Rasagiline, a suicide inhibitor of monoamine oxidases, binds reversibly to α-synuclein.
Rasagiline (N-propargyl-1-R-aminoindan) and selegiline (1-deprenyl) are MAO-B inhibitors which are used in the treatment of Parkinson's disease. The binding of rasagiline, selegiline, and their metabolites including 1-aminoindan, 2-aminoindan, and methamphetamine to α-synuclein was investigated by nanopore analysis and isothermal titration calorimetry. Blockade current histograms of α-synuclein alone give a peak at -86 pA which is due to translocation of the protein through the pore. In the presence of rasagiline and R-1-aminoindan, this peak shifts to about -80 pA. In the presence of selegiline and R-methamphetamine, the number of events at -86 pA is reduced and there is a higher proportion of bumping events at about -25 pA which are due to a more compact conformation. Rasagiline can also bind to sites in both the N- and C-terminal regions of α-synuclein. The binding constants of rasagiline and selegiline were estimated by isothermal titration calorimetry to be about 5 × 10(5) and <10(4) M(-1), respectively. A model is presented in which both rasagiline and R-1-aminoindan bind to α-synuclein, forming a loop structure which is less likely to aggregate or form fibrils. In contrast, selegiline binds and forms a more compact structure similar to that formed by methamphetamine.


Clinical Evaluation of a Microwave-Based Device for Detection of Traumatic Intracranial Hemorrhage.
Traumatic brain injury (TBI) is the leading cause of death and disability among young persons. A key to improve outcome for patients with TBI is to reduce the time from injury to definitive care by achieving high triage accuracy. Microwave technology (MWT) allows for a portable device to be used in the pre-hospital setting for detection of intracranial hematomas at the scene of injury, thereby enhancing early triage and allowing for more adequate early care. MWT has previously been evaluated for medical applications including the ability to differentiate between hemorrhagic and ischemic stroke. The purpose of this study was to test whether MWT in conjunction with a diagnostic mathematical algorithm could be used as a medical screening tool to differentiate patients with traumatic intracranial hematomas, chronic subdural hematomas (cSDH), from a healthy control (HC) group. Twenty patients with cSDH and 20 HC were measured with a MWT device. The accuracy of the diagnostic algorithm was assessed using a leave-one-out analysis. At 100% sensitivity, the specificity was 75%-i.e., all hematomas were detected at the cost of 25% false positives (patients who would be overtriaged). Considering the need for methods to identify patients with intracranial hematomas in the pre-hospital setting, MWT shows promise as a tool to improve triage accuracy. Further studies are under way to evaluate MWT in patients with other intracranial hemorrhages.


Ties that bind, and double-bind: visual impairment, help, and the shaping of relationships.
Purpose: Scholars agree that effective rehabilitation relies on a bedrock of reciprocity, relational trust, and authenticity. It is therefore essential for practitioners to develop insight into the complex dynamics within helping relationships. This study aims to provide an in-depth understanding of visually impaired students' experience of informal helping relationships. Methods: Ten visually impaired students at a South African university participated in one of two semi-structured focus group interviews (six and four in each group, respectively) wherein we explored their experience of informal helping relationships. Interpretive phenomenological analysis was used to make sense of the data. Results: Help, according to the participants, can militate against visibility and complete acceptance, and has the potential to cause helpers to feel entrapped. By contrast, some students found that help offered benefits to relationships by boosting the helper's self-esteem and affording disabled students the opportunity to make friends. Conclusion: Decisions whether to accept help were mediated more by relationship factors than by the need for help. These findings are important for rehabilitation professionals, as deep relationship can come into being during the course of a rehabilitation process. Although this study was conducted in an informal setting, the relational dynamics that we explore are also applicable to clinical relationships between disabled persons and rehabilitation professionals. Implications for rehabilitation In this paper, we provide an overview of the intricacies involved in care and helping relationships; In order for rehabilitation to be successful, these relationships should ideally be real, trusting, and authentic; Yet, authenticity and spontaneity often get lost in helping relationships, as help-recipients may deny help when they need it, and accept help when perfectly able to cope without it. These decisions are mediated more by relationship factors than by the need for help; In their daily practice, it is essential for health professionals to be mindful of these relational intricacies within care relationships; We recommend that professionals remain motivated to continuously reflect on their own actions and on the emotional investment they might have in their role as a helper; Our last recommendation is for rehabilitation professionals to spend energy on exploring, through open and transparent discussions with their disabled patients, the relational dynamics in their relationship.


Venous gas emboli in normal and dehydrated rats following decompression from a saturation dive.
Dehydration may increase the risk for decompression sickness (DCS). Since DCS most probably is caused by endogenous gas phase formation, we hypothesized that decompression will induce more venous gas emboli (VGE) in dehydrated rats compared to controls. Two groups of rats were pressurized to 0.5 MPa (5 ATA) on heliox for 16 h, and thereafter decompressed to atmospheric pressure at a rate of 0.3 MPa x min(-1). The nine control rats had free access to water ad libitum whereas the eight dehydrated rats were water-deprived for 48 h before decompression. During and after decompression, VGE was measured in the vena cava for 60 min with the Doppler technique and graded into six bubble grade (BG) categories. Body mass (BM), and food and water intake were registered daily, and venous blood samples were taken before and after pressure exposure. Serum osmolality and hematocrit increased significantly in dehydrated rats (306 +/- 5.2 to 315 +/- 7.3 mosmol x kg(-1) and 39.3 +/- 4.9 to 49.6 +/- 5.2%) but not in controls (300 +/- 8.9 to 303 +/- 6.7 mosmol x kg(-1) and 40.3 +/- 5.2 to 41.4 +/- 6.1%). Plasma volume decreased by 9.2% (P < 0.05) and 2.8% (n.s.) in dehydrated and control rats. VGE were detected in all control animals (average BG: 2.8 +/- 1.9), but only in four water-deprived rats (BG: 1.6 +/- 2.2). This difference was not significant. Our experiments do not support the idea that dehydration increases circulatory VGE.


Understanding the interaction of concanavalin a with mannosyl glycoliposomes: A surface plasmon resonance and fluorescence study.
The specificity of carbohydrate-protein interaction is a key factor in many biological processes and it is the foundation of technologies using glycoliposomes in drug delivery. The incorporation of glycolipids in vesicles is expected to increase their specificity toward particular targets such as lectins; however, the degree of exposure of the carbohydrate moiety at the liposome surface is a crucial parameter to be considered in the interaction. Herein we report the synthesis of mannose derivatives with one or two hydrophobic chains of different length, designed with the purpose of modifying the degree of exposure of the mannose when they were incorporated into liposomes. The interaction of glycovesicles with Con A was studied using: (i) agglutination assays; measured by dynamic laser light scattering (DLS); (ii) time resolved fluorescence methods and (iii) surface plasmon resonance (SPR) kinetic measurements. DLS data showed that an increase in hydrophobic chain length promotes a decrease of liposomes hydrodynamic radius. A longer hydrocarbon chain favors a deeper insertion into the bilayer and mannose moiety results less exposed at the surface to interact with lectin. Fluorescence experiments showed changes in the structure of glycovesicles due to the interaction with the protein. From SPR measurements the kinetic and equilibrium constants associated to the interaction of ConA with the different glycolipid synthetized were determined. The combination of SPR and fluorescence techniques allowed to study the interaction of Con A with mannosyl glycovesicles at three levels: at the surface, at the interface and deeper into the bilayer.


[Acquired chorio-retinal anastomoses (author's transl)].
The acquired chorio-retinal anastomoses occur when the rupture of the Bruch's membrane happens. In these arterial of venous anastomoses, the blood circulates in one way or the other according to the local conditions, as showed in the nine reported cases.


Asylum and the protection of human rights.
There are now some 18.5 million refugees in the world, many more displaced persons within their own country, and the number in both groups is steadily increasing. Some of the problems of seeking asylum and providing the resources for the individual needs of displaced persons are considered. Small non-governmental agencies such as the Ockenden Venture have a degree of flexibility which is particularly helpful. The increasing reluctance of all countries to offer asylum makes work in the displaced persons' home countries increasingly important and the need for preventive protection more urgent.


Development and evaluation of a high-fidelity canine laparoscopic ovariectomy model for surgical simulation training and testing.
OBJECTIVE To develop and evaluate a high-fidelity simulated laparoscopic ovariectomy (SLO) model for surgical training and testing. DESIGN Evaluation study. SAMPLE 15 veterinary students (novice group), 5 veterinary surgical interns or residents (intermediate group), and 6 veterinary surgeons (experienced group). PROCEDURES Laparoscopic surgery experience was assessed by questionnaire and visual analog scales. Basic laparoscopic skills were assessed with a commercial training model. A commercial canine abdomen model was customized with a high-fidelity simulated canine female genital tract. Each subject's SLO performance (laparoscopic entry, dissection along marked planes, and left ovariectomy) was evaluated by measurement of surgical time and errors (splenic puncture and deviation from dissection marks) and with global and operative component rating scales. Construct and concurrent validity were assessed by correlation of SLO results with self-estimated measures of experience level and with basic laparoscopic skills test results, respectively. Face validity was assessed with a questionnaire completed by intermediate and experienced group participants. RESULTS 13 participants (3/15, 5/5, and 5/6 in the novice, intermediate, and experienced groups, respectively) completed SLO within the preset time. No difference in errors was found among groups. Completion time was significantly correlated with self-estimated experience level (r = -0.626), confirming construct validity, and with basic laparoscopic skills scores (r = -0.552) and global (r = -0.624) and operative component (r = -0.624) rating scale scores, confirming concurrent validity. Overall mean face validity score was low (64.2/100); usefulness of the model for surgical training received the highest score (8/10). CONCLUSIONS AND CLINICAL RELEVANCE Results suggested the SLO model may be a useful surgical training tool. Further studies are needed to confirm usefulness of the model in veterinary laparoscopy training.


