oxygen Species Generation in Chondrocytes and Alleviates Osteoarthritis in vivo.
Osteoarthritis (OA) is a progressive disease characterized by pain and impaired joint functions. Engeletin is a natural compound with anti-inflammatory and antioxidant effects on other diseases, but the effect of engeletin on OA has not been evaluated. This study aimed to elucidate the protective effect of engeletin on cartilage and the underlying mechanisms. Chondrocytes were isolated from rat knee cartilage, and TNF-α was used to simulate OA in vitro. After treatment with engeletin, the expression of extracellular matrix (ECM) components (collagen II and aggrecan) and matrix catabolic enzymes (MMP9 and MMP3) was determined by Western blotting and qPCR. Chondrocyte apoptosis was evaluated using Annexin V-FITC/PI and flow cytometry. Apoptosis-related proteins (Bax, Bcl-2, and cleaved caspase-3) were evaluated by Western blotting. The mitochondrial membrane potential of chondrocytes was measured with JC-1, and intracellular reactive oxygen species (ROS) levels were determined with DCFH-DA. Changes in signaling pathways (Nrf2, NF-κB and MAPK) were evaluated by Western blotting. In vivo, anterior cruciate ligament transection (ACLT) was used to induce the rat OA model, and engeletin was administered intraarticularly. The therapeutic effect of engeletin was analyzed by histopathological analysis. Pretreatment with engeletin alleviated TNF-α-induced inhibition of ECM components (collagen II and aggrecan) and upregulation of matrix catabolic enzymes (MMP9 and MMP3). Engeletin ameliorated chondrocyte apoptosis by inhibiting Bax expression and upregulating Bcl-2 expression. Engeletin maintained the mitochondrial membrane potential of chondrocytes and scavenged intracellular ROS by activating the Nrf2 pathway. The NF-κB and MAPK pathways were inhibited by treatment with engeletin. In vivo, ACLT-induced knee OA in rats was alleviated by intraarticular injection of engeletin. Engeletin ameliorated OA in vitro and in vivo. It may be a potential therapeutic drug for OA.


Preparation of Highly Concentrated Uniform-Sized Silver Nanoparticles via Use of Thermoresponsive Zwitterionic Surfactants.
Despite the popular use of citrate for the reduction of silver ions, this process suffers from slow crystal growth and broad size distribution. The rapid and effective synthesis of highly concentrated and stable spherical silver nanoparticles (AgNPs) confined in the surfactant-rich phase of thermoresponsive 3-(alkyldimethylammonio)-propyl sulfate surfactants obtained after reaction with citrate ions at high temperature is described. The present approach using the zwitterionic surfactant offers an alternative rapid approach for production of AgNPs and an in situ phase separation step that serves to "extract" and concentrate the AgNPs in the surfactant-rich phase. Almost all (synthetic yield 99.9%, extraction efficiency 98.6%) of the synthesized AgNPs with a diameter of 21.0 ± 2.5 nm were incorporated into the phase-separated surfactant-rich phase at pH 11, and the capacity (maximum concentration) was 3.4 × 1013 particles/mL. The AgNPs were stable upon long-term storage (at least 3 months).


Alkalization of dissolving cellulose pulp with highly concentrated caustic at low NaOH stoichiometric excess.
We present a quantitative study, using Raman spectroscopy combined with multivariate data analysis, to determine the degree of activation of softwood sulphite dissolving cellulose pulp by aqueous sodium hydroxide. We have chosen industrially relevant conditions, including low stoichiometric ratio of NaOH/Anhydroglucose Unit (AGU)<2 and highly concentrated caustic (≥45% w/w [NaOH]). A design of experiments is used to investigate the effects of simultaneous variation of a set of key parameters on the degree of activation (i.e. transformation to alkali cellulose, denoted as DoA): (a) the NaOH/AGU stoichiometric ratio, denoted (r); (b) the concentration of NaOH, denoted [NaOH]; (c) temperature, denoted (T); and (d) reaction time, denoted (t). Solid-state 13C CP/MAS NMR spectroscopy was applied to investigate the reproducibility of the experiments and to select the range for (t). According to the model, (r) is found to have a statistically significant effect on DoA (increasing from DoA=6-30% at the lowest (r)=0.8, to DoA=48-87% at the highest (r)=1.8), together with [NaOH]. The influence of [NaOH] depends strongly on (r). The other studied variables are found to be insignificant in the model and has a complicated influence on the activation. In particular, (T) is found to be unimportant in the studied range (30-60°C), but increasing (t) from 5 to 25min shows a positive influence on DoA, depending on both (r) and [NaOH]. A mercerisation mechanism that is controlled by diffusion is proposed to explain these phenomena.


Long term radiographic study of bilateral second premolars with immature root treated by apexogenesis and apexification.
A ten-year-old girl broke the central cusps of the mandibular second premolars. The mandibular right second premolar was treated with apexification and the left with apexogenesis. These methods were chosen in view of the presented clinical symptoms, radiographic findings, and outcome of bacterial cultures of root canal samples. At postoperative 2 years 8 months, disappearance of the focus, closure of the root canal, and formation of the root apex were observed in both mandibular premolars. The mandibular left second premolar demonstrated a nearly normal root formation and root apex morphology. Immediately beneath the extracted pulp, regular, uniform, and thick hard tissue was formed. Meanwhile, in the mandibular right second premolar, root growth was suspended, making the root short, and the contour was constructed in such a way that it encircled the distal apical area from the mesial side forming the root apex.


Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies.
Central Nervous System (CNS) homeostasis and function rely on intercellular synchronization of metabolic pathways. Developmental and neurochemical imbalances arising from mutations are frequently associated with devastating and often intractable neurological dysfunction. In the absence of pharmacological treatment options, but with knowledge of the genetic cause underlying the pathophysiology, gene therapy holds promise for disease control. Consideration of leukodystrophies provide a case in point; we review cell type - specific expression pattern of the disease - causing genes and reflect on genetic and cellular treatment approaches including ex vivo hematopoietic stem cell gene therapies and in vivo approaches using adeno-associated virus (AAV) vectors. We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future.


Population regulation of territorial species: both site dependence and interference mechanisms matter.
Spatial patterns of site occupancy are commonly driven by habitat heterogeneity and are thought to shape population dynamics through a site-dependent regulatory mechanism. When examining this, however, most studies have only focused on a single vital rate (reproduction), and little is known about how space effectively contributes to the regulation of population dynamics. We investigated the underlying mechanisms driving density-dependent processes in vital rates in a Mauritius kestrel population where almost every individual was monitored. Different mechanisms acted on different vital rates, with breeding success regulated by site dependence (differential use of space) and juvenile survival by interference (density-dependent competition for resources). Although territorial species are frequently assumed to be regulated through site dependence, we show that interference was the key regulatory mechanism in this population. Our integrated approach demonstrates that the presence of spatial processes regarding one trait does not mean that they necessarily play an important role in regulating population growth, and demonstrates the complexity of the regulatory process.


Harnessing the CD1 restricted T cell response for leukemia adoptive immunotherapy.
Disease recurrence following chemotherapy and allogeneic hematopoietic cell transplantation is the major unmet clinical need of acute leukemia. Adoptive cell therapy (ACT) with allogeneic T lymphocytes can control recurrences at the cost of inducing detrimental GVHD. Targeting T cell recognition on leukemia cells is therefore needed to overcome the problem and ensure safe and durable disease remission. In this review, we discuss adoptive cells therapy based on CD1-restricted T cells specific for tumor associated self-lipid antigens. CD1 molecules are identical in every individual and expressed essentially on mature hematopoietic cells and leukemia blasts, but not by parenchymatous cells, while lipid antigens are enriched in malignant cells and unlike to mutate upon immune-mediated selective pressure. Redirecting T cells against self-lipids presented by CD1 molecules can thus provide an appealing cell therapy strategy for acute leukemia that is patient-unrestricted and can minimize risks for GVHD, implying potential prognostic improvement for this cancer.


Dicarbonyl/L-xylulose reductase (DCXR) producing xylitol regulates egg retention through osmolality control in Caenorhabditis elegans.
To support life, the osmolality of the cellular fluid is tightly regulated by various means, including osmolyte control. Dicarbonyl/L-xylulose reductase (DCXR) is a highly conserved enzyme reducing L-xylulose to xylitol, which serves as an effective osmolyte in various mammalian and human tissues such as lung epithelium, sperm, and lens. DHS-21 is the only DCXR ortholog in Caenorhabditis elegans, and DCXR null mutant worms accumulate eggs in the uterus. However, it has been unknown how and why the mutant worms impair egg retention. In this study, we tested whether the egg-retention in dhs-21 (jh129), the DCXR null mutant worm, is sensitive to changes in osmolarity. Low osmolality reverted the egg retention phenotype of dhs-21(jh129), while high osmolarity aggravated it. Also, knock-down of either one of osr-1, osm-7, or osm-11, osmoregulatory genes, also rescued egg-retention phenotypes of the null mutants. The study indicates that DCXR functions in fluid homeostasis by regulating cellular osmolality in C. elegans and provides insights into DCXR-involved clinical conditions, such as congenital cataracts and malfunctioning lung and kidney.