The utility of apoptosis inhibitor of macrophages as a possible diagnostic marker in patients with Crohn's disease.
Apoptosis inhibitor of macrophages (AIM) was initially identified as an apoptosis inhibitor that supports the survival of macrophages against various apoptosis-inducing stimuli, and AIM produced by macrophages may contribute to the pathogenesis of inflammatory bowel diseases (IBDs). However, there have been no reports on the kinetics of AIM in IBD and the impact of AIM on the pathogenesis of IBD. In this study, we aimed to investigate the diagnostic utility of levels of AIM and their correlation with the activity of Crohn's disease (CD) and IBD. We used an enzyme-linked immunosorbent assay (ELISA) to examine AIM serum levels in 16 healthy subjects and 90 patients with inflammatory bowel diseases, namely 39 with CD and 51 with ulcerative colitis (UC), as well as 17 patients with Behcet's disease (BD) as intestinal disease controls. We compared serum AIM levels among groups and examined whether there were correlations between serum AIM levels and disease activity and type. We also performed immunohistochemical staining of AIM in intestinal tissues of patients with CD. Serum AIM levels were significantly higher in patients with CD than in patients with UC, BD, and controls (3.27 ± 2.14, 1.88 ± 1.43, 2.34 ± 1.37, and 2.13 ± 0.64 μg/ml, respectively; P < 0.01). There was no difference in serum AIM levels before and after treatment in patients with CD. However, in these patients the diagnostic rate using AIM was better than that based on anti-Saccharomyces cerevisiae antibodies. AIM was expressed in macrophages that were positive for CD14, CD16, or both in the intestinal tissues of patients with CD. AIM is a novel biomarker of CD that can distinguish CD from UC or BD. It is suggested that AIM may contribute to intestinal inflammation by inhibiting the apoptosis of macrophages.


Complete dentures for a patient after a stroke by means of orofacial myofunctional therapy: A clinical report.
After a stroke, patients frequently show compromised swallowing, mastication, and speech, as well as unfavorable motion and deviation of the tongue and mandible. The dentist can improve the oral rehabilitation of a patient with deteriorated facial and oral muscles after a stroke by incorporating orofacial myofunctional therapy. This report describes a method for tongue exercises and correction of mandible deviation in an edentulous patient after a stroke by using a pearl on a wire in the anteriomedian palatal part of the maxillary denture.


The use of bacteriophage as tracers of aerosols liberated by sludge suction appliances.
Three bacteriophage tracers were added to 600-1 containers of water and simulated latrine sludge to provide high titres of tracer in aqueous and semi-aqueous media. After a period of mixing and stabilization, media were removed from the containers with suction hoses coupled to the vacuum pump of one of two sludge suction tankers. Exhaust air from the appliances was sampled by cyclone sampler and assayed for the presence of tracer organisms carried over during the emptying process. In the experiments the appliances were operated at different vacuum pump speeds, drawing both aqueous and semi-aqueous (simulated sludge) media. Air around one tanker was also sampled during the emptying, under pressure, of the vacuum vessel. The degree of aerosolization and expulsion of tracer bacteriophage by the vacuum appliances was consistently low, regardless of medium and pump air flow. In contrast, the proportion of tracer retained within the appliances was very high, exceeding the proportion expelled by a minimum of 8 log10 orders of magnitude and a maximum of greater than 11 log10 orders. The highest total of tracer bacteriophage was recovered during the pressure emptying of the vacuum vessel of one tanker. The results may be used for assessing and comparing potential public health hazards associated with the handling of wastewater sludge by vacuum appliances.


Novel mechanisms of resistance to β-lactam antibiotics in Haemophilus parainfluenzae: β-lactamase-negative ampicillin resistance and inhibitor-resistant TEM β-lactamases.
To determine the mechanisms of resistance to β-lactam antibiotics in clinical isolates of Haemophilus parainfluenzae. Twenty clinical isolates of H. parainfluenzae with decreased susceptibility to aminopenicillins were examined and compared with a control group of 20 fully susceptible isolates. In this collection, the presence of amino acid substitutions in the transpeptidase domain of penicillin-binding protein 3 (PBP3), β-lactamase production and the surrounding genetic regions of blaTEM genes in selected isolates were analysed. Of the 20 non-susceptible isolates, 8 produced TEM β-lactamase (gBLPAR), 7 had mutations in the transpeptidase domain of the ftsI gene related to decreased susceptibility to β-lactams (gBLNAR) and 5 had both resistance mechanisms (gBLPACR). No resistance mechanisms were identified in the susceptible control group (gBLNAS). gBLNAR isolates had MIC90 values 4- to 16-fold higher than gBLNAS isolates for ampicillin, amoxicillin/clavulanic acid, cefuroxime, cefotaxime and cefixime, and the most common PBP3 mutation was Asn526Ser. The additional Ser385Thr substitution (III-like group) may confer decreased susceptibility to cefotaxime, cefixime and aztreonam, as in Haemophilus influenzae. In two β-lactamase-positive isolates without PBP3 mutations, the inhibitor-resistant TEM (IRT) β-lactamases TEM-34 and the novel TEM-182 were detected and carried by a TnA transposon of the Tn2 type; both isolates had an amoxicillin/clavulanic acid MIC of ≥8 mg/L. The TnA transposons of two β-lactamase-positive isolates (TEM-1 and TEM-182) were inserted between the tfc20 and tfc21 genes, typically associated with integrative and conjugative elements in Haemophilus spp.; the TEM-34 IRT β-lactamase was harboured in a ∼5.5 kb plasmid. Clinical isolates of H. parainfluenzae express a variety of aminopenicillin resistance mechanisms, either alone or in combination, including PBP3 modifications, blaTEM-1 and IRT β-lactamase production.


Phosphorylation of epidermal keratins.
When human and rat epidermis are exposed to 32P-orthophosphoric acid, labeled phosphate is incorporated into several proteins. The pattern of phosphorylation is identical whether the isotope is delivered in vivo or in vitro. The predominant phosphorylated proteins are insoluble in Tris-HCl buffer but soluble in SDS-beta-mercaptoethanol. They migrate in SDS-polyacrylamide gels with apparent molecular weights between 45,000 and 65,000. When analyzed by two-dimensional gel electrophoresis, the labeled phosphoproteins co-migrate with keratins isolated from human callus. Serine is the phosphate acceptor in these proteins. The pattern of phosphorylation of these SDS-beta-mercaptoethanol soluble epidermal proteins is not changed in basal cell carcinoma, icthyosis vulgaris, Kyrle's disease or Netherton's syndrome. The pattern is altered in psoriasis. Others have demonstrated that a 63,000 molecular weight protein is absent from active psoriatic lesions. We have found that a 63,000 molecular weight phosphoprotein is present in uninvolved skin but absent in the psoriatic plaques.


Saturable absorber Q- and gain-switched all-Yb3+ all-fiber laser at 976 and 1064 nm.
We demonstrate a novel passively pulsed all-Yb3+ all-fiber laser pumped by a continuous-wave 915-nm pump laser diode. The laser was saturable absorber Q-switched at 976 nm and gain-switched at 1064 nm, using the method of mode-field-area mismatch. With a pump power of 105 mW, the laser iteratively produced a 976-nm pulse with an energy of 2.8 μJ and a duration of 280 ns, followed by a 1064-nm pulse with 1.1 μJ and a 430-ns duration at a repetition rate of 9 kHz. A set of rate equations was established to simulate the self-balancing mechanism and the correlation between the Q- and gain-switched photon numbers and the populations of the gain and absorber fibers.


[Dyspnea. II. Clinical and treatment problems].
In a previous paper (Balanova, Surcheva and Ichev, 2001) we have proposed a scheme about pathophysiological mechanisms involved in dyspnea. Some of the clinical problems in dyspnea were discussed in this paper on the base of that scheme, as well as clinical observations on the patients with dyspnea. Two groups of symptoms were considered--subjective and objective, and their significance for the diagnosis of the dyspnea and of the disease that provokes dyspnea were evaluated. A critical analysis of the different forms of dyspnea has been made, and suggestions about the treatment of the subjective symptoms in dyspnea were proposed.


A neural network model for timing control with reinforcement.
How do humans and animals perform trial-and-error learning when the space of possibilities is infinite? In a previous study, we used an interval timing production task and discovered an updating strategy in which the agent adjusted the behavioral and neuronal noise for exploration. In the experiment, human subjects proactively generated a series of timed motor outputs. Positive or negative feedback was provided after each response based on the timing accuracy. We found that the sequential motor timing varied at two temporal scales: long-term correlation around the target interval due to memory drifts and short-term adjustments of timing variability according to feedback. We have previously described these two key features of timing variability with an augmented Gaussian process, termed reward-sensitive Gaussian process (RSGP). In a nutshell, the temporal covariance of the timing variable was updated based on the feedback history to recreate the two behavioral characteristics mentioned above. However, the RSGP was mainly descriptive and lacked a neurobiological basis of how the reward feedback can be used by a neural circuit to adjust motor variability. Here we provide a mechanistic model and simulate the process by borrowing the architecture of recurrent neural networks (RNNs). While recurrent connection provided the long-term serial correlation in motor timing, to facilitate reward-driven short-term variations, we introduced reward-dependent variability in the network connectivity, inspired by the stochastic nature of synaptic transmission in the brain. Our model was able to recursively generate an output sequence incorporating internal variability and external reinforcement in a Bayesian framework. We show that the model can generate the temporal structure of the motor variability as a basis for exploration and exploitation trade-off. Unlike other neural network models that search for unique network connectivity for the best match between the model prediction and observation, this model can estimate the uncertainty associated with each outcome and thus did a better job in teasing apart adjustable task-relevant variability from unexplained variability. The proposed artificial neural network model parallels the mechanisms of information processing in neural systems and can extend the framework of brain-inspired reinforcement learning (RL) in continuous state control.


Systematic differences among patients initiated on home haemodialysis and peritoneal dialysis: the fallacy of potential competition.
The adoption of home-based dialysis therapies is growing internationally. There is a possibility that competition for patients may exist between peritoneal dialysis (PD) and home haemodialysis (HHD) for their respective growth. Clinical demographics of patients initiating PD and HHD from 2004 to 2008 in our centre were abstracted using institutional electronic records. We compared clinical demographics, laboratory data and process of care to describe potential factors leading to patients choosing home-based dialysis therapies. Between 2004 and 2008, 236 patients initiated home dialysis therapy in our centre: 153 patients to PD and 83 patients to HHD. PD and HHD patients differed in age (PD 62 +/- 16 vs HHD 46 +/- 13 years; P < 0.001) and gender distribution (PD 57 vs HHD 70% male; P = 0.05). A higher proportion of PD patients had diabetes and hypertension as the primary cause of their end-stage renal disease (ESRD). In contrast, there were more patients with glomerulonephritis among the HHD cohort. Cardiovascular and peripheral vascular diseases were more common among patients on PD. HHD patients had longer ESRD vintage (PD 0.34 +/- 0.69 and HHD 4.8 +/- 6.8 years on therapy; P = 0.002). The proportion of patients receiving chronic kidney disease care was higher among PD starters (PD 86 vs HHD 65%; P < 0.001). Sixteen percent of PD patients and 9% of HHD patients initiated their home-based renal replacement therapy after an acute hospitalization without prior modality education. There is a systematic difference between patients initiated on PD and HHD. Our data reaffirm that modality selection is a complex process. Patients on the two home therapies differ demographically and arrive through different routes. This finding suggests that the two home-based modalities are not in competition.


A review of our development of dental adhesives--effects of radical polymerization initiators and adhesive monomers on adhesion.
This paper reviews the development of dental adhesives by collating information of related studies from original scientific papers, reviews, and patent literatures. Through our development, novel radical polymerization initiators, adhesive monomers, and microcapsules were synthesized, and their effects on adhesion were investigated. It was found that 5-monosubstituted barbituric acid (5-MSBA)-containing ternary initiators in conjunction with adhesive monomers contributed to effective adhesion with good polymerization reactivity. Several kinds of novel adhesive monomers bearing carboxyl group, phosphonic acid group or sulfur-containing group were synthesized, and investigated their multi-purpose bonding functions. It was suggested that the flexible methylene chain in the structure of adhesive monomers played a pivotal role in their enhanced bonding durability. It was found that the combination of acidic monomers with sulfur-containing monomer markedly improved adhesion to enamel, dentin, porcelain, alumina, zirconia, non-precious metals and precious metals. A new poly(methyl methacrylate) (PMMA)-type adhesive resin comprising microencapsulated polymerization initiators was also found to exhibit both good formulation stability and excellent adhesive property.


Water pollution and health.
Water is the important constituent of life support system. No one can live and even dream to live without water. Most of our water bodies have become polluted due to industrial growth; urbanization and man-made problems mainly the result of population growth. Poor sanitation and contaminated drinking water arising from human activity and natural phenomena create serious problems in human health. The chief sources of water pollution are sewage and other waste, industrial effluents, agricultural discharges and industrial wastes from chemical industries, fossils fuel plants and nuclear power plants. They create a larger problem of water pollution rendering water no longer fit for drinking, agriculture and, as well as for aquatic life. More than 2.6 billion people--40% of the world's population--lack basic sanitation facilities and over one billion people still use unsafe drinking water sources. As a result thousands of children die everyday from diarrhoea and other water, sanitation and hygiene-related diseases and many suffer and are weakened by illness.


[Progress of research on microRNA and Alzheimer's disease].
MicroRNA are a group of non-coding RNA which, through regulating expression of proteins at post-transcription level, plays an important role in modulating growth and development of nervous system, cell differentiation and functions. Altered expression of microRNA in the brain may influence development and advance of Alzheimer's disease from multiple perspectives. Research on microRNA will facilitate in depth understanding of the pathogenesis of Alzheimer's disease.


Food Insecurity and Blood Pressure in a Multiethnic Population.
Food insecurity is a social determinant of health and is increasingly recognized as a risk factor for hypertension. Native Hawaiians bear a disproportionate burden of hypertension and known risk factors. Despite this, the relative effects of food insecurity and financial instability on blood pressure have yet to be investigated in this population. This study examines the relative effects of food insecurity and financial instability on blood pressure, controlling for potential confounders in a multiethnic sample. Participants (n = 124) were recruited from a U.S. Department of Agriculture-funded study called the Children's Healthy Living Center of Excellence. Biometrics (i.e., blood pressure, weight, and height) were measured. Demographics, physical activity, diet, psychosocial variables, food insecurity, and financial instability were assessed via self-report questionnaires. Hierarchical linear regression models were conducted. Model 1, which included sociodemographic variables and known biological risk factors, explained a small but significant amount of variance in systolic blood pressure. Model 2 added physical activity and daily intake of fruit, fiber, and whole grains, significantly improving the model. Model 3 added financial instability and food insecurity, further improving the model (R2 = 0.37, F = 2.67, p = 0.031). Food insecurity, female sex, and BMI were significantly and independently associated with increased systolic blood pressure. These results suggest a direct relationship between food insecurity and systolic blood pressure, which persisted after controlling for physical activity, consumption of fruits, fiber, and whole grains, and BMI. Efforts to reduce food insecurity, particularly among Native Hawaiians, may help reduce hypertension in this high-risk population.


[Congenital central hypoventilation syndrome: analysis of PHOX2B gene mutation in a case].
OBJECTIVE To report on the phenotype of an infant with central hypoventilation syndrome (CCHS) and result of PHOX2B gene mutation analysis for the purpose of genetic counseling and prenatal diagnosis. METHODS Clinical data of an infant with CCHS was collected and analyzed. Potential mutation of PHOX2B gene was analyzed by amplified fragment length polymorphism (amp-FLP) and DNA sequencing. RESULTS The patient had typical clinical features of CCHS including frequent hypoventilation during sleeping, hypoxemia and hypercapnia which could be corrected by continuous ventilatory support. She also had repeated bruising and was difficult-to-wean, but without any cardiac, pulmonary, neuromuscular or brainstem lesions. DNA sequencing and amp-FLP of the PHOX2B gene showed that the patient has carried a polyalanine expansion repeat mutation (PARM) in exon 3. A 27 bp duplication was confirmed in the repeat sequence of 20 alanines by cloned and sequenced. This has led to an expansion of the repeat tract to 29 alanines. The genotype was therefore 20/29. CONCLUSION A patient with CCHS has been described. Mutation screening of PHOX2B gene can be used as an important support for diagnosis and genetic counseling for such patients.


Comparative analysis of the priming effect of human interferon-gamma, -alpha, and -beta on synergism with muramyl dipeptide analog for anti-tumor expression of human blood monocytes.
Freshly isolated human peripheral blood monocytes from healthy volunteers were not cytotoxic to allogeneic A375 melanoma cells, but they were activated to the cytotoxic state by incubation in vitro with either des-methyl muramyl dipeptide (norMDP; minimal effective dose, 0.5 micrograms/ml) or recombinant human interferon-gamma (rIFN-gamma; minimal effective dose, 1 U/ml). A combination of subthreshold concentrations of these agents (norMDP, 0.5 micrograms/ml; rIFN-gamma, 10 U/ml) also induced significant cytotoxicity, indicating that the effects of norMDP and rIFN-gamma in monocyte activation are synergistic. Natural human IFN-gamma (nIFN-gamma) and norMDP also had similar synergistic effects. Pretreatment of rIFN-gamma with anti-IFN-gamma antibody completely inhibited its synergistic effect with norMDP in monocyte activation. Because pretreatment of rIFN-gamma and norMDP with polymyxin B did not interfere with their effects in monocyte activation, the preparations were not contaminated with lipopolysaccharide. Moreover, because pretreatment of monocyte monolayers with anti-Leu-11b antibody (anti-natural killer (NK) cell antibody) and complement did not interfere with the synergistic effects of norMDP and rIFN-gamma, whereas pretreatment with anti-Leu-M1 antibody (anti-monocyte antibody) caused complete inhibition of their effects, the observed tumor cytotoxicity of monocyte-rich monolayers was probably not due to a small number of adherent NK cells, but to the stimulation of the monocytes. Natural and recombinant IFN-alpha and IFN-beta at concentrations of greater than or equal to 100 U/ml also induced tumoricidal activity of monocytes, but unlike IFN-gamma, their effects were additive with norMDP, and they had less priming effect than IFN-gamma when they were added before norMDP to monocytes. These findings suggest that recombinant human IFN-gamma has much more synergistic potential with norMDP than IFN-alpha or IFN-beta, and this synergism of rIFN-gamma and norMDP for monocyte activation could be of clinical value in treatment of disseminated malignant diseases, because these compounds are readily available at standardized concentrations.


[45Ca-uptake, mitochondrial protein bound Ca2+ and ultrastructural distribution of Ca2+ in some brain regions of mice during drug-induced analgesia].
After buprenorphine (Bup, 0.8 mg/kg ip) treatment 45Ca-uptake (cpm/mg fresh brain) in vivo by brain slices decreased from 589 +/- 12 and 486 +/- 12 to 522 +/- 14 and 408 +/- 10 and mitochondrial protein bound Tb3+ (Tb3+ relative fluorescent intensity) reduced from 41 +/- 5 and 32 +/- 2 to 30 +/- 3 and 22 +/- 2 in periaqueductal grey and hypothalamus, respectively. A large amount dense precipitate occurred in the myelin sheath and mitochondria in both regions. The 45Ca-uptake evoked by buprenorphine at 16 micrograms/40 microliter in vitro has the similar tendency with that in vivo. Treated by ruthenium red (20 micrograms/mouse ip or icv) before buprenorphine, the above-mentioned effects were all abolished. Similar results were obtained with morphine (Mor, 10 mg/kg ip) and verapamil (Ver, 8 micrograms/mouse icv) instead of buprenorphine and ruthenium red, respectively. These results suggest that Ca2+ transport across neuroplasmic membranes plays a mediator role in drug-induced analgesia.


Terminal care: the last weeks of life.
The care of patients in their last weeks of life is a fundamental palliative care skill, but few evidence-based reviews have focused on this critical period. A systematic review of published literature and expert opinion related to care in the last weeks of life. The evidence base informing terminal care is largely descriptive, retrospective, or extrapolated. While home deaths and hospice use are increasing, medical care near death is becoming more aggressive and hospice lengths of stay remain short. Though the prediction of impending death remains imprecise, studies have identified several common terminal signs and symptoms. Decreased communication near death complicates the determination of patient wishes, and advanced directives prior to the terminal stage are recommended. Anorexia and cachexia are common in dying patients but there is no evidence that this process is painful or responsive to intervention. While there is general consensus that artificial nutrition is not beneficial in dying patients, the use of artificial hydration is controversial, especially in the setting of delirium. Breathlessness has been shown to benefit from oral and parenteral opioids but not anxiolytics. Accumulation of respiratory tract secretions (death rattle) is common and usually responds to antimuscarinics. Physical pain typically decreases toward death but its assessment in dying patients is difficult. Terminal delirium may occur in up to one-third of patients, may have a reversible cause, and may respond to antipsychotics or benzodiazepines. Palliative sedation is controversial but widely used, especially internationally. Caregiver stress and bereavement may benefit from improved communication and hospice involvement. While the terminal care literature is characterized by varying quality, numerous knowledge gaps, and frequent inconsistencies, it supports several common clinical interventions. More research is needed to resolve controversies, define effective therapies, and improve the outcomes of dying patients.


HMG1-related DNA-binding protein isolated with V-(D)-J recombination signal probes.
In order to isolate cDNA clones for DNA-binding components of the V-(D)-J recombinase, phage libraries from a pre-B-cell line were screened with a radiolabeled probe containing recombination signal sequences (RSS). Among prospective clones, cDNA T160 was analyzed further. It produced a protein of 80.6 kDa which bound to DNA containing RSS but not to DNA in which the RSS had been mutated. A search of a data base revealed that the T160 protein has significant sequence homology (56%) to the nonhistone chromosomal protein HMG1 within the C-terminal region of 80 amino acids. DNA-binding analysis with truncated proteins showed that the HMG homology region is responsible for DNA binding. Using restriction fragment length polymorphisms, the T160 gene was mapped at the proximal end of mouse chromosome 2. Evidence was obtained for genetic linkage between the T160 gene and the recombination activator genes RAG-1 and RAG-2.