Observation of the Unconventional Photon Blockade.
We observe the unconventional photon blockade effect in quantum dot cavity QED, which, in contrast to the conventional photon blockade, operates in the weak coupling regime. A single quantum dot transition is simultaneously coupled to two orthogonally polarized optical cavity modes, and by careful tuning of the input and output state of polarization, the unconventional photon blockade effect is observed. We find a minimum second-order correlation g^{(2)}(0)≈0.37, which corresponds to g^{(2)}(0)≈0.005 when corrected for detector jitter, and observe the expected polarization dependency and photon bunching and antibunching; close by in parameter space, which indicates the abrupt change from phase to amplitude squeezing.


Hoxa11 regulates stromal cell death and proliferation during neonatal uterine development.
Increasing evidence indicates that the Hoxa11 gene plays a critical role in the proper development of the uterus. In this report, we describe potential altered cellular processes in the developing uterus of Hoxa11 mutants. Histologic analysis demonstrates normal uterine morphology in Hoxa11 mutants as compared with controls at the newborn stage and d 7 after birth. Stromal tissue was moderately reduced in the Hoxa11 mutant uterus by d 14 after birth and was absent by d 21 after birth. There is decreased cellular proliferation in the Hoxa11 mutant uterus both at 7 and 14 d after birth. Terminal deoxyribonucleotide transferase-mediated deoxyuridine triphosphate nick-end labeling analysis demonstrates that apoptosis was markedly increased in the Hoxa11 mutant uterus at d 14 after birth. p27 is decreased in the Hoxa11 mutant as evidenced by real-time PCR. Epidermal growth factor receptor expression is dramatically decreased as evidenced by both real-time PCR and immunohistochemistry results. These findings suggest that Hoxa11 is required for proper cellular proliferation and apoptotic responses in the developing neonatal uterus and that the regulation of epidermal growth factor receptor is critical to these processes.


Loop-Mediated Isothermal Amplification for Detection of the 5.8S Ribosomal Ribonucleic Acid Internal Transcribed Spacer 2 Gene Found in Trypanosoma brucei gambiense.
The loop-mediated isothermal amplification (LAMP) assay with its advantages of cost effectiveness, rapidity, and simplicity, has evolved as a sensitive and specific method for the detection of African trypanosomes. Highly sensitive LAMP reactions specific for Trypanosoma brucei rhodesiense or that recognize but do not discriminate between Trypanosoma brucei brucei, T. b. rhodesiense, Trypanosoma brucei gambiense, and Trypanosoma evansi have been developed. A sensitive LAMP assay targeting the T. b. gambiense 5.8S ribosomal RNA internal transcribed spacer 2 (5.8S-ITS2) gene is also available but this assay does not target binding sites that span the CCCA (C3A) (557-560 bps) insertion site that further differentiates T. b. gambiense from T. b. brucei Here we describe 5.8S-ITS2-targeted LAMP assay that fit these criteria. The LAMP primer sets containing the T. b. gambiense-specific C3A tetranucleotide at the start of the outer forward primer sequences showed high specificity and sensitivity down to at least 0.1 fg T. b. gambiense genomic DNA.


[Severe paroxysmal drug eruptions].
Some drug reactions showing cutaneous expression exhibit a paroxysmal course. These diseases encompass the toxic epidermal necrolysis, the drug hypersensitivity syndrome, and the acute generalized exanthematic pustulosis. These syndromes are associated with dismal outcome. They represent medical emergencies needing hospitalization in specialized care units.


Cardiovascular Screening for the Asymptomatic Patient with Diabetes: More Cons Than Pros.
Diabetes mellitus is associated with an increased risk of coronary heart disease (CHD) morbidity and mortality. Although it frequently coexists with other cardiovascular disease (CVD) risk factors, it confers an increased risk for CVD events on its own. Coronary atherosclerosis is generally more aggressive and widespread in people with diabetes (PWD) and is frequently asymptomatic. Screening for silent myocardial ischaemia can be applied in a wide variety of ways. In nearly all asymptomatic PWD, however, the results of screening will generally not change medical therapy, since aggressive preventive measures, such as control of blood pressure and lipids, would have been already indicated, and above all, invasive revascularization procedures (either with percutaneous coronary intervention or coronary artery bypass grafting) have not been shown in randomized clinical trials to confer any benefit on morbidity and mortality. Still, unresolved issues remain regarding the extent of the underlying ischaemia that might affect the risk and the benefit of revascularization (on top of optimal medical therapy) in ameliorating this risk in patients with moderate to severe ischaemia. The issues related to the detection of coronary atherosclerosis and ischaemia, as well as the studies related to management of CHD in asymptomatic PWD, will be reviewed here.


Acute myocardial infarction associated to DPP-4 inhibitors.
Diabetes mellitus is associated with cardiovascular disease. Anti-diabetic therapy has a limited capability (if any) of changing the incidence of either death or major cardiovascular disease, and cardiovascular safety concerns have been raised. We aimed at identifying episodes of acute myocardial infarction associated to a relatively new class of drugs, dipeptidyl peptidase-4 inhibitors. Retrospective study: from 954 admissions (15 month period) in the coronary care unit, we selected 200 admissions corresponding to 196 patients with myocardial infarction and diabetes. 35 of these patients were receiving therapy with dipeptidyl peptidase-4 inhibitors (the vast majority, in association to metformin). We evaluated the peak plasma cardiac troponin I as the main study parameter. Patients on dipeptidyl peptidase-4 inhibitors therapy had a mean peak cardiac troponin plasma level of 50.2±121.3 ng/ml (n=35), the corresponding value for insulin being 39.2±108.4 ng/ml (n=56), for metformin the value was 45.8±97.3 ng/ml (n=93) and for sulfonylureas, 42.4±77.7 ng/ml (n=52). None of these values differed significantly from the corresponding control group of patients not taking each class of drug. The linear regression study also yielded a negative result relating therapy with dipeptidyl peptidase-4 inhibitors and peak troponin values. Acute myocardial infarctions associated to dipeptidyl peptidase-4 inhibitors varied widely in the clinical characteristics of the patients. We found no evidence that peak plasma troponin I was different between patient with acute myocardial infarction and use of dipeptidyl peptidase-4 inhibitors when compared to cases not under such therapy.


Risky and rushed public crack cocaine smoking: the potential for supervised inhalation facilities.
Despite the multitude of public health and community harms associated with crack cocaine use, little is known about factors associated with smoking crack in public and related risks such as rushed public crack smoking. Data were derived from two prospective cohort studies of people who use illicit drugs in Vancouver, Canada between 2010 and 2014. Multivariable generalized estimating equations were used to identify the prevalence and correlates of public crack smoking and rushed public crack smoking. In total, 1085 participants who had smoked crack in the prior six months were eligible for the analysis, of which 379 (34.9 %) reported always or usually smoking crack in public in the previous six months at some point during the study period. Factors positively and independently associated with public crack smoking included public injection drug use (adjusted odds ratio [AOR]: 5.42, 95 % confidence interval [CI]: 3.76-7.82), homelessness (AOR: 3.48, 95 % CI: 2.77-4.36), at least daily crack use (AOR: 2.69, 95 % CI: 2.19-3.31), crack pipe sharing (AOR: 1.98, 95 % CI: 1.60-2.46), drug dealing (AOR: 1.59, 95 % CI: 1.30-1.94), recent incarceration (AOR: 1.47, 95 % CI: 1.09-1.98), noticing police presence when buying or using drugs (AOR: 1.30, 95 % CI: 1.06-1.60), and younger age (AOR: 1.03, 95 % CI: 1.01-1.04). Rushed public crack smoking, which was reported by 216 (28.8 %) of 751 participants who had smoked crack in public at least once during the study period, was positively and independently associated with homelessness (AOR: 2.61, 95 % CI: 1.96-3.49), at least daily crack use (AOR: 1.48, 95 % CI: 1.11-1.98), crack pipe sharing (AOR: 1.44, 95 % CI: 1.10-1.89), drug dealing (AOR: 1.39, 95 % CI: 1.04-1.86), and younger age (AOR: 1.02, 95 % CI: 1.01-1.04). A high prevalence of public crack smoking and rushed public crack smoking was observed in this setting. These findings point to the need for implementing and evaluating evidence-based public health interventions, such as supervised inhalation facilities, to reduce the risks and harms associated with smoking crack in public.


Regulated expression and function of the somatodendritic catecholamine neurotransmitter transporters.
Termination of neurotransmission at catecholaminergic synapses is well documented by the transporters for dopamine and norepinephrine, members of the Na(+)/Cl(-)-dependent neurotransmitter transporter family, which accumulates released transmitters within their nerve endings, respectively. Although somatodendritic expression of the transporters and the effects of cocaine and amphetamine on those have been reported, their role is still obscure. Recent findings of the transporter function as an ion channel and/or its reverse transport property provide a clue to identify the role of these transporters in the somatodendrites and their consequential interaction with uptake inhibitors. Differences in ionic environment and maturity of the release machinery in the somatodendrites at developmental stages influence the transporter functions, resulting in the formation of both positive and negative feedback loop of catecholaminergic neurons.