Efficacy and tolerability of a complex homeopathic drug in children suffering from dry cough-A double-blind, placebo-controlled, clinical trial.
A randomised, placebo-controlled clinical trial in children suffering from acute dry cough was performed to assess the efficacy and tolerability of a complex homeopathic drug (Drosera, Coccus cacti, Cuprum Sulfuricum, Ipecacuanha=Monapax syrup, short: verum). 89 children received verum and 91 received placebo daily for 7 days (age groups 0.5-3, 4-7 and 8-12 years). The primary efficacy variable was the improvement of the Cough Assessment Score. Tolerability and compliance were also assessed. A confirmatory statistical analysis was performed for the primary efficacy variable and a descriptive analysis for the secondary parameters. The Cough Assessment Score showed an improvement of 5.2±2.6 points for children treated with verum and 3.2±2.6 points in the placebo group (p<0.0001). The difference of the least square means of the improvements was 1.9±0.4. The effect size of Cohen´s d was d=0.77. In all secondary parameters the patients in the verum group showed higher rates of improvement and remission than those in the placebo group. In 15 patients (verum: n=6; placebo: n=9) 18 adverse drug reactions of mild or moderate intensity were observed. Administering verum resulted in a statistically significantly greater improvement of the Cough Assessment Score than the placebo. The tolerability was good and not inferior to that of the placebo.


Wnt signaling, de novo lipogenesis, adipogenesis and ectopic fat.
Wnt signaling is as a major regulator of adipogenesis. It differentially regulates the fate of mesenchymal stem cells (MSC) by promoting osteogenesis and myogenesis, and inhibiting adipogenesis[1]. Its loss of function has been associated with impaired osteogenesis[2] and diverse congenital and adult cardiovascular disorders[3,4]. Our group has identified loss of function mutations in Wnt coreceptor LRP6 that underlie autosomal dominant early onset coronary artery (CAD), osteoporosis and most features of the metabolic syndrome, including high plasma triglyceride and LDL-C, diabetes, hypertension, hyperuricemia and fatty liver disease (unpublished data). Following we will describe our most pertinent findings related to Wnt/LRP6 regulation of de novo lipogenesis and adipogenesis and the role of impaired Wnt signaling in generation of ectopic fat, insulin resistance, elevated plasma lipids and non-alcoholic fatty liver disease (NAFLD).


Punicalagin, a polyphenol from pomegranate fruit, induces growth inhibition and apoptosis in human PC-3 and LNCaP cells.
Prostate cancer (PCa) is an international health problem and search for its effective treatment is in progress. Punicalagin (PN), polyphenol from pomegranate fruit, is known to exhibit potent anticancer activity in lung, breast and cervical cells. However, there is paucity of information on its effect in PCa. This study evaluated anti-proliferative effects of PN and its effects on extrinsic pathway of apoptosis in PCa cells, and angiogenesis in chicken chorioallantoic membrane (CAM). Antioxidant activities of PN were determined by 2,2-diphenyl-1-picryhydrazyl (DPPH) radical scavenging and inhibition of lipid peroxidation (LPO) methods. PCa (PC-3 and LNCaP) and normal prostate (BPH-1) cells were cultured and treated with PN (10, 50 and 100 μM). Cytotoxicity and viability effects of PN were determined by lactate dehydrogenase (LDH) and XTT assays, respectively. Antiangiogenic effects were measured using CAM assay, while apoptosis was assessed by DNA fragmentation, enrichment factor by Cell Death Detection ELISA kit and expressions of caspases-3 and -8. Results showed that PN (10-200 μM) significantly scavenged DPPH and inhibited LPO in a concentration-dependent manner. Furthermore, PN (10-100 μM) concentration-dependently inhibited viability in PC-3 and LNCaP, while viability in BPH-1 was insignificantly affected. PN had low toxicity on cells in vitro at concentrations tested. Also, PN (100 μM) increased enrichment factor in PC-3 (2.34 ± 0.05) and LNCaP (2.31 ± 0.26) relative to control (1.00 ± 0.00). In addition, PN (50 μM) decreased the network of vessels in CAM, suggesting its anti-angiogenic effect. Moreso, PN increased the expressions of caspases-3 and -8 in PC-3. Overall, PN exerts anti-proliferative activity in PCa cells via induction of apoptosis and anti-angiogenic effect.


Improving empiric antibiotic prescribing in pediatric bloodstream infections: a potential application of weighted-incidence syndromic combination antibiograms (WISCA).
Increasing antibiotic resistance to WHO-recommended first- and second-line treatments of pediatric sepsis requires adaptation of prescribing guidelines. We discuss the potential and limitations of a weighted-incidence syndromic combination antibiogram (WISCA) as a practical tool for incorporating local microbiology data when assessing empiric coverage of commonly used antibiotics. A brief questionnaire of 18 clinically significant isolates from pediatric blood cultures (Jan-Dec 2018) was sent to a global network of pediatric hospitals in July 2019. Weighted coverage estimates of non-antipseudomonal third-generation cephalosporins (3GC) and meropenem were estimated using Monte-Carlo simulation for each site reporting >100 isolates. 52 hospitals in 23 countries in 5 WHO regions responded to the questionnaire; 13 sites met the sample size requirement. The most common isolates were S. aureus, Klebsiella spp., E. coli and Enterococcus spp. Coverage of 3GC ranged from 39% [95%CrI: 34-43%] to 73% (two sites: [95%CrI: 65-80%]; [95%CrI: 68-86%]) and meropenem coverage ranged from 54% [95%CrI: 47-60%] to 88% [95%CrI:84-91%]. A WISCA is a data-driven, clinically intuitive tool that can be used to compare empiric antibiotic regimens for pediatric sepsis using existing large datasets. The estimates can be further refined using more complex meta-analytical methods and patient characteristics.


Diet Quality and Upper Gastrointestinal Cancers Risk: A Meta-Analysis and Critical Assessment of Evidence Quality.
We aimed to assess the effect of a high-quality diet on the risk of upper gastrointestinal cancer and to evaluate the overall quality of our findings by searching PubMed, EMBASE, Web of Science, Cochrane, and the references of related articles to February 2020. Two reviewers independently retrieved the data and performed the quality assessments. We defined the highest-quality diet as that with the lowest Diet Inflammatory Index category and the highest Mediterranean Diet Score category. Overall odds ratios and 95% confidence intervals were estimated for upper gastrointestinal cancer risk comparing the highest- versus lowest-diet quality. A random-effects meta-analysis was then applied with Review Manager, and the quality of the overall findings was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation approach. The highest-quality diets were significantly associated with reduced risk of upper gastrointestinal cancers, achieving odds ratios of 0.59 (95% confidence interval: 0.48-0.72) for the Diet Inflammatory Index, pooling the findings from nine studies, and 0.72 (95% confidence interval: 0.61-0.88) for the Mediterranean Diet Score, pooling the findings from 11 studies. We observed a minimum of 69% heterogeneity in the pooled results. The pooled results were graded as low quality of evidence. Although it may be possible to offer evidence-based general dietary advice for the prevention of upper gastrointestinal cancers, the evidence is currently of insufficient quality to develop dietary recommendations.


[Analysis of the swimming pattern and the velocity of bacteria using video tracking method].
The swimming patterns and the velocities of several flagellated bacteria were measured by a computer assisted video tracking method. The moving path of the individual bacterium revealed that the bacterium frequently changed its swimming direction and velocity. The velocity among bacterial strains varies widely. In low viscous environment. Campylobacter jejuni has characteristic swimming pattern with frequent changes in their swimming direction. As the viscosity increase, C. jejuni increases its velocity at a little higher viscosity of 3 centipoise (cP) and secondly increases at about 40 cP. Different from other flagellated bacteria, the swimming pattern of C. jejuni in these two velocity peaks were changed. C. jejuni exhibited continuously forward moving path in the first peak, but in the second it repeated back and forth swimming pattern. We thus assumed that C. jejuni may use a different swimming mode in high viscous media from the original mode mediated by the propelling force of the flagella. This method is useful for a detail analysis of bacterial movement and moving patterns in different environmental conditions.


Use of general clinical research centers for nursing research.
This study examines to what extent academic nursing faculty members understand the purpose of general clinic research centers (GCRCs) and use this resource in their programs of research. GCRCs provide a controlled research-oriented infrastructure to conduct safe, innovative, and multidisciplinary studies. Survey questionnaires were sent to associate deans of research at schools of nursing accredited by the Commission on Collegiate Nursing Education or the National League for Nursing Accrediting Commission within 60 miles of a GCRC. They were asked to distribute questionnaires to 20% of faculty members. Of the 186 nurse faculty members responding, 85% had not conducted research at a GCRC as a principal investigator and 69% of the sample reported that their colleges or universities do not make information about GCRCs available to new faculty. Making greater use of this valuable resource allows nurse researchers to become more involved in developing new knowledge and testing interventions and in psychological and physiologic measurements, thus doing more to fulfill the mission of nursing research and increasing the involvement of nurses in the broader community of health science research.


Anti-insulin serum coupled to Sepharose 4B as a tool for the investigation of insulin biosynthesis in the B-cells of obese hyperglycemic mice.
The biosynthetic activity of the B-cells of obese hyperglycemic mice (obob) was measured by the incorporation of [3H]leucine into proteins in collagenase-isolated pancreatic islets. To quantitate the incorporation into proinsulin and insulin, an immune binding method was used. For this purpose, anti-insulin serum was coupled to cyanogen bromide-activated SepharoseR 4B. This turned out to be a specific and versatile technique for the measurement of newly synthesized proinsulin and insulin in the B-cells. The B-cells of obob mice appear to be well adapted to a high rate of hormone biosynthesis, since at 16.7 mM glucose 44% of [3H]leucine incorporated into TCA-precipitable proteins was bound to the insulin antibodies coupled to Sepharose 4B. The insulin biosynthetic rate was stimulated 9 times at 16.7 mM glucose, during a 3-h incubation, compared with the basal insulin biosynthesis rate.