A rare intrahepatic portacaval tubular shunt in a patient with spastic paraparesis.
Although there are numerous communications between the portal and systemic venous systems, intrahepatic portosystemic venous shunts are not frequently encountered in clinical practice. Here we report a patient who presented with spastic paraparesis, who was found to have chronic liver disease with tubular intrahepatic portacaval shunting.


Adherence to disease-modifying drugs in patients with multiple sclerosis: a consensus statement from the Middle East MS Advisory Group.
Adherence to therapy is a key issue in chronic illnesses. In addition, several features of multiple sclerosis (MS) and its treatment may increase the likelihood of patient nonadherence and discontinuation of treatment. Nonadherence will obviously compromise the efficacy of disease-modifying drugs in patients with MS. This subject was discussed by a group of local MS specialists from the Middle East. The group debated several key questions about the features and causes of patient nonadherence and its management. Further, they made recommendations for optimizing treatment adherence in this area.


Immunogenic properties of mannose-containing ceramide tetrasaccharide from fresh-water bivalve, Hyriopsis schlegelii.
Antiserum against GlcNAc beta 1----2Man alpha 1----3Man beta 1----4Glc beta 1----1Cer (MlOse4Cer), a mannolipid isolated from spermatozoa of the fresh-water bivalve Hyriopsis schlegelii, was elicited in rabbits by repeated injection of a mixture of hapten-bovine serum albumin with Freund's adjuvant. The specificity of the affinity-purified antibody obtained from the serum was based on two forms of enzyme-immunodetection of its binding to structurally related glycolipids, either adsorbed to microtiter plates or chromatographed on thin-layer plates. The purified antibody exhibited a significant cross-reactivity with GlcNAc beta 1----2Man alpha 1----3(Xyl beta 1----2)Man beta 1----4Glc beta 1----1Cer, (MIXOse5Cer) containing a core structure closely related to MlOse4Cer, but almost unrelated to other glycolipids. Distribution of MlOse4Cer and MlXOse5Cer in various bivalve and snail glycolipid extracts were screened in thin-layer immunobinding assays by using this purified specific antibody. The presence of the glycolipid antigens was limited to certain taxonomic orders of shellfish species.


Structure of the Schizosaccharomyces pombe Gtr-Lam complex reveals evolutionary divergence of mTORC1-dependent amino acid sensing.
mTORC1 is a protein kinase complex that controls cellular growth in response to nutrient availability. Amino acid signals are transmitted toward mTORC1 via the Rag/Gtr GTPases and their upstream regulators. An important regulator is LAMTOR, which localizes Rag/Gtr on the lysosomal/vacuole membrane. In human cells, LAMTOR consists of five subunits, but in yeast, only three or four. Currently, it is not known how variation of the subunit stoichiometry may affect its structural organization and biochemical properties. Here, we report a 3.1 Å-resolution structural model of the Gtr-Lam complex in Schizosaccharomyces pombe. We found that SpGtr shares conserved architecture as HsRag, but the intersubunit communication that coordinates nucleotide loading on the two subunits differs. In contrast, SpLam contains distinctive structural features, but its GTP-specific GEF activity toward SpGtr is evolutionarily conserved. Our results revealed unique evolutionary paths of the protein components of the mTORC1 pathway.


Misonidazole combined with radiotherapy in the treatment of non-small cell lung cancer. A randomized double-blind trial.
Forty-one patients with inoperable non-small cell lung cancer were randomized to receive irradiation therapy 45 Gy in ten fractions over eight weeks, plus either placebo or misonidazole 1.2 g/m2 orally on treatment day. The irradiated area was the primary tumour. Twenty-one patients received misonidazole and 20 received placebo. Minimal observation time for the study was 36 months. No clear difference was observed in the pattern of relapse between the groups. 43% of the patients in the misonidazole group attained a complete response (CR) or partial response (PR) as compared with 65% in the placebo group. Median survival time was twelve months in the misonidazole group and 14 months in the placebo group.


Contributions to a Brazilian Code of Conduct for Fieldwork in Geology: an approach based on Geoconservation and Geoethics.
When considering the numerous events that have prohibited the development of scientific projects or caused destruction of outcrops, it is clear that there is rapidly increasing necessity to define a Brazilian Code of Conduct for geological fieldwork. In general, this destruction is attributed to lack of knowledge as to the relevance of geological sites. The aim of this Code of Conduct is to guide geologists to adopt good practices during geoscience activities. Proposed guidelines are based on Codes of Conduct from other countries, mainly Scotland and England, on situations described in papers and on the personal experience of the authors. In this paper 29 points are suggested, in order to guarantee that fieldwork is conducted in accordance with geoethics, geoconservation and sustainability values. The proposal is structured in three parts: (1) Behavior and practices in respect to local traditions and providing information to the population; (2) Measures to minimize degradation on outcrops; and (3) Safety. The proposal seeks to broaden the debate on the need for responsible behavior during fieldwork, in order to promote respect for geodiversity. Through this code, Brazilian geoscientists will be able to contribute to the conservation of geological heritage and of outcrops with special educational relevance.


Lactic acidosis expediting a diagnosis of acute lymphoblastic leukaemia.
We report the finding of a low venous bicarbonate and lactic acidosis in a patient with mild pancytopenia which raised the suspicion of haematological malignancy and expedited the diagnosis of acute lymphoblastic leukaemia. This report highlights the value of testing for lactic acidosis when haematological malignancies are considered and reviews the metabolism of lactic acidosis.


Impact of naled on honey bee Apis mellifera L. survival and productivity: aerial ULV application using a flat-fan nozzle system.
A study was conducted to evaluate the impact of naled on honey bees as a result of their exposure to aerial ULV applications of this insecticide during three routine mosquito spray missions by Manatee County Mosquito Control District in Florida during the summer of 1999. Naled deposits were collected on filter paper and subsequently analyzed by gas chromatography. Mortality of adult honey bees Apis mellifera L. was estimated based on numbers from dead bee collectors placed in front of the entrance of the beehives. We found that honey bees clustering outside of the beehives were subject to naled exposure. Bee mortality increased when higher naled residues were found around the hives. The highest average naled deposit was 6,227 +/- 696 microg/m2 at the site 1 forest area following the mosquito spray mission on July 15, 1999. The range of naled deposition for this application was 2,818-7,101 microg/m2. The range of dead bees per hive was 0-39 prior to spraying and 9-200 within 24 h following this spray mission. The average yield of honey per hive was significantly lower (p < 0.05) for naled-exposed hives compared with unexposed hives. Because reduction of honey yield also may be affected by other factors, such as location of the hives relative to a food source and vigor of the queen bee, the final assessment of honey yield was complicated.


[Contrast ultrasound imaging in focal liver lesions: diagnostic value and guidelines].
The recent introduction of high quality scanners and contrast agents for ultrasound deeply modifies diagnosis strategy in focal liver lesions by using validated criteria. Non-linear imaging methods using low mechanical index (MI<0.2) and second generation contrast agents allow real-time continuous imaging with concomitant limitation in background tIssue signal and also in agent collapse for a high quality contrast imaging giving dramatic improvement in detection and characterization of lesions. Interpretation is based on the presence of contrast agent within the lesion or not (hyper-, hypo- or isosignal) and the delay after injection (arterial, portal or parenchymal or late phase) as previously used by non-ultrasound methods. This allows an easy differentiation of benign from malignant lesions. Moreover, this allows complete characterization in 85 to 95% of all focal liver lesions and 75% in hepatocellular carcinomas. Those results markedly improve ultrasound accuracy compared to conventional sonography and so put contrast-enhanced sonography among recommended non-invasive imaging methods for focal liver lesions with changes in diagnostic strategy according to the lesion type and actual place of US methods. It is recommended to use contrast ultrasound methods in cancer staging for an optimal detection of liver metastases as well as in characterization of lesions detected during conventional sonography with a consecutive decrease of cost-diagnosis ratio.


Determination of the total nitrogen content of hard, semihard, and processed cheese by the Kjeldahl method: collaborative study.
The objective of this collaborative study was to determine interlaboratory performance statistics for a modified and optimized version of AOAC Method 920.123 for the determination of the total nitrogen content of hard, semihard, and processed cheese by Kjeldahl analysis. Details included addressing the issues of material homogeneity, test portion size (1 g), quantitative transfer (weighing on to filter paper), ensuring system suitability (nitrogen recoveries), and using AOAC Method 991.20 as the basis for nitrogen analysis. Fifteen laboratories tested 18 pairs of blind duplicate cheese materials with a crude protein content between 18 and 36%. Materials represented hard, semihard, and processed commercial cheeses with a wide range of composition. Statistical performance parameters expressed as crude protein (nitrogen x 6.38), g/100 g, with invalid and outlier data removed were mean = 26.461, repeatability standard deviation (Sr) 0.111, reproducibility standard deviation (S(R)) = 0.153, repeatability relative standard deviation (RSDr) = 0.42%, reproducibility relative standard deviation (RSDR) = 0.58%, repeatability (r) = 0.312, and reproducibility (R) = 0.428. The interlaboratory study results were acceptable and comparable to those for the milk Kjeldahl nitrogen method on a relative nitrogen basis. The Study Directors recommend that this modified method for the determination of total nitrogen in hard, semihard, and processed cheese by Kjeldahl analysis be adopted First Action as an improved method to replace Method 920.123.


A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) Study.
The development of inhibitory antibodies to factor VIII is a serious complication of hemophilia. FEIBA (factor VIII inhibitor-bypassing activity), an activated prothrombin complex concentrate (aPCC), and NovoSeven, recombinant factor VIIa (rFVIIa), are used as hemostatic bypassing agents in treating patients with inhibitors. The FENOC study was designed to test equivalence of the products in the treatment of ankle, knee, and elbow joint bleeding. A prospective, open-label, randomized, crossover, equivalency design was used. The parameters of interest were the percentage of patients who reported efficacy in response to FEIBA and the percentage that reported efficacy in response to NovoSeven. A difference in these percentages of no more than 15% was determined to be a clinically acceptable magnitude for equivalence of the 2 products. The primary outcome was evaluation 6 hours after treatment. Data for 96 bleeding episodes contributed by 48 participants were analyzed. The criterion for declaring the 2 products equivalent at 6 hours was not met; however, the confidence interval of the difference in percentages of efficacy reported for each product only slightly exceeded the 15% boundary (-11.4%-15.7%), P=.059. FEIBA and NovoSeven appear to exhibit a similar effect on joint bleeds, although the efficacy between products is rated differently by a substantial proportion of patients. This trial was registered at www.clinicaltrials.gov as #NCT00166309.


Milk fatty acids. I. Variation in the concentration of individual fatty acids in bovine milk.
Data from 29 published experiments on Holstein cows, providing 120 dietary treatments, were collated to obtain means, standard deviations, and ranges for the concentrations (mg/g) of 26 major individual fatty acids in bovine milk fat. The influence of diet type (total mixed ration- vs. pasture-based diet) on concentrations of individual fatty acids was examined. Pairwise correlations for concentrations (g/kg) of individual fatty acids in milk showed that almost all of the individual de novo fatty acids were significantly correlated with each other and with the total concentration of de novo fatty acids. Concentrations of individual unsaturated preformed fatty acids were generally positively correlated with each other but were negatively correlated with concentrations of total de novo fatty acids. Substantial variation was found in the concentrations of individual milk fatty acids and, apart from those synthesized de novo, concentrations of individual fatty acids did not vary in concert. The adequacy of literature data for the development of a model to predict the production of the major individual fatty acids in milk is discussed. The limitations associated with the currently available studies that may be used in a predictive model are 1) failure of many publications to adequately describe dietary details, 2) reporting poorly defined milk fatty acids, 3) aggregating a number of closely related fatty acids under a single category, and 4) the selective reporting of only those fatty acids that are present in milk fat in appreciable quantities. Despite these limitations, the data are sufficient to enable development of a model to predict the concentrations and production of major individual fatty acids in milk fat. The extreme variability in concentrations of individual milk fatty acids and the complex matrix of positive and negative correlations among the concentrations of many individual fatty acids suggest that separate equations will be needed to predict the production of each individual milk fatty acid.


Palladium-Catalyzed Aminocarbonylation of Allylic Alcohols.
A benign and efficient palladium-catalyzed aminocarbonylation reaction of allylic alcohols is presented. The generality of this novel process is demonstrated by the synthesis of β,γ-unsaturated amides including aliphatic, cinnamyl, and terpene derivatives. The choice of ligand is crucial for optimal carbonylation processes: Whereas in most cases the combination of PdCl2 with Xantphos (L6) gave best results, sterically hindered substrates performed better in the presence of simple triphenylphosphine (L10), and primary anilines gave the best results using cataCXium® PCy (L8). The reactivity of the respective catalyst system is significantly enhanced by addition of small amounts of water. Mechanistic studies and control experiments revealed a tandem allylic alcohol amination/C-N bond carbonylation reaction sequence.


Comparison of Plantar Pressure Distribution Between Postoperative Hallux Valgus Feet and Healthy Feet.
Proximal crescentic osteotomy (PCO) in patients with moderate-to-severe hallux valgus (HV) is a well-established and effective procedure for correcting the deformity. However, there are no published studies comparing plantar pressure in postoperative HV feet with healthy feet. This study aimed to compare the plantar pressure distribution in postoperative HV feet with healthy feet. Twenty-six patients were included in the HV group, and 24 healthy participants were included in the control (C) group. All patients in the HV group underwent unilateral PCO. After undergoing PCO, this group was defined as the OP group. All subjects were women with no significant differences in age, height, weight, and body mass index. There were no significant differences in demographic characteristics between patients in each group. We divided the subjects' feet into 8 regions and measured the peak pressure (Peak-P), maximum force (Max-F), contact time, contact area, and the force-time integral in each region. All parameters of the great toe were significantly higher in the OP group than in the HV group. All forefoot parameters were not significantly different between the 2 groups. No parameter of the great toe was significantly different between the OP and C groups. However, mean Peak-P and Max-F of the central forefoot were significantly higher in the OP group than in the C group. PCO can improve the plantar pressure of the great toe in patients with moderate-to-severe HV to a level similar to that in healthy subjects. Level III, comparative study.


A Smart Power Electronic Multiconverter for the Residential Sector.
The future of the grid includes distributed generation and smart grid technologies. Demand Side Management (DSM) systems will also be essential to achieve a high level of reliability and robustness in power systems. To do that, expanding the Advanced Metering Infrastructure (AMI) and Energy Management Systems (EMS) are necessary. The trend direction is towards the creation of energy resource hubs, such as the smart community concept. This paper presents a smart multiconverter system for residential/housing sector with a Hybrid Energy Storage System (HESS) consisting of supercapacitor and battery, and with local photovoltaic (PV) energy source integration. The device works as a distributed energy unit located in each house of the community, receiving active power set-points provided by a smart community EMS. This central EMS is responsible for managing the active energy flows between the electricity grid, renewable energy sources, storage equipment and loads existing in the community. The proposed multiconverter is responsible for complying with the reference active power set-points with proper power quality; guaranteeing that the local PV modules operate with a Maximum Power Point Tracking (MPPT) algorithm; and extending the lifetime of the battery thanks to a cooperative operation of the HESS. A simulation model has been developed in order to show the detailed operation of the system. Finally, a prototype of the multiconverter platform has been implemented and some experimental tests have been carried out to validate it.


Acute Thyroiditis and Bilateral Optic Neuritis following SARS-CoV-2 Vaccination with CoronaVac: A Case Report.
To describe a case of acute thyroiditis and bilateral optic neuritis associated with SARS-CoV-2 vaccination. A single case report from a tertiary referral center. The patient described in the following case report developed acute thyroiditis and bilateral optic neuritis following SARS-CoV-2 vaccination. The patient underwent pulse therapy followed by oral tapering corticosteroid therapy with an improvement of the bilateral disc swelling and the visual field, and recovery of thyroid-stimulating hormone to the normal limits. Although the association between immunization and the onset of demyelinating manifestations of the central nervous system is well documented, this is the first reported case of bilateral optic neuritis and acute thyroiditis and subsequent to administration of vaccination against SARS-CoV-2.


Caring for children with new medical technology at home: parental perspectives.
This qualitative descriptive study explores the experiences of family caregivers (FCs) of children with medical complexity who are initiated on new medical technology in the hospital and transition to new daily life at home. The study aims to investigate FCs' response and readiness for medical technology use, the value of education and transition support and the challenges associated with managing new medical technology in the home. A qualitative descriptive approach was used to conduct and analyse 14 semistructured interviews with a group of FCs composed of 11 mothers and 3 fathers. Content analysis was used to analyse transcripts of the caregiver interviews. The study was conducted at a tertiary paediatric hospital in Toronto, Canada. Our study revealed three main themes: FC's response and readiness for medical technology use, the value of education and transition support for initiation of new medical technology and the challenges associated with managing new medical technology in the home. FCs expressed emotional distress related to coping with the realisation that their child required medical technology. Although the theoretical and hands-on practice training instilled confidence in families, FCs reported feeling overwhelmed when they transitioned home with new medical technology. Finally, FCs reported significant psychological, emotional and financial challenges while caring for their technology-dependent child. Our study reveals the unique challenges faced by FCs who care for technology-dependent children. These findings highlight the need to implement a comprehensive education and transition programme that provides longitudinal support for all aspects of care.


Histologically distinctive papular neutrophilic xanthomas in HIV-1 + patients.
Xanthomas may be associated with benign or malignant lymphoproliferative diseases, often with associated hypergammaglobulinema. In human immunodeficiency virus type 1 (HIV-1) disease, there is a high lymphoproliferative rate despite the immunodeficiency and increased cell death. We report three HIV-1-positive patients with facial papular xanthomatosis eruptions associated with hypergammaglobulinema, and an immunoglobulin A (IgA) gammopathy. Histopathologic features include lipid-laden macrophages, extracellular nuclear dust with phagocytosized nuclear debris, and hyalinization with areas of hyaline necrosis of collagen fibers. These distinctive papular xanthomas may be a marker of HIV-1 disease and of a pattern of immunodysregulation, immunodeficiency, and lymphoid proliferation seen in HIV-1 disease.