Regulation of CD38 on Multiple Myeloma and NK Cells by Monoclonal Antibodies.
CD38 is highly expressed on multiple myeloma (MM) cells and plays a role in regulating tumor generation and development. CD38 monoclonal antibodies (mAbs) have been used as an effective therapy for MM treatment by various mechanisms, including complement-dependent cytotoxic effects, antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, programmed cell death, enzymatic modulation, and immunomodulation. Although CD38 mAbs inhibit the proliferation and survival of MM cells, there are substantial side effects on antitumoral NK cells. The NK-mediated immune response needs to be further evaluated to minimize the adverse effects of NK cell loss. The killing effect of CD38 mAbs on CD38high NK cells should be minimized and the potential combination of CD38low/- NK cells and CD38 mAbs should be maximized to better benefit from their therapeutic efficacy against MM. CD38 mAb effects against MM can be maximized by combination therapies with immunomodulatory imide drugs (IMiDs), proteasome inhibitors (PIs), anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies, or cellular therapies for the treatment of MM, especially in patients with relapsed or refractory MM (R/R MM) and drug-resistant MM.


Methimazole-Induced Goitrogenesis in an Adult Patient With the Syndrome of Resistance to Thyroid Hormone.
Patients with the syndrome of resistance to thyroid hormone (RTH) have clinical (tachycardia and anxiety) and biochemical (elevated thyroid hormones level) features of hyperthyroidism. Based on previous reports in pediatric patients with the RTH, antithyroid treatment in these patients is not indicated. Clinical and biochemical sequel of antithyroid therapy in an adult patient with RTH was not previously reported. A 63-year-old African American female with history of RTH was treated with a therapy consisting of methimazole 15 mg daily and atenolol. Methimazole treatment resulted in reduction in thyroid hormone level while the patient's TSH increased with a peak of 24.88 mIU/L. Having achieved biochemical euthyroidism, the patient developed thyroid gland enlargement associated with progressive symptoms of dysphagia and dyspnea. Examination demonstrated globally enlarged firm thyroid gland with areas of nodularity in both lobes. A computed tomography of the neck showed enlarged thyroid gland with extension around bilateral sternocleidomastoid muscles and compression onto the trachea. Methimazole therapy was discontinued and patient was treated just on atenolol. Over 12 months following discontinuation of methimazole, the patient experienced marked clinical and radiographic improvement of the goiter size associated with TSH reduction to 1.26 mIU/L and modest free thyroxine increase as expected in RTH. It seems appealing to treat patients with the RTH with antithyroid medications. However, in these patients decrease in thyroid hormone levels will stimulate TSH production, which can, in turn, predispose to goiter formation. Our report supports prior observations in children with RTH that treatment with methimazole is not indicated in adult patients with RTH.


A meta-analysis of prognostic factors of osteosarcoma.
To systemically evaluate the factors influencing the prognosis of osteosarcoma. Case-control studies (sample size>100) investigating the factors influencing the prognosis of osteosarcoma published from 1st January 1980 to 1st February 2019 were searched in the databases, including PubMed, Embase, and CBM. The meta-analysis was conducted within the Review Manager 5.3 software. 22 studies were included. The 5-year overall survival (OS) of male patients was significantly lower than that of female patients (OR=0.84, 95% CI=0.76-0.93). There was no significant statistical difference in 5-year OS between the adolescent group (≤14 years old) and the adult group (>14 years old) (OR=0.88, 95% CI=0.68-1.14). Before standardized chemotherapy, which was started in 2000, the 5-year OS of patients receiving surgery and chemotherapy was significantly higher than patients only receiving surgery (OR=3.20, 95% CI=2.30-4.46). After 2000, the 5-year OS of patients receiving standardized chemotherapy was significantly higher than those undergoing non-standardized chemotherapy (OR=2.17, 95% CI=1.77-2.67). The 5-year OS of the limb-salvage surgery group was higher than that of the amputation surgery group (OR=2.17, 95% CI=1.77-2.67). The 5-year OS of patients with a good response to chemotherapy (Huvos III+IV) was higher than that of patients with poor response to chemotherapy (Huvos I+II) (OR=2.45, 95% CI=2.10-2.87). Patients without bone metastasis had significantly better 5-year OS than those with bone metastasis at initial diagnosis (OR=0.2, 95% CI=0.11-0.39). The prognosis of male osteosarcoma patients was slightly worse than that of female patients. Surgery plus standardized chemotherapy can improve the 5-year OS of osteosarcoma patients. Patients who had undergone limb-salvage surgery had a better prognosis. Poor response to chemotherapy and bone metastasis had a negative influence on the prognosis of osteosarcoma.


Immunogenicity in African Green Monkeys of M Protein Mutant Vesicular Stomatitis Virus Vectors and Contribution of Vector-Encoded Flagellin.
Recombinant vesicular stomatitis virus (VSV) is a promising platform for vaccine development. M51R VSV, an attenuated, M protein mutant strain, is an effective inducer of Type I interferon and dendritic cell (DC) maturation, which are desirable properties to exploit for vaccine design. We have previously evaluated M51R VSV (M51R) and M51R VSV that produces flagellin (M51R-F) as vaccine vectors using murine models, and found that flagellin enhanced DC activation and VSV-specific antibody production after low-dose vaccination. In this report, the immunogenicity of M51R vectors and the adjuvant effect of virus-produced flagellin were evaluated in nonhuman primates following high-dose (10⁸ pfu) and low-dose (10⁵ pfu) vaccination. A single intramuscular vaccination of African green monkeys with M51R or M51R-F induced VSV-specific, dose-dependent humoral immune responses. Flagellin induced a significant increase in antibody production (IgM, IgG and neutralizing antibody) at the low vaccination dose. A VSV-specific cellular response was detected at 6 weeks post-vaccination, but was neither dose-dependent nor enhanced by flagellin; similar numbers of VSV-specific, IFNγ-producing cells were detected in lymph node and spleen of all animals. These results indicate that virus-directed, intracellular flagellin production may improve VSV-based vaccines encoding heterologous antigens by lowering the dose required to achieve humoral immunity.


MAM-E17 rat model impairments on a novel continuous performance task: effects of potential cognitive enhancing drugs.
Impairments in attention and inhibitory control are endophenotypic markers of neuropsychiatric disorders such as schizophrenia and represent key targets for therapeutic management. Robust preclinical models and assays sensitive to clinically relevant treatments are crucial for improving cognitive enhancement strategies. We assessed a rodent model with neural and behavioral features relevant to schizophrenia (gestational day 17 methylazoxymethanol acetate treatment (MAM-E17)) on a novel test of attention and executive function, and examined the impact of putative nootropic drugs. MAM-E17 and sham control rats were trained on a novel touchscreen-based rodent continuous performance test (rCPT) designed to closely mimic the human CPT paradigm. Performance following acute, systemic treatment with an array of pharmacological compounds was investigated. Two cohorts of MAM-E17 rats were impaired on rCPT performance including deficits in sensitivity (d') and increased false alarm rates (FARs). Sulpiride (0-30 mg/kg) dose-dependently reduced elevated FAR in MAM-E17 rats whereas low-dose modafinil (8 mg/kg) only improved d' in sham controls. ABT-594 (5.9-19.4 μg/kg) and modafinil (64 mg/kg) showed expected stimulant-like effects, while LSN2463359 (5 mg/kg), RO493858 (10 mg/kg), atomoxetine (0.3-1 mg/kg), and sulpiride (30 mg/kg) showed expected suppressant effects on performance across all animals. Donepezil (0.1-1 mg/kg) showed near-significant enhancements in d', and EVP-6124 (0.3-3 mg/kg) exerted no effects in the rCPT paradigm. The MAM-E17 model exhibits robust and replicable impairments in rCPT performance that resemble attention and inhibitory control deficits seen in schizophrenia. Pharmacological profiles were highly consistent with known drug effects on cognition in preclinical and clinical studies. The rCPT is a sensitive and reliable tool with high translational potential for understanding the etiology and treatment of disorders affecting attention and executive dysfunction.


The living experience of difficulty telling the truth: a parse method study.
The purpose of this study was to investigate the living experience of difficulty telling the truth. Parse's research method was used to answer the question: What is the structure of the living experience of difficulty telling the truth? The participants were 9 nurses and 1 physician. The central finding of the study is the structure: difficulty telling the truth is uncomfortable dialogues with knowing silences arise with anguishing deliberations anticipating potential adversity, while contemplating intentional withholding gives rise to calm acquiescence. The findings are discussed in relation to the humanbecoming school of thought and extant literature.


Chemically Active, Porous 3D-Printed Thermoplastic Composites.
Metal-organic frameworks (MOFs) exhibit exceptional properties and are widely investigated because of their structural and functional versatility relevant to catalysis, separations, and sensing applications. However, their commercial or large-scale application is often limited by their powder forms which make integration into devices challenging. Here, we report the production of MOF-thermoplastic polymer composites in well-defined and customizable forms and with complex internal structural features accessed via a standard three-dimensional (3D) printer. MOFs (zeolitic imidazolate framework; ZIF-8) were incorporated homogeneously into both poly(lactic acid) (PLA) and thermoplastic polyurethane (TPU) matrices at high loadings (up to 50% by mass), extruded into filaments, and utilized for on-demand access to 3D structures by fused deposition modeling. Printed, rigid PLA/MOF composites display a large surface area (SAavg = 531 m2 g-1) and hierarchical pore features, whereas flexible TPU/MOF composites achieve a high surface area (SAavg = 706 m2 g-1) by employing a simple method developed to expose obstructed micropores postprinting. Critically, embedded particles in the plastic matrices retain their ability to participate in chemical interactions characteristic of the parent framework. The fabrication strategies were extended to other MOFs and illustrate the potential of 3D printing to create unique porous and high surface area chemically active structures.


Is mild vascular cognitive impairment reversible? Evidence from a study on the effect of carotid endarterectomy.
Mild vascular cognitive impairment (mVCI) is a broader term that is intended to detect cognitive loss before the development of dementia. The identification of preventable risk factors as well as therapeutic strategies of intervention is still unclear. It has been suggested that carotid endarterectomy (CEA) improves cognitive functions, beyond the well-known preventive effect upon future stroke events. In the present study, we evaluated the beneficial effect of CEA in restoring mVCI. Among a large sample of subjects, who underwent CEA for severe carotid stenosis, two groups were identified according to the absence (CON) or the presence of cognitive impairment (mVCI). A multidimensional neuropsychological and behavioural assessment was performed in the week prior, and at a 3-month follow-up after CEA. The incidence of mVCI in this sample was 38%. Seventy-eight patients completed the follow-up (48 CON, 30 mVCI). Both groups showed a clinical improvement after CEA, although the effect was significantly higher in the mVCI group in regard to verbal memory (short story, p < 0.05), and attention (digit span, p < 0.05) scores. At follow-up, 60% of mVCI subjects were classified as having normal cognitive functions. Index of disease severity and peripheral arterial disease were found to be the predictors of improvement. These findings support that mVCI represents a heterogeneous, in some cases reversible condition. CEA might be considered a therapeutic option to treat and prevent cognitive decline in mVCI patients.