Insulin clearance is associated with carotid artery intima-media thickness.
The aim of this study was to investigate whether insulin clearance is independently associated with carotid artery intima-media thickness (IMT), a well-recognized index of vascular damage. 361 Non-diabetic Caucasian subjects were subjected to euglycemic hyperinsulinemic clamp to assess insulin sensitivity, and insulin clearance. IMT of the common carotid was measured by ultrasonography. Among the study group, 270 subjects had normal glucose tolerance, 33 had impaired fasting glucose, and 58 had impaired glucose tolerance. Univariate correlations showed that age, BMI, waist, blood pressure, triglycerides, fasting and 2-h post-load glucose and insulin levels were positively correlated with carotid IMT whereas HDL, insulin clearance, and insulin-stimulated glucose disposal were negatively correlated with IMT. A multivariate regression analysis in a model including, in addition to insulin clearance, age, gender, BMI, waist, blood pressure, triglycerides, HDL, fasting and 2-h post-load glucose, insulin-stimulated glucose disposal, fasting and 2-h post-load insulin showed that the traits independently associated with carotid IMT were BMI (β = 0.42, P < 0.0001), insulin clearance (β = -0.29, P < 0.0001), age (β = 0.19, P < 0.0001), waist (β = 0.18, P = 0.01), diastolic blood pressure (β = 0.17, P = 0.01), and 2-h post-load glucose (β = 0.12, P = 0.03). These factors explained 26% of the variance in carotid IMT. Subjects in the lowest tertile of insulin clearance had a 4.06-fold higher odds of having vascular damage (IMT > 0.9 mm) as compared with those in the highest tertile (OR 4.06, 95%CI 1.15-13.24). Insulin clearance is independently associated with carotid IMT in adult non-diabetic subjects. Individuals with lower levels of insulin clearance have a higher odds of vascular damage.


[Treatment and prevention of pneumococcal pneumonia].
Streptococcus pneumoniae is the most commonly identified pathogen in patients with community-acquired pneumonia. 40% of isolated strains in France are of decreased sensibility to penicillin, two third being multiresistant to antibiotics. However, high doses of some beta-lactams are effective in vivo against the majority of circulating strains (MIC > 2 mg/L). For this reason according to French guidelines amoxicillin (3 g/day) is the first line recommended treatment. Telithromycin is an alternative, or ceftriaxone (1 g/day) in more severe cases. If the level of resistance increases (MIC > 4 mg/L) guidelines would be revisited. Effectiveness of pneumococcal vaccination has been confirmed in cases of bacteriemic pneumococcal pneumonia (elderly patients included). Vaccine is recommended among persons with comorbiditie(s) and 65 years old population.


Metabolic studies in physically outstanding elderly men.
Forty-seven elderly men engaged in regular and vigorous exercise had significantly lower plasma insulin levels during oral glucose tolerance tests than their controls. Pasma-glucose and growth-hormone levels showed no difference. However, when the glucose tolerance test was extended to four hours follow up, for which 19 subjects of each group volunteered, the control subjects showed a blunted post-suppression recovery of growth-hormone secretion in comparison to the athletic group. This difference could be explained by differences in hypothalamic control of the pituitary.


Red Flags: Clinical Signs for Identifying Autoimmune Encephalitis in Psychiatric Patients.
Autoimmune mechanisms causing diverse psychiatric symptoms are increasingly recognized and brought about a paradigm shift in neuropsychiatry. Identification of underlying antibodies against neuronal ion channels or receptors led to the speculation that a number of patients go misdiagnosed with a primary psychiatric disease. However, there is no clear consensus which clinical signs in psychiatric patients should prompt further investigations including measurement of anti-neuronal autoantibodies. We therefore aimed to analyze the presenting symptoms in patients with autoimmune encephalitis and the time between symptom onset and initiation of antibody diagnostics. For this, we recruited 100 patients from the Charité Center for Autoimmune Encephalitis between May and October 2016, including all types of autoimmune encephalitides. Psychiatric abnormalities were the most common clinical symptoms and were the presenting sign in 60%. One-third of patients were initially hospitalized in a psychiatric ward. All patients positive for antibodies against the N-methyl-d-aspartate receptor showed behavioral changes, hallucinations, memory deficits, catatonia, or delusions. Patients positive for antibodies against other cell surface or intracellular antigens were often hospitalized with a psychosomatic diagnosis. The time between occurrence of first symptoms and antibody testing was often alarmingly prolonged. In patients with symptom onset between 2013 and 2016, the mean delay was 74 days, in cases diagnosed between 2007 and 2012 even 483 days, suggesting though that increased awareness of this novel disease group helped to expedite proper diagnosis and treatment. By analyzing the medical records in detail, we identified clinical signs that may help to assist in earlier diagnosis, including seizures, catatonia, autonomic instability, or hyperkinesia. Indeed, reanalyzing the whole cohort using these "red flags" led to a 58% reduction of time between symptom onset and diagnosis. We conclude that the timely diagnosis of an autoimmune psychiatric disease can be facilitated by use of the described clinical warning signs, likely enabling earlier immunotherapy and better prognosis. Also, the threshold for cerebrospinal fluid analysis and autoantibody testing should be low.


Renal artery anatomy affects the blood pressure response to renal denervation in patients with resistant hypertension.
Renal denervation (RDN) has been shown to reduce blood pressure (BP), muscle sympathetic nerve activity (MSNA) and target organ damage in patients with resistant hypertension (RH) and bilateral single renal arteries. The safety and efficacy of RDN in patients with multiple renal arteries remains unclear. We measured office and 24-hour BP at baseline, 3 and 6 months following RDN in 91 patients with RH, including 65 patients with single renal arteries bilaterally (group 1), 16 patients with dual renal arteries on either one or both sides (group 2) and 10 patients with other anatomical constellations or structural abnormalities (group 3). Thirty nine out of 91 patients completed MSNA at baseline and follow-up. RDN significantly reduced office and daytime SBP in group 1 at both 3 and 6 months follow-up (P<0.001) but not in groups 2 and 3. Similarly, a significant reduction in resting baseline MSNA was only observed in group 1 (P<0.05). There was no deterioration in kidney function in any group. While RDN can be performed safely irrespective of the underlying renal anatomy, the presence of single renal arteries with or without structural abnormalities is associated with a more pronounced BP and MSNA lowering effect than the presence of dual renal arteries in patients with RH. However, when patients with dual renal arteries received renal nerve ablation in all arteries there was trend towards a greater BP reduction. Insufficient renal sympathetic nerve ablation may account for these differences.


Influence of vitamin D status on vertebral fractures, bone mineral density, and bone turnover markers in normocalcemic postmenopausal women with high parathyroid hormone levels.
The aims of the study were to analyze whether there is an association between serum PTH and the prevalence of vertebral fractures and its possible dependence on vitamin D status, and to assess the influence of serum 25-hydroxyvitamin D (25OHD) in the relationship between PTH and bone mineral density (BMD) or bone turnover markers (BTMs). A total of 820 postmenopausal women were recruited after excluding those with any known condition that could influence serum PTH levels, except for a possible low serum 25OHD. Serum PTH and 25OHD concentrations, as well as vertebral fracture prevalence, BMD, and BTM (CTX and PINP) values were recorded. Serum PTH levels were divided into tertiles, and women were grouped into those in the highest tertile (>58 pg/ml) and those below. Serum 25OHD levels were stratified in 3 categories (<20, 20-30, and >30 ng/ml). Vertebral fracture prevalence was greater in women with PTH above 58 pg/ml (odds ratio [OR], 1.72; 95% confidence interval [CI], 1.04-2.84). After stratifying by 25OHD, this difference was only significant in women below 20 ng/ml (OR, 2.00; 95% CI, 1.02-3.87), those with 25OHD between 20 and 30 ng/ml showing a trend toward this (OR, 1.99; 95% CI, 0.92-4.36). Differences in BMD or BTM between women above and below 58 pg/ml of PTH were also observed only in those below 20 ng/ml. Elevated PTH levels are associated with increased prevalence of vertebral fractures, low bone mass, or higher BTM only in the presence of hypovitaminosis D. An adequate nutritional status in the vitamin appears to protect the bone from the deleterious effect of a high PTH.


Identification of neuronal subpopulations that project from hypothalamus to both liver and adipose tissue polysynaptically.
The autonomic nervous system regulates fuel availability and energy storage in the liver, adipose tissue, and other organs; however, the molecular components of this neural circuit are poorly understood. We sought to identify neural populations that project from the CNS indirectly through multisynaptic pathways to liver and epididymal white fat in mice using pseudorabies virus strains expressing different reporters together with BAC transgenesis and immunohistochemistry. Neurons common to both circuits were identified in subpopulations of the paraventricular nucleus of the hypothalamus (PVH) by double labeling with markers expressed in viruses injected in both sites. The lateral hypothalamus and arcuate nucleus of the hypothalamus and brainstem regions (nucleus of the solitary tract and A5 region) also project to both tissues but are labeled at later times. Connections from these same sites to the PVH were evident after direct injection of virus into the PVH, suggesting that these regions lie upstream of the PVH in a common pathway to liver and adipose tissue (two metabolically active organs). These common populations of brainstem and hypothalamic neurons express neuropeptide Y and proopiomelanocortin in the arcuate nucleus, melanin-concentrating hormone, and orexin in the lateral hypothalamus and in the corticotrophin-releasing hormone and oxytocin in the PVH. The delineation of this circuitry will facilitate a functional analysis of the possible role of these potential command-like neurons to modulate autonomic outflow and coordinate metabolic responses in liver and adipose tissue.


Candidemia in a tertiary care cancer center: in vitro susceptibility and its association with outcome of initial antifungal therapy.
Since the 1990s, changing trends have been documented in species distribution and susceptibility to bloodstream infections caused by Candida species in cancer patients. However, few data are available regarding the association between in vitro antifungal susceptibility and outcome of candidemia in this patient population. We therefore evaluated the association of in vitro antifungal susceptibility and other risk factors with failure of initial antifungal therapy in cancer patients with candidemia. Candidemia cases in cancer patients from 1998 to 2001 (n = 144) were analyzed retrospectively along with their in vitro susceptibility to amphotericin B, fluconazole, and itraconazole (National Committee for Clinical and Laboratory Standards M27-A method). Patients were evaluable for outcome analysis if they received continuous unchanged therapy with either fluconazole or amphotericin B for >/=5 days. We excluded cases of mixed candidemia. In vitro susceptibility testing data of the first Candida bloodstream isolate were analyzed. Appropriate therapy was defined as that using an active in vitro antifungal for >/=5 days. For fluconazole susceptible-dose dependent Candida species, we defined appropriate therapy as a fluconazole dose of >/=600 mg/day. The Candida species distribution was 30% Candida albicans, 24% Candida glabrata, 23% Candida parapsilosis, 10% Candida krusei, 9% Candida tropicalis, and 3% other. Overall, amphotericin B was the most active agent in vitro, with only 3% of the isolates exhibiting resistance to it (>1 mg/L). Dose-dependent susceptibility to fluconazole and itraconazole was seen in 13% and 21% of the isolates, respectively, while resistance to fluconazole and itraconazole was seen in 13% and 26%, respectively.Eighty patients were evaluable for outcome analysis. In multivariate analysis, the following factors emerged as independent predictors of failure of initial antifungal therapy: leukemia (p = 0.01), bone marrow transplantation (p = 0.006), and intensive care unit stay at onset of infection (p = 0.02). Inappropriate antifungal therapy, as defined by daily dose and in vitro susceptibility, was not shown consistently to be a significant factor (it was significant in multivariate analysis, p = 0.04, but not in univariate analysis), indicating the complexity of the variables that influence the response to antifungal treatment in cancer patients with candidemia.


Environmental Factors Affecting the Community of Methane-oxidizing Bacteria.
Methane-oxidizing bacteria (MOB) are ubiquitous and play an important role in the mitigation of global warming by reducing methane. MOB are commonly classified into Type I and Type II, belonging to Gammaproteobacteria and Alphaproteobacteria, respectively, and the diversity of MOB has been examined. However, limited information is currently available on favorable environments for the respective MOB. To investigate the environmental factors affecting the dominant type in the MOB community, we performed MOB enrichment using down-flow hanging sponge reactors under 38 different environmental conditions with a wide range of methane (0.01-80%) and ammonium concentrations (0.001-2,000 mg N L-1) and pH 4-7. Enrichment results revealed that pH was a crucial factor influencing the MOB type enriched. Type II was dominantly enriched at low pH (4-5), whereas Type I was dominant around neutral pH (6-7). However, there were some unusual cultivated biomass samples. Even though high methane oxidation activity was observed, very few or zero conventional MOB were detected using common FISH probes and primer sets for the 16S rRNA gene and pmoA gene amplification. Mycobacterium mostly dominated the microbial community in the biomass cultivated at very high NH4+ concentrations, strongly implying that it exhibits methane oxidation activity. Collectively, the present results revealed the presence of many unknown phylogenetic groups with the capacity for methane oxidation other than the reported MOB.


Transurethral procedures for lower urinary tract symptoms resulting from benign prostatic enlargement: a quality and meta-analysis.
Thanks to advancements in surgical techniques and instruments, many surgical modalities have been developed to replace transurethral resection of the prostate (TURP). However, TURP remains the gold standard for the surgical treatment of benign prostatic hyperplasia (BPH). We conducted a meta-analysis on the efficacy and safety of minimally invasive surgical therapies for BPH compared with TURP. This meta-analysis used a Medline search assessing the period from 1997 to 2011. A total of 784 randomized controlled trials were identified in an electronic search. Among the 784 articles, 36 randomized controlled trials that provided the highest level of evidence (level 1b) were included in the meta-analysis. We also conducted a quality analysis of selected articles. Only 2 articles (5.56%) were assessed as having a low risk of bias by use of the Cochrane collaboration risk of bias tool. On the other hand, by use of the Jadad scale, there were 26 high-quality articles (72.22%). Furthermore, 28 articles (77.78%) were assessed as high-quality articles by use of the van Tulder scale. Holmium laser enucleation of the prostate (HoLEP) showed the highest reduction of the International Prostate Symptom Score compared with TURP (P<0.0001). Bipolar TURP, bipolar transurethral vaporization of the prostate, HoLEP, and open prostatectomy showed superior outcome in postvoid residual urine volume and maximum flow rate. The intraoperative complications of the minimally invasive surgeries had no statistically significant inferior outcomes compared with TURP. Also, there were no statistically significant differences in any of the modalities compared with TURP. The selection of an appropriate surgical modality for BPH should be assessed by fully understanding each patient's clinical conditions.


Effects of early life stress on adult male aggression and hypothalamic vasopressin and serotonin.
Early life stress in humans enhances the risk for psychopathologies, including excessive aggression and violence. In rodents, maternal separation is a potent early life stressor inducing long-lasting changes in emotional and neuroendocrine responsiveness to stress, associated with depression- and anxiety-like symptoms. However, effects of maternal separation on adult male aggression and underlying neurobiological mechanisms remain unknown. Therefore, we investigated the effects of maternal separation on adult intermale aggression in Wistar rats and on hypothalamic arginine vasopressin (AVP) mRNA expression, and AVP and serotonin (5-HT) immunoreactivity, as both AVP and 5-HT have been implicated in stress-coping and aggression. We showed that maternal separation induced depression-like behaviour (increased immobility) and higher adrenocorticotropin hormone responses to an acute stressor (forced swimming). Intermale aggression (lateral threat, offensive upright and keep down) was significantly higher in maternally separated rats compared with control rats. AVP mRNA expression and AVP immunoreactivity were higher in the hypothalamic paraventricular and supraoptic nuclei upon resident-intruder test exposure, whereas 5-HT immunoreactivity was decreased in the anterior hypothalamus of maternally separated rats. Moreover, 5-HT immunoreactivity in the anterior hypothalamus and supraoptic nucleus correlated negatively with aggression. These findings show that exposure to early life stress increases adult male aggression in an animal model of maternal separation. Furthermore, the maternal separation-induced changes in hypothalamic AVP and 5-HT systems may underlie these behavioural alterations.


Eotaxin increases the expression of CD11b/CD18 and adhesion properties in IL5, but not fMLP-prestimulated human peripheral blood eosinophils.
A selective recruitment of eosinophils to sites of inflammation is claimed to be controlled by regulation of cytokines, chemokines and adhesion molecules. In animal models, eotaxin has been suggested to be a potent chemokine since it in cooperation with interleukin-5 induce selective chemotaxis and infiltration of eosinophils to lung tissue after an allergen provocation. We have investigated the in vitro effect of eotaxin on human peripheral blood eosinophils with respect to CD11b/CD18 expression and adhesion properties to the matrix protein fibronectin. We did not find any effect of eotaxin per se on CD11b/CD18 expression, neither on eosinophils from healthy subjects nor from patients with asymptomatic pollen related asthma. However, eotaxin significantly upregulated the quantitative level of CD11b/CD18 and increased the adhesion to fibronectin in eosinophils from healthy subjects preincubated in vitro with interleukin-5, but not in eosinophils preincubated with fMLP. Moreover, eosinophils harvested 24 hours after an in vivo allergen inhalation provocation in asthmatics, upregulated CD11b/CD18 after in vitro incubation with eotaxin alone.


Antimicrobial nanocapsules: from new solvent-free process to in vitro efficiency.
Skin and mucosal infections constitute recurrent pathologies resulting from either inappropriate antiseptic procedures or a lack of efficacy of antimicrobial products. In this field, nanomaterials offer interesting antimicrobial properties (eg, long-lasting activity; intracellular and tissular penetration) as compared to conventional products. The aim of this work was to produce, by a new solvent-free process, a stable and easily freeze-dryable chlorhexidine-loaded polymeric nanocapsule (CHX-NC) suspension, and then to assess the antimicrobial properties of nanomaterials. The relevance of the process and the physicochemical properties of the CHX-NCs were examined by the assessment of encapsulation efficiency, stability of the nanomaterial suspension after 1 month of storage, and by analysis of granulometry and surface electric charge of nanocapsules. In vitro antimicrobial activities of the CHX-NCs and chlorhexidine digluconate solution were compared by measuring the inhibition diameters of two bacterial strains (Escherichia coli and Staphylococcus aureus) and one fungal strain (Candida albicans) cultured onto appropriate media. Based on the findings of this study, we report a new solvent-free process for the production of nanomaterials exhibiting antimicrobial activity, suitable stability, and easily incorporable as a new ingredient in various pharmaceutical products.