MiR-140-5p exerts a protective function in pregnancy-induced hypertension via mediating TGF-β/Smad signaling pathway.
Animal experiments showed that PIH rats had increased mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP), but decreased litter size, number of viable fetuses, fetal weight, and placental weight. The higher Flt-1 and lower VEGF was observed in PIH rats with elevated TNF-α and IL-6 levels and decreased IL-10 levels. Treatment with agomiR-140-5p improved regarding the above indicators. Cell experiments demonstrated that miR-140-5p mimic increased cell invasion and migration abilities and decreased the activity of TGF-β/Smad pathway, while TGFBR1 can reverse the role of miR-140-5p mimic in trophoblasts.


The mitosis-specific monoclonal antibody MPM-2 recognizes phosphoproteins associated with the nuclear envelope in Chlamydomonas reinhardtii cells.
The monoclonal antibody MPM-2 recognizes a family of phosphorylated proteins present in mitotic cells. In a number of organisms it stains nuclei and also cytoskeletal structures which contain or organize tubulin. In mitotic Chlamydomonas reinhardtii cells MPM-2 reacts with phosphoproteins associated with the nuclear envelope (NE). Staining of the NE region appears in preprophase, reaches a maximum intensity in metaphase/anaphase and disappears rapidly in telophase. Localized hyperphosphorylation of the anterior NE region is apparent in many cells throughout mitosis. The distribution and timing of MPM-2 labeling suggests that in Chlamydomonas MPM-2 may be interacting with lamin-like phosphoproteins.


Expression of Toll-like receptors 2 and 4 in gingivitis and chronic periodontitis.
Periodontal disease is the major cause of adult tooth loss and is commonly characterized by a chronic inflammation caused by infection by oral bacteria. Members of Toll-like receptor (TLR) family recognize conserved microbial structures, such as bacterial lipopolysaccharides, and activate signaling pathways that result in immune responses against microbial infections. The aim of the present study was to assess the mRNA expression of TLR-2 and TLR-4 in gingivitis and chronic periodontitis. Gingival tissue samples were collected from patients with chronic periodontitis, gingivitis, and healthy controls. Total RNA was extracted and RT-PCR was done for TLR-2 and TLR-4. The results showed that TLR-2 was significantly increased in gingivitis compared to TLR-4 expression and decreased in chronic periodontitis.


Effects of slime produced by clinical isolates of coagulase-negative staphylococci on activities of various antimicrobial agents.
A novel in vitro semiquantitative method was developed to investigate the influence of staphylococcal slime on the activities of 22 antimicrobial agents. Pefloxacin, teicoplanin, and vancomycin demonstrated remarkable decreases in efficacy: 30, 52, and 63%, respectively. The activity of rifampin was not significantly reduced (0.99%), whereas all other agents tested were modestly affected (<15% decrease). These data could be influential in the treatment of implant-associated infections caused by slime-producing staphylococci.


The anti-malarial artemisinin inhibits pro-inflammatory cytokines via the NF-κB canonical signaling pathway in PMA-induced THP-1 monocytes.
Several kinds of sesquiterpene lactones have been proven to inhibit NF-κB and to retard atherosclerosis by reducing lesion size and changing plaque composition. The anti-malarial artemisinin (Art) is a pure sesquiterpene lactone extracted from the Chinese herb Artemisia annua (qinghao, sweet wormwood). In the present study, we demonstrate that artemisinin inhibits the secretion and the mRNA levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 in a dose-dependent manner in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 human monocytes. We also found that the NF-κB specific inhibitor, Bay 11-7082, inhibited the expression of these pro-inflammatory cytokines, suggesting that the NF-κB pathway may be involved in the decreased cytokine release. At all time-points (1-6 h), artemisinin impeded the phosphorylation of IKKα/ß, the phosphorylation and degradation of IκBα and the nuclear translocation of the NF-κB p65 subunit. Additionally, artemisinin inhibited the translocation of the NF-κB p65 subunit as demonstrated by confocal laser scanning microscopic analysis and by NF-κB binding assays. Our data indicate that artemisinin exerts an anti-inflammatory effect on PMA-induced THP-1 monocytes, suggesting the potential role of artemisinin in preventing the inflammatory progression of atherosclerosis.


MCL1 Inhibition Overcomes the Aggressiveness Features of Triple-Negative Breast Cancer MDA-MB-231 Cells.
Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial-Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as OCT3/4, SOX2, NANOG, as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC.


Phosphorylation of cardiac protein kinase B is regulated by palmitate.
In this study isolated perfused working rat hearts were used to investigate the role of palmitate-regulated protein kinase B (PKB) phosphorylation on glucose metabolism. Rat hearts were perfused aerobically in working mode with 11 mM glucose and either 100 microU/ml insulin or 100 microU/ml insulin and 1.2 mM palmitate. PKB activity and phosphorylation state were reduced in the presence of 1.2 mM palmitate, which correlates with a decrease in glycolysis (47%), glucose oxidation (84%), and glucose uptake (43%). In contrast to skeletal muscle, neither p38 nor ERK underwent changes in their phosphorylation states in response to insulin or insulin and palmitate. Moreover, pharmacological restoration of glucose oxidation rates in hearts perfused with 1.2 mM palmitate demonstrated no increase in PKB phosphorylation state. In cultured mouse cardiac muscle HL-1 cells, insulin markedly increased PKB phosphorylation, which was blunted by pre- and cotreatment with 1.2 mM palmitate. However, neither palmitate nor C(2)-ceramide treatment of insulin-stimulated cells was able to accelerate PKB dephosphorylation beyond that observed following the removal of insulin alone. Taken together, these experiments show the control of PKB phosphorylation by palmitate is independent of ceramide and suggest that this signaling event may be an important regulator of myocardial glucose uptake and oxidation.


High resistance index of Doppler ultrasound in tuberculous peritonitis presenting as abdominal carcinomatosis: report of two cases.
The radiologic features of tuberculous peritonitis (TB peritonitis) are seldom reported, and the use of color Doppler ultrasound in the diagnosis of TB peritonitis is even less common. Herein, we present two patients (a 29-year-old woman and a 56-year-old woman) who were evaluated for months of progressive enlargement of the abdomen, poor appetite and weight loss. In both patients, clinical and laboratory examinations suggested carcinoma, except a very high vascular resistance (resistance index 1.0 and 0.89, respectively) of the tumor feeding vessels detected by color Doppler ultrasound. TB peritonitis was finally diagnosed by exploratory laparotomy. Both patients were treated using a four-drug regimen of isoniazid, rifampicin, ethambutol hydrochloride and pyrazinamide for nine months and were clinically cured. In conclusion, if color Doppler ultrasound reveals normal ovaries, ascites containing thin, delicate incomplete or complete septa, and only a few high-resistance tumor feeding vessels in the abdominal cavity (resistance index > or = 0.80), TB peritonitis should be considered.


Fixed-dose ibuprofen/famotidine: a review of its use to reduce the risk of gastric and duodenal ulcers in patients requiring NSAID therapy.
A fixed-dose combination of the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and the histamine H(2) receptor antagonist famotidine (ibuprofen/famotidine; DUEXIS(®)) is now available for the symptomatic treatment of arthritic symptoms and to reduce the risk of upper gastrointestinal (GI) ulcers in patients who require ibuprofen therapy. The gastroprotective efficacy of oral ibuprofen/famotidine 800/26.6 mg three times daily in patients requiring NSAID therapy for inflammatory conditions and/or pain was evaluated in two 24-week, well-designed trials (REDUCE-1 and -2). According to the post-adjudication analysis of these studies, ibuprofen/famotidine significantly reduced the life table estimated rate of gastric ulcers (primary endpoint of REDUCE-1) but not upper GI ulcers (i.e. gastric or duodenal ulcers) [primary endpoint of REDUCE-2] compared with ibuprofen alone. When life table estimated rates of secondary endpoints were assessed, significantly fewer recipients of the fixed-dose combination than of ibuprofen alone developed upper GI ulcers or duodenal ulcers in REDUCE-1, whereas the between-group difference in gastric ulcers and duodenal ulcers was considered to be nonsignificant in REDUCE-2 because of hierarchical testing. However, in a prespecified pooled analysis of REDUCE-1 and -2, the rate of upper GI ulcers as well as each of the upper GI ulcer components was significantly lower with ibuprofen/famotidine than with ibuprofen. Ibuprofen/famotidine was generally well tolerated, with a tolerability profile consistent with those established for the individual agents.


Potential use of microarray patches for vaccine delivery in low- and middle- income countries.
Microarray patches (MAPs), also referred to as microneedle patches, are a novel methodology that have the potential to overcome barriers to vaccine delivery in low- and middle-income countries (LMICs), and transform the way that vaccines are delivered within immunization programs. The World Health Organization's Initiative for Vaccine Research and its partners are working to understand how MAPs could ease vaccine delivery and increase equitable access to vaccines in LMICs. Global stakeholders have been engaged to evaluate technical, economic, and programmatic challenges; to validate assumptions where possible; and to propose areas of focus to facilitate future vaccine-MAP product development. This report summarizes those learnings.


Synaptic control of an endogenous pacemaker network.
1. The present study consists of an analysis of the coordinating effects of monosynaptic EPSPs and IPSPs on the discharge of the endogenous pacemaker neurons which drive the pyloric motor system of the spiny lobster. The experiments were performed on isolated nervous systems. 2. An analysis of the characteristic phase response curves to both classes of input (fig. 1) shows that the pyloric oscillator possesses the necessary characteristic for entrainment: i.e. a periodically varying sensitivity to synaptic drive. 3. By repetitive stimulation of either input at frequencies near the endogenous frequency of the PD slow wave, it was possible to entrain the discharge of the pacemaker system to the cyclic stimulus (figs. 2b and 3b). The pyloric discharge tends to occur at different characteristic phase relations in response to the two inputs (figs. 2c and 3c), which reflect features of the corresponding phase response curves (fig. 1). 4. It is argued that the periodic sensitivity of these neurons to synaptic input reflects interactions between the synaptically induced currents and the endogenous currents which underlie the slow wave.