Strategy in manipulating transglycosylation activity of glycosyl hydrolase for oligosaccharide production.
The increasing market demand for oligosaccharides has intensified the need for efficient biocatalysts. Glycosyl hydrolases (GHs) are still gaining popularity as biocatalyst for oligosaccharides synthesis owing to its simple reaction and high selectivity. Over the years, research has advanced mainly directing to one goal; to reduce hydrolysis activity of GHs for increased transglycosylation activity in achieving high production of oligosaccharides. This review concisely presents the strategies to increase transglycosylation activity of GHs for oligosaccharides synthesis, focusing on controlling the reaction equilibrium, and protein engineering. Various modifications of the subsites of GHs have been demonstrated to significantly modulate the hydrolysis and transglycosylation activity of the enzymes. The clear insight of the roles of each amino acid in these sites provides a platform for designing an enzyme that could synthesize a specific oligosaccharide product. The key strategies presented here are important for future improvement of GHs as a biocatalyst for oligosaccharide synthesis.


The Lingulodinium circadian system lacks rhythmic changes in transcript abundance.
Almost all cells display circadian rhythms, approximately 24-hour period changes in their biochemistry, physiology or behavior. These rhythms are orchestrated by an endogenous circadian clock whose mechanism is based on transcription-translation feedback loops (TTFL) where the translated products of clock genes act to inhibit their own transcription. We have used RNA-Seq to measure the abundance of all transcripts in an RNA-Seq-derived de novo gene catalog in two different experiments. One compared midday and midnight in a light-dark cycle (ZT6 and ZT18) and under constant light (CT6 and CT18). The second compared four different times (ZT2, ZT6, ZT14 and ZT18) under a light dark cycle. We show here that despite an elaborate repertoire of biological rhythms, the unicellular dinoflagellate Lingulodinium had no detectable daily variation in the abundance of any transcript in an RNA-Seq-derived de novo gene catalog. We also examined the timing of the bioluminescence and photosynthesis rhythms in the presence of the transcription inhibitors actinomycin D and cordycepin. We found that the timing of the two rhythms was unchanged even when transcription rates had decreased to roughly 5% the levels of untreated cells. The lack of detectable daily variation in transcript levels indicates that the endogenous circadian timer of Lingulodinium does not require rhythmic RNA. If the circadian timer is considered as a limit cycle oscillator, then cellular time in this organism must be defined by variations in state variables that do not include the amount of a clock gene transcript.


Identification of a 6-base pair element involved in the sterol-mediated transcriptional regulation of farnesyl diphosphate synthase.
Previous studies identified a 115-base pair (bp) region of the farnesyl diphosphate (FPP) synthase promoter which is involved in the transcriptional regulation of this gene by sterols (Spear, D. H., Kutsunai, S. Y., Correll, C. C., and Edwards, P. A. (1992) J. Biol. Chem. 267, 14462-14469). In the current study we fused a 117-bp fragment, containing this region of interest, upstream of the heterologous minimal promoter of the herpes simplex virus thymidine kinase gene linked to the chloramphenicol acetyltransferase (CAT) reporter gene. Chinese hamster ovary (CHO) cells were stably transfected with this fusion gene and incubated in the absence or presence of sterols. Analysis of CAT mRNA by primer extension indicated that transcription of the fusion gene was under sterol-mediated control. Thus, when cellular sterols were present, the CAT mRNA levels were reduced 2-4-fold. To further localize the FPP synthase sterol-responsive element(s), additional promoter-reporter gene constructs containing either deletions or mutations were constructed and transfected into CHO or CV-1 cells. These studies localized a 6-bp region (ATTGGC) that is required for both transcriptional induction in the absence of sterols and transcriptional repression in the presence of sterols. Gel shift and footprinting analyses demonstrated that nuclear proteins isolated from CHO cells bound to six distinct regions of the promoter between nucleotides -293 to -47. Taken together, these results further define both the cis-acting elements controlling normal transcription of the FPP synthase gene and identify a novel sequence involved in sterol regulation.


Soft-landed protein voltammetry: a tool for redox protein characterization.
Microperoxidase-11 (MP-11) was first soft landed onto the gold surface of a screen-printed electrode. Intact protein deposition was verified by time-of-flight secondary ion mass spectrometry. The coupling of soft landing with electrochemical techniques allowed unique information to be obtained about the deposition features. A full characterization of the direct electron-transfer properties was performed by modeling data obtained from cyclic voltammetry experiments; calculated values of kinetic electron-transfer constant, formal redox potential, and reorganization energy allow us to hypothesize the mechanism involved in soft landing immobilization and demonstrate the different conformation of the enzyme deposited from two different charged species. The strong interaction between MP-11 and the gold surface and long-term stability of the functionalized electrode characterizes the peculiar features of this procedure, which enhance its power with respect to the existing immobilization procedure and ensure its suitability for those practical applications that could benefit from an unmediated bridgeless bioeletrochemical electron transfer (e.g., biosensor transducers or electrode elements in biofuel cells).


Leptin induces mitogen-activated protein kinase-dependent proliferation of C3H10T1/2 cells.
Leptin, secreted by adipocytes, regulates satiety and energy expenditure. Several forms of leptin receptors produced by alternative mRNA splicing are found in many tissues, including the hypothalamus, liver, lung, kidney, hematopoietic cells, and gonads, suggesting that leptin exerts effects in these tissues. In accordance with the distribution of leptin receptors, there is accumulating evidence that leptin plays various roles in reproduction, hematopoiesis, and the immune systems in addition to the regulation of food intake and energy expenditure. In the present study, we examined the in vitro effects of leptin on proliferation of a mouse embryonic cell line, C3H10T1/2, and its mechanism of action. Leptin caused a dose- and time-dependent increase in mitogen-activated protein kinase (MAPK) activity that was accompanied by an increase in C3H10T1/2 cell number. The MAPK kinase-1-specific inhibitor PD98059 completely blocked the increases in both MAPK activity and cell proliferation caused by leptin. These findings indicate that leptin stimulates the proliferation of C3H10T1/2 cells via the MAPK cascade.


YC-1 Inhibits VEGF and Inflammatory Mediators Expression on Experimental Central Retinal Vein Occlusion in Rhesus Monkey.
To investigate the therapeutic potential of YC-1 for experimental central retinal vein occlusion (CRVO) of rhesus monkey. Six adult rhesus monkeys were recruited in this study. Laser-induced CRVO was established in both eyes of all subjects. Intravitreal injection of YC-1 90 μl (200 μM with 0.01% dimethyl sulfoxide (DMSO) as vehicle) was administrated in right eye and 0.01% DMSO 90 μl in left eye respectively at 1 week after CRVO established. All eyes underwent routine examination at 1 day, 1 week, 2 week, and 1 month after intravitreal injection of YC-1 or DMSO. Meanwhile, vitreous fluid was collected at each time points to analyze concentration of VEGF, HIF-1α, IL-6, IL-8, and MCP-1 mediators by CBA or ELASA method. The experimental CRVO was successfully established in six rhesus monkeys. As expected, the thickness of macular edema significantly decreased at 1 week and 2 weeks after YC-1 injection compared with that of DMSO injection. Subsequently, the central macular thickness in all eyes was recovered to the initial levels at 1 month after photocoagulation. Intraocular pressure (IOP) was not significantly different between two groups during all follow up. Meanwhile, the concentration of IL-6, IL-8, VEGF, and HIF-1α in vitreous fluid significantly decreased after YC-1 injection compared with that of DMSO injection, MCP-1 was not significantly different between both groups. Intravitreal injection of YC-1 significantly alleviated macular edema compared with that of DMSO control group. Meanwhile, both inflammatory factors and angiogenesis-related factors expression were inhibited in vitreous by YC-1 injection.


Targeting TRP ion channels for itch relief.
Acute itch (pruritus) is unpleasant and acts as an alerting mechanism for removing irritants. However, severe chronic itch is debilitating and impairs the quality of life. Rapid progress has been made in recent years in our understanding of the fundamental neurobiology of itch. Notably, several temperature-sensitive transient receptor potential (thermo-TRP) ion channels have emerged as critical players in many types of itch, in addition to pain. They serve as markers that define the itch neural pathway. Thermo-TRP ion channels are thus becoming attractive targets for developing effective anti-pruritic therapies.


[The diagnostic value of immunologic findings in the differentiation of chronic liver diseases].
Various types of virus induced and non-virus induced chronic active hepatitis (CAH) as well as chronic non-suppurative destructive cholangitis (PBC) and primary sclerosing cholangitis have to be distinguished. Classical autoimmune type "lupoid" CAH is characterized by antinuclear antibodies (ANA), liver membrane antibodies (LMA) and smooth muscle antibodies (SMA). A second subgroup of autoimmune type CAH is characterized by anti liver kidney-microsomal antibodies (LKM) which are directed against a specific cytochrome p-450 isoenzyme. A third subgroup of autoimmune type CAH is identified by auto-antibodies to a soluble cytoplasmic liver antigen (SLA). Autoimmune type CAH profits from immuno-suppressive therapy, i.e. corticosteroids alone or in combination with azathioprin. Chronic hepatitis B virus infection is nowadays treated with Interferon when HBV-DNA is detectable in serum, duration of liver disease is less than 5 years and superinfection with HDV and HIV can be excluded. PBC is diagnosed through the detection of antimitochondrial antibodies (AMA) and its PBC specific subtypes anti p 62 (M2) and anti p 48. Aetiology and pathogenesis of PBC are still unknown. Liver transplantation is an established therapy for endstage PBC. This is also true for primary sclerosing cholangitis (PSC).


Epidemic in pandemic: Fungal sinusitis in COVID-19.
To describe the clinical pattern of invasive fungal sinusitis in COVID-19 and post-COVID-19 cases. All patients affected by COVID-19 or having a history of COVID-19 infection with an invasive fungal lesion (mucormycosis/aspergillosis) of the paranasal sinuses, orbit, palate, brain, lung, skin/cheek, and dental has been evaluated for possible description in tertiary care hospital in May 2021. Twenty-four patients presented with clinical signs and symptoms of fungal infection with a history of COVID-19. Paranasal sinuses were involved in all patients. Palatal involvement was seen in seven cases. Intraorbital extension was seen in 13 cases. Intracerebral involvement was seen in three cases. Comorbid type 2 diabetes was seen in 20 patients. The use of steroids was noticed in 16 cases. Our observation revealed that uncontrolled diabetes, overuse of steroids, increased ferritin levels, and low hemoglobin percentage are the main factors aggravating mucormycosis.


Coding of shape and position in macaque lateral intraparietal area.
The analysis of object shape is critical for both object recognition and grasping. Areas in the intraparietal sulcus of the rhesus monkey are important for the visuomotor transformations underlying actions directed toward objects. The lateral intraparietal (LIP) area has strong anatomical connections with the anterior intraparietal area, which is known to control the shaping of the hand during grasping, and LIP neurons can respond selectively to simple two-dimensional shapes. Here we investigate the shape representation in area LIP of awake rhesus monkeys. Specifically, we determined to what extent LIP neurons are tuned to shape dimensions known to be relevant for grasping and assessed the invariance of their shape preferences with regard to changes in stimulus size and position in the receptive field. Most LIP neurons proved to be significantly tuned to multiple shape dimensions. The population of LIP neurons that were tested showed barely significant size invariance. Position invariance was present in a minority of the neurons tested. Many LIP neurons displayed spurious shape selectivity arising from accidental interactions between the stimulus and the receptive field. We observed pronounced differences in the receptive field profiles determined by presenting two different shapes. Almost all LIP neurons showed spatially selective saccadic activity, but the receptive field for saccades did not always correspond to the receptive field as determined using shapes. Our results demonstrate that a subpopulation of LIP neurons encodes stimulus shape. Furthermore, the shape representation in the dorsal visual stream appears to differ radically from the known representation of shape in the ventral visual stream.


Genome-wide identification of long non-coding RNA and mRNA profiling using RNA sequencing in subjects with sensitive skin.
Sensitive skin (SS) is a condition of subjective cutaneous hyper-reactivity. The role of long non-coding RNAs (lncRNAs) in subjects with SS is unclear. Therefore, the aim of the present study was to provide a comprehensive profile of the mRNAs and lncRNAs in subjects with SS. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis presented the characteristics of associated protein-coding genes. In addition, a co-expression network of lncRNA and mRNA was constructed to identify potential underlying regulation targets; the results were verified by quantitative real-time PCR (qRT-PCR) and RNA-seq analyses in patients with SS and normal samples. Compared with the normal skin group, 266 novel lncRNAs and 6750 annotated lncRNAs were identified in the SS group. A total of 71 lncRNA transcripts and 2615 mRNA transcripts were differentially expressed (P < 0.05). The heat signature of the SS samples could be distinguished from the normal skin samples, whereas the majority of the genes that were present in enriched pathways were those that participated in focal adhesion, PI3K-Akt signaling, and cancer-related pathways. Five transcripts were selected for qRT-PCR analysis and the results were consistent with RNA-seq. The results suggested that LNC_000265 may play a role in the epidermal barrier structure of patient with SS. The data suggest novel genes and pathways that may be involved in the pathogenesis of SS and highlight potential targets that could be used for individualized treatment applications.


Possible evidence for care and treatment in the Tyrolean Iceman.
The Tyrolean Iceman is the world's oldest glacier mummy. He was found in September 1991 in the Italian part of the Ötztal Alps. Since his discovery a variety of morphological, radiological and molecular analyses have been performed that revealed detailed insights into his state of health. Despite the various pathological conditions found in the Iceman, little is known about possible forms of care and treatment during the Copper Age in Northern Italy. A possible approach to this topic is the presence of tattoos on the mummified body. In previous work, it was already believed that the tattoos were administered as a kind of treatment for his lower back pain and degenerative joint disease of his knees, hip and wrist. In other studies, the tattoos of the Iceman have been related to an early form of acupuncture. We carefully re-evaluated the various health issues of the Iceman, including joint diseases, gastrointestinal problems and arterial calcifications and compared them to the location and number of tattoos. Together with the finding of medically effective fungi and plants, such as the birch polypore or fern in his equipment and intestines, we suggest that care and treatment was already common during the Iceman's time.


A novel injection method for high-speed proteome analysis by capillary electrophoresis.
We have developed a new sample injection method for capillary electrophoresis (CE) that reduces the required migration time. We demonstrated a pressurization technique that was performed with buffer in the outlet after the electrokinetic sample injection with no buffer in the outlet. To reduce the migration time, the sample injection had to be performed with no buffer in the outlet; water should be pressurized while the buffer is in the outlet. Though the resolution was slightly decreased using this method, the addition of a separation carrier (curdlan) to the run buffer restored the resolution without delaying the migration time. The use of our new sample injection method combined with our high-quality separation carrier will enable us to improve the efficiency of the high-throughput screening (HTS) system for proteome analysis.


In Chronic Hepatitis C Infection, Myeloid-Derived Suppressor Cell Accumulation and T Cell Dysfunctions Revert Partially and Late After Successful Direct-Acting Antiviral Treatment.
Chronic HCV infection is characterized by several immunological alterations, such as the accumulation of suppressor cells and of hyperactivated T lymphocytes. However, it is unclear whether direct-acting antiviral (DAA)-mediated HCV clearance restores immune dysfunctions. We performed a phenotypic characterization by flow cytometry of different immune cell subsets, including monocytic myeloid-derived suppressor cells (M-MDSCs) and T lymphocytes in 168 patients with persistent HCV infection not treated, under DAA therapies and sustained virological responders. Chronic HCV infection prompted the accumulation of M-MDSCs independently of patient and clinical characteristics, and altered their metabolic properties. HCV RNA was undetectable in the majority of patients just after few weeks of DAA therapy, whereas M-MDSC levels normalized only 6 months after therapy. In addition, HCV infection deeply perturbed the T cell compartment since a re-distribution of memory CD4+ and CD8+ T cells was observed at the expenses of naïve cells, and memory T lymphocytes displayed increased activation. Notably, these features were only partially restored by DAA therapies in the CD4, but not in the CD8, compartment as high immune activation levels persisted in the terminally differentiated memory CD8+ T cells even more than 1 year after sustained virological response. Together, these results suggest that successful DAA therapies do not lead to full immunological reconstitution as fast as viral clearance.


N-methyl-D-aspartate receptor activation increases cAMP levels and voltage-gated Ca2+ channel activity in area CA1 of hippocampus.
Tetanic stimulation of the Schaffer collateral inputs into area CA1 of the hippocampus causes N-methyl-D-aspartate (NMDA) receptor activation, an effect that contributes to the induction of long-term potentiation (LTP) in this region. The present studies demonstrate that LTP-inducing tetanic stimulation in rat hippocampal area CA1 elicited increased levels of cAMP. The elevation of cAMP was blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV). Bath application of NMDA also resulted in an increase in cAMP in CA1, an effect that was blocked by both APV and removal of extracellular Ca2+. These findings suggest that activation of NMDA receptors elicits a Ca(2+)-dependent increase in cAMP, and taken together with the data from tetanic stimulation, suggest that NMDA-receptor-mediated increases in cAMP could play a role in the induction of LTP in area CA1. One role for cAMP may be to increase Ca2+ influx through voltage-gated Ca2+ channels, as it was observed that application of either 8-bromo-cAMP or NMDA increased the fractional open time of high-threshold Ca2+ channels in CA1 pyramidal cells. Our results raise the possibility that a positive-feedback loop for Ca2+ influx in area CA1 exists. In this model, NMDA receptor-mediated Ca2+ influx leads to an enhancement of further Ca2+ influx via intermediate steps of increased cAMP and subsequent increased voltage-gated Ca2+ channel activity.