Resonant Tuning of Langevin Transducers for Ultrasonically Assisted Machining Applications.
This article provides a fundamental study into the trade-offs between the location of piezoceramic elements, resonant frequency, and achievable ultrasonic vibration amplitude at the working end of the bolted Langevin-style transducers (BLTs) for ultrasonically assisted machining (UAM) applications. Analytical models and finite-element (FE) models are established for theoretical study, which are then validated by experiments on four real electromechanical transducers. The results suggest that resonant frequency and oscillation amplitude of the BLTs depend essentially on the dimensions of the system and the location of the piezoceramic elements. The highest resonant frequency and the maximal vibration are achieved when the piezoceramic elements are at the longitudinal displacement node, where the highest effective electromechanical coupling coefficient value is exhibited. However, the minimal resonant frequency and the lowest vibration, which is almost equal to zero, are observed when the piezoceramic elements are located at the displacement antinode. In addition, the longitudinal displacement node locations are dependent on the resonant frequency of the devices rather than the locations of the piezoceramic elements.


Green tea polyphenols alleviate early BBB damage during experimental focal cerebral ischemia through regulating tight junctions and PKCalpha signaling.
It has been supposed that green tea polyphenols (GTPs) have neuroprotective effects on brain damage after brain ischemia in animal experiments. Little is known regarding GTPs' protective effects against the blood-brain barrier (BBB) disruption after ischemic stroke. We investigated the effects of GTPs on the expression of claudin-5, occludin, and ZO-1, and the corresponding cellular mechanisms involved in the early stage of cerebral ischemia. Male Wistar rats were subjected to a middle cerebral artery occlusion (MCAO) for 0, 30, 60, and 120 min. GTPs (400 mg/kg/day) or vehicle was administered by intragastric gavage twice a day for 30 days prior to MCAO. At different time points, the expression of claudin-5, occludin, ZO-1, and PKCα signaling pathway in microvessel fragments of cerebral ischemic tissue were evaluated. GTPs reduced BBB permeability at 60 min and 120 min after ischemia as compared with the vehicle group. Transmission electron microscopy also revealed that GTPs could reverse the opening of tight junction (TJ) barrier at 60 min and 120 min after MACO. The decreased mRNA and protein expression levels of claudin-5, occludin, and ZO-1 in microvessel fragments of cerebral ischemic tissue were significantly prevented by treatment with GTPs at the same time points after ischemia in rats. Furthermore, GTPs could attenuate the increase in the expression levels of PKCα mRNA and protein caused by cerebral ischemia. These results demonstrate that GTPs may act as a potential neuroprotective agent against BBB damage at the early stage of focal cerebral ischemia through the regulation of TJ and PKCα signaling.


Objective Assessment of Visual Field Defects Caused by Optic Chiasm and Its Posterior Visual Pathway Injury.
To investigate the characteristics and objective assessment method of visual field defects caused by optic chiasm and its posterior visual pathway injury. Typical cases of visual field defects caused by injuries to the optic chiasm, optic tracts, optic radiations, and visual cortex were selected. Visual field examinations, visual evoked potential (VEP) and multifocal visual evolved potential (mfVEP) measurements, craniocerebral CT/MRI, and retinal optical coherence tomography (OCT) were performed, respectively, and the aforementioned visual electrophysiological and neuroimaging indicators were analyzed comprehensively. The electrophysiological manifestations of visual field defects caused by optic chiasm injuries were bitemporal hemianopsia mfVEP abnormalities. The visual field defects caused by optic tract, optic radiation, and visual cortex injuries were all manifested homonymous hemianopsia mfVEP abnormalities contralateral to the lesion. Mild relative afferent pupil disorder (RAPD) and characteristic optic nerve atrophy were observed in hemianopsia patients with optic tract injuries, but not in patients with optic radiation or visual cortex injuries. Neuroimaging could provide morphological evidence of damages to the optic chiasm and its posterior visual pathway. Visual field defects caused by optic chiasm, optic tract, optic radiation, and visual cortex injuries have their respective characteristics. The combined application of mfVEP and static visual field measurements, in combination with neuroimaging, can maximize the assessment of the location and degree of visual pathway damage, providing an effective scheme for the identification of such injuries.


Anorexia induced by interleukin 1: involvement of corticotropin-releasing factor.
It has recently been demonstrated by three independent research groups including ours that interleukin 1 (IL-1), a polypeptide hormone produced by activated monocytes or macrophages, or both, stimulates the release of hypothalamic corticotropin-releasing factor (CRF). Since CRF acts centrally in the brain to reduce food intake, we hypothesized that IL-1 might induce anorexia through this central action of CRF. The present study was carried out to examine the hypothesis, using male Wistar rats. Based on three lines of evidence, we report here that IL-1, both endogenously released and exogenously administered, induces the suppression of food intake in rats and that endogenous CRF in the brain is involved in the IL-1-induced anorexia. First, lipopolysaccharide (LPS), a potent stimulant of the release and production of endogenous IL-1, caused anorexia in a dose-related manner, and this effect was significantly blocked by pretreatment with glucocorticoid hormones, which have been shown to inhibit the production of endogenous IL-1 by LPS. Second, intraperitoneal injection of IL-1 resulted in a dose-related suppression of food intake. Third, anorexia induced by IL-1 was diminished by the immunoneutralization of endogenous CRF in the brain. These results provide further evidence of the existence of bidirectional communication between the immune and neuroendocrine systems. Furthermore, this connection between IL-1 and CRF may represent a mechanism by which anorexia results from the activation of the immune system by such immunological challenges as acute infectious diseases.


Treatment for acute lymphoblastic leukemia in children is associated with papillary carcinoma of thyroid, but not with thyroid disfunction.
The treatment of acute lymphoblastic leukemia (ALL) in children may cause sequelae, some appearing only at long-term follow-up. We investigated the thyroid gland morphology and the function of the pituitary-thyroid axis in a group of patients treated for ALL in childhood. A cohort study was conducted at a tertiary medical center. Thirty-three children (22 males and 11 females; age: 11.9+/-3 years; range: 6 to 18 years) were studied. The mean age at the time of chemotherapy and prophylactic cranial irradiation (12-24 Gy) was 5.5+/-2.6 years (range: 1 to 14 years). The average length of the follow-up was 6.1+/-3 years (range: 2 to 12 years). Thyroid morphology (n=33) was evaluated by palpation and ultrasonography. Thyroid function (n=30) was evaluated measuring total T3 and T4, and by the thyrotrophin-releasing hormone (TRH) test. Prolactin secretion was assessed before and after injection of TRH to evaluate the diagnostic test accuracy. One out of the 33 children (3%) was found to have a papillary carcinoma of thyroid four years after ALL treatment. Thyroid function was normal in all the patients, however one case (3%) showed high TSH (9.2 microU/mL) and prolactin (37.5 ng/mL) basal levels, but normal responses to TRH (TSH = 17.8 microU/mL; prolactin = 82.3 ng/mL). These hormonal alteration were not confirmed at follow-up: TSH = 1.6 microU/mL and prolactin = 13.7 ng/mL. In this cohort of patients, the treatment of ALL was associated with one case of thyroid carcinoma, but it did not produce adverse effect on the thyroid function, at least after a follow-up lasted on average 6 years.


Disparities in Mpox Vaccination Among Priority Populations During the 2022 Outbreak.
The 2022 mpox outbreak disproportionately affected men who have sex with men and persons living with HIV (PLWH). A 2-dose mpox vaccine series was deployed in mid-2022. Structural racism and insurance status may have affected equitable vaccination. We defined 3 cohorts: PLWH with at least 1 clinic visit between 1 July 2021 and 1 July 2022 (n = 2066), HIV preexposure prophylaxis (PrEP) recipients as of 1 January 2022 (n = 262), and all mpox-vaccinated patients in our health system between 1 July 2022 and 30 November 2022 (n = 807). We identified patients with prior diagnosed sexually transmitted infections (STIs) as having a positive test result for gonorrhea, chlamydia, or syphilis between 1 July 2021-1 July 2022. The primary outcome was receipt of at least 1 dose of mpox vaccine. We identified 224 (10.8%) PLWH and 50 (19.0%) PrEP patients who received at least 1 dose of mpox vaccine. Among PLWH, White race (odds ratio [OR], 1.55; 95% CI, 1.11-2.16), private insurance (OR, 1.83; 95% CI, 1.01-3.34), prior STI (OR, 3.04; 95% CI, 2.16-4.27), prior COVID-19 vaccination (OR, 3.17; 95% CI, 1.93-5.20), and prior influenza vaccination (OR, 1.42; 95% CI, 1.30-1.96) independently predicted mpox vaccination. Within the PrEP cohort, prior COVID-19 vaccination and seasonal influenza vaccination predicted mpox vaccination. Uninsured patients were vaccinated later in the outbreak than patients with private insurance (median time to vaccination, 41 days in the privately insured group vs 83 days in the uninsured group; P < .0001). Race, insurance status, prior STI, and previous receipt of other vaccines influenced uptake of mpox vaccine. Addressing health disparities and vaccine acceptance will be essential in improving future outbreak response.


Genomic characterization of ciprofloxacin resistance in a laboratory-derived mutant and a clinical isolate of Streptococcus pneumoniae.
The broad-spectrum fluoroquinolone ciprofloxacin is a bactericidal antibiotic targeting DNA topoisomerase IV and DNA gyrase encoded by the parC and gyrA genes. Resistance to ciprofloxacin in Streptococcus pneumoniae mainly occurs through the acquisition of mutations in the quinolone resistance-determining region (QRDR) of the ParC and GyrA targets. A role in low-level ciprofloxacin resistance has also been attributed to efflux systems. To look into ciprofloxacin resistance at a genome-wide scale and to discover additional mutations implicated in resistance, we performed whole-genome sequencing of an S. pneumoniae isolate selected for resistance to ciprofloxacin in vitro (128 μg/ml) and of a clinical isolate displaying low-level ciprofloxacin resistance (2 μg/ml). Gene disruption and DNA transformation experiments with PCR fragments harboring the mutations identified in the in vitro S. pneumoniae mutant revealed that resistance is mainly due to QRDR mutations in parC and gyrA and to the overexpression of the ABC transporters PatA and PatB. In contrast, no QRDR mutations were identified in the genome of the S. pneumoniae clinical isolate with low-level resistance to ciprofloxacin. Assays performed in the presence of the efflux pump inhibitor reserpine suggested that resistance is likely mediated by efflux. Interestingly, the genome sequence of this clinical isolate also revealed mutations in the coding region of patA and patB that we implicated in resistance. Finally, a mutation in the NAD(P)H-dependent glycerol-3-phosphate dehydrogenase identified in the S. pneumoniae clinical strain was shown to protect against ciprofloxacin-mediated reactive oxygen species.


Responders and non-responders to aerobic exercise training: beyond the evaluation of V˙O2max.
The evaluation of the maximal oxygen uptake ( V˙O2max ) following exercise training is the classical assessment of training effectiveness. Research has lacked in investigating whether individuals that do not respond to the training intervention ( V˙O2max ), also do not improve in other health-related parameters. We aimed to investigate the cardiovascular and metabolic adaptations (i.e., performance, body composition, blood pressure, vascular function, fasting blood markers, and resting cardiac function and morphology) to exercise training among participants who showed different levels of V˙O2max responsiveness. Healthy sedentary participants engaged in a 6-week exercise training program, three times a week. Our results showed that responders had a greater increase in peak power output, second lactate threshold, and microvascular responsiveness, whereas non-responders had a greater increase in cycling efficiency. No statistical differences were observed in body composition, blood pressure, fasting blood parameters, and resting cardiac adaptations. In conclusion, our study showed, for the first time, that in addition to the differences in the V˙O2max , a greater increase in microvascular responsiveness in responders compared to non-responders was observed. Additionally, responders and non-responders did not show differences in the adaptations on metabolic parameters. There is an increasing need for personalized training prescription, depending on the target clinical outcome.


Learning and memory performance following acute intranasal insulin administration in abstinent smokers.
The highest incidence of relapse to smoking occurs within the first 2 weeks of a cessation attempt. In addition to enhanced nicotine craving, this phase of smoking cessation is also marked by learning and memory dysfunction. Many smokers are not able to overcome these symptoms, and they relapse to smoking shortly after trying to quit. In two clinical studies, we evaluated intranasal insulin for efficacy in improving learning and memory function during nicotine withdrawal. Our first study was a crossover evaluation (N = 19) following 20 hr of smoking abstinence. Study 2 was a parallel design study (N = 50) following 16 hr of abstinence. Intranasal insulin (60 IU) dose was administered in both studies and cognitive function was measured using California Verbal Learning Test-II. Intranasal insulin did not improve learning over the 5 verbal learning trials. In addition, intranasal insulin did not improve either short- or long-delay recall in either study. In summary, the one-time administration of intranasal insulin does not improve verbal learning and memory in smokers. Whether longer administration schedules may be of benefit should be evaluated in future studies.


Factors affecting return to play after anterior cruciate ligament reconstruction: a review of the current literature.
Anterior cruciate ligament reconstruction has been reported to produce normal or near-normal knee results in > 90% of patients. A recent meta-analysis suggested that, despite normal or near-normal knees, many athletes do not return to sports. Rates and timing of return to competitive athletics are quite variable depending on the graft type, the age of the patient, the sport, and the level of play. Even when athletes do return to play, often they do not return to their previous level. Graft failure, subjective physical factors, and psychological factors, including fear of reinjury and lack of motivation, appear to play a large role in patients' ability to return to sporting activities.


[Reoperation for recurrent carcinoma of the large intestine and rectum].
Based on their own experience with reoperations of relapses of colorectal carcinoma the authors draw attention to the very poor results of these operations; even in case of early detection of a relapse of the tumour in the majority only a palliative operation could be performed and only in 10% patients a radical operation. Therefore the authors emphasize prevention of relapses.


Molecular and biochemical responses of vitellogenin in the mussel Mytilus galloprovincialis exposed to the glyphosate-based herbicide Roundup® Power 2.0.
Glyphosate-based herbicides (GBHs) occur in aquatic ecosystems at concentrations of hundreds of micrograms per liter. As formulation adjuvants are suspected to be endocrine-disrupting chemicals, we assessed the effects of the recent GBH formulation Roundup® Power 2.0 on vitellogenin (VTG) in Mytilus galloprovincialis. Mussels were exposed for 7, 14, and 21 days to two concentrations of the commercial formulation, corresponding to 100 and 1000 μg/L of glyphosate. The expression of the vtg gene in gonads of females and males, as well as the levels of alkali labile phosphates (ALP) in gonads and non-gonadal tissues from the two sexes were measured. No significant alterations were observed in vtg expression values during the exposure. Conversely, a significant reduction in gonadal ALP levels was observed in females exposed for 21 days and in males exposed for 7 days. In addition, ALP levels increased significantly in gonads from males exposed for 21 days to the two concentrations of Roundup®. As for non-gonadal tissues, ALP levels did not change significantly in females, whereas ALP levels decreased significantly in non-gonadal tissues from males exposed for 21 days to the lowest concentration tested. An overall statistically significant difference in ALP levels was found between females and males. Although preliminary, our study suggests that GBH can affect reproduction-related parameters in mussels.


Phenylalanyl-tRNA synthetase of Escherichia coli K10. Effects of zinc(II) on partial reactions of diadenosine 5',5"'-P1,P4-tetraphosphate synthesis, conformation, and protein aggregation.
The synthesis of diadenosine 5',5"'-P1-,P4-tetraphosphate (Ap4A) catalyzed by phenylalanyl-tRNA synthetase in the presence of Zn2+ involves the same partial reactions (synthesis of phenylalanyladenylate and transfer of the adenylate moiety to ATP) as occur in the absence of this metal ion. However, transfer is strongly stimulated while adenylate synthesis is depressed. Also inhibited are pyrophosphorolysis of phenylalanyladenylate and transfer of phenylalanine from the adenylate to cognate tRNA, because overall tRNA phenylalanylation is depressed [Mayaux, J.-F., & Blanquet, S. (1981) Biochemistry 20, 4647-4654], whereas binding of tRNA to the synthetase is not. At moderate concentrations of Zn2+, and in the presence of 5 microM phenylalanine and 0.5 mM ATP, transfer of AMP is rate limiting, while at higher concentrations of Zn2+ synthesis of adenylate is rate determining. The Zn2+ concentration optimum for stimulation depends on the concentration of phenylalanine and ATP. The effects of Zn2+ are mediated through two classes of binding site(s) on the synthetase, the half-saturations of which are 1-4 and 20-30 microM Zn2+, respectively. Binding of Zn2+ to the second class of site(s) causes inhibition of the synthetase, whereas binding to the first class is responsible for activation and inhibition, which may be caused by a conformational change. Evidence for the latter is the observed decrease in protein intrinsic fluorescence intensity and the decrease in fluorescence intensity of 6-(p-toluidinyl)naphthalene-2-sulfonate, which is used as a reporter group. The kinetics of the binding reaction show a saturation dependence on Zn2+, also suggesting that a conformational change occurs.(ABSTRACT TRUNCATED AT 250 WORDS)


Susceptibility of 4410 clinical isolates to doxycycline.
In an 1100-bed hospital where doxycycline has been widely used, the susceptibility to doxycycline of 4410 clinical isolates was examined. Ninety-one and 80.8 per cent of the Staphylococcus aureus and Haemophilus influenzae strains, respectively, were susceptible to 1 mg doxycycline/l. Seventy-four per cent of the Escherichia coli and 81.7 per cent of the Klebsiella strains were inhibited by 4 mg/l. The Enterobacter and Enterococcus strains were less susceptible. Nearly all Proteus mirabilis isolates were resistant. The results are comparable to those of other studies.


Laminin expression patterns in human ureteral tissue.
Laminins are extracellular matrix proteins that are involved in various cellular functions, including adhesion, proliferation and differentiation. In this study we examined the expression patterns of the laminin chains in human ureteral tissue in vitro and in vivo. We screened the expression of laminin chains at the mRNA level and determined the major laminins expressed in epithelial and stromal cells of human ureteral tissue by reverse transcriptase-polymerase chain reaction and Western blot analysis. We also examined their expression in vivo by immunofluorescence study. Reverse transcriptase-polymerase chain reaction analysis revealed that urothelial cells in vitro expressed laminins alpha1, alpha3, alpha5, beta1, beta2, beta3, gamma1 and gamma2, while stromal cells expressed alpha1, alpha2, alpha4, alpha5, beta1, beta2 and gamma1. Western blot analysis under reduced conditions confirmed that urothelial cells expressed laminin alpha3 and alpha5, while stromal cells strongly expressed alpha4 and alpha2. Immunofluorescence labeling with antilaminin alpha chain antibodies in human ureteral tissues confirmed that laminin alpha2, alpha3 and alpha5 chains were strongly expressed in the basement membrane of the urothelium, while alpha4 was expressed predominantly in smooth muscle cells. The most prominent laminin of urothelial cells was laminin 5 (alpha3beta3gamma2), whereas in stromal cells we noted laminins 8/9 (alpha4beta1/2gamma1). Laminin alpha5 showed the widest distribution pattern in vivo. Our data may be useful for understanding the mechanism involved not only in cell growth and differentiation, but also in cancer invasion in the urinary tract.


Sex differences in social stress-induced pressor and behavioral responses in normotensive and prehypertensive rats.
This study investigated sex differences in chronic social stress-induced pressor and behavioral responses in normotensive and prehypertensive rats. Adult Wistar and borderline hypertensive (BH) rats (offspring of Wistar dams and spontaneously hypertensive sires) of both sexes were exposed to crowding stress (200 cm²/rat, 5 rats/cage) for 6 weeks. Controls were kept 4 rats/cage (480 cm²/rat). Blood pressure (BP) and open field activity were determined before experiment and after 1, 3 and 6 weeks of stress. Basal BP of BH rats was higher than in Wistar (p < 0.001) in both males and females. Horizontal and vertical activity of BH males and females was elevated vs. Wistar (p < 0.01) and females in both phenotypes were more active than the respective males (p < 0.01). Crowding resulted in delayed between-session habituation and significant elevation of BP only in BH males (143 ± 2 vs. 134 ± 3 mmHg in controls after 6-week crowding). No changes of BP were observed in crowded females of both phenotypes regardless of their delayed between-session habituation. Thus chronic social stress produced by crowding seems to represent a significant risk factor for development of stress-related hypertension only in males with genetic predisposition to high blood pressure while females of both phenotypes responded to stress by impaired between-session habituation.


Recent advances in research and treatment of neurological disorders.
This year the American Academy of Neurology celebrated its 60th Annual Meeting that brought together over 10,000 neurologists and neuroscientists from all over the world in Chicago, Illinois. This report highlights relevant presentations covering the pathophysiology of neurological disorders, investigational therapies and biomarkers that will allow better diagnosis, monitoring and treatment of patients with neurological disease.


Carotid cavernous fistula with bilateral thalamic infarct.
Carotid cavernous fistula (CCF) is an abnormal communication between cavernous sinus and carotid arterial system. Diagnosis depends on clinical manifestations and MRI findings and angiography. Clinical presentation of CCFs is characterized with chemosis, orbital bruit and pulsatile proptosis. Cranial nerve dysfunction and orbital pain might accompany these symptoms. Although spontaneous remission might occur, sometimes CCF might develop life threatening complications. Here in this case we presented a patient with CCF who afterwards developed bilateral thalamic infarct. Cerebral ischemia in CCF is a rare complication and CCF together with bilateral thalamic infarct has not been reported before.