A Novel Approach for Detecting Unique Variations among Infectious Bacterial Species in Endocarditic Cardiac Valve Vegetation.
Infectious endocarditis (IE) remains one of the deadliest heart diseases with a high death rate, generally following thrombo-embolic events. Today, therapy is based on surgery and antibiotic therapy. When thromboembolic complications in IE patients persist, this is often due to our lack of knowledge regarding the pathophysiological development and organization of cells in the vegetation, most notably the primordial role of platelets and further triggered hemostasis, which is related to the diversity of infectious microorganisms involved. Our objective was to study the organization of IE vegetations due to different bacteria species in order to understand the related pathophysiological mechanism of vegetation development. We present an approach for ultrastructural analysis of whole-infected heart valve tissue based on scanning electron microscopy and energy-dispersive X-ray spectroscopy. Our approach allowed us to detect differences in cell organization between the analyzed vegetations and revealed a distinct chemical feature in viridans Streptococci ones. Our results illustrate the benefits that such an approach may bring for guiding therapy, considering the germ involved for each IE patient.


Selective sodium sensing with gold-coated silicon nanowire field-effect transistors in a differential setup.
Ion-sensitive field-effect transistors based on silicon nanowires with high dielectric constant gate oxide layers (e.g., Al2O3 or HfO2) display hydroxyl groups which are known to be sensitive to pH variations but also to other ions present in the electrolyte at high concentration. This intrinsically nonselective sensitivity of the oxide surface greatly complicates the selective sensing of ionic species other than protons. Here, we modify individual nanowires with thin gold films as a novel approach to surface functionalization for the detection of specific analytes. We demonstrate sodium ion (Na(+)) sensing by a self-assembled monolayer (SAM) of thiol-modified crown ethers in a differential measurement setup. A selective Na(+) response of ≈-44 mV per decade in a NaCl solution is achieved and tested in the presence of protons (H(+)), potassium (K(+)), and chloride (Cl(-)) ions, by measuring the difference between a nanowire with a gold surface functionalized by the SAM (active) and a nanowire with a bare gold surface (control). We find that the functional SAM does not affect the unspecific response of gold to pH and background ionic species. This represents a clear advantage of gold compared to oxide surfaces and makes it an ideal candidate for differential measurements.


Structural insights into GDP-mediated regulation of a bacterial acyl-CoA thioesterase.
Thioesterases catalyze the cleavage of thioester bonds within many activated fatty acids and acyl-CoA substrates. They are expressed ubiquitously in both prokaryotes and eukaryotes and are subdivided into 25 thioesterase families according to their catalytic active site, protein oligomerization, and substrate specificity. Although many of these enzyme families are well-characterized in terms of function and substrate specificity, regulation across most thioesterase families is poorly understood. Here, we characterized a TE6 thioesterase from the bacterium Neisseria meningitidis Structural analysis with X-ray crystallographic diffraction data to 2.0-Å revealed that each protein subunit harbors a hot dog-fold and that the TE6 enzyme forms a hexamer with D3 symmetry. An assessment of thioesterase activity against a range of acyl-CoA substrates revealed the greatest activity against acetyl-CoA, and structure-guided mutagenesis of putative active site residues identified Asn24 and Asp39 as being essential for activity. Our structural analysis revealed that six GDP nucleotides bound the enzyme in close proximity to an intersubunit disulfide bond interactions that covalently link thioesterase domains in a double hot dog dimer. Structure-guided mutagenesis of residues within the GDP-binding pocket identified Arg93 as playing a key role in the nucleotide interaction and revealed that GDP is required for activity. All mutations were confirmed to be specific and not to have resulted from structural perturbations by X-ray crystallography. This is the first report of a bacterial GDP-regulated thioesterase and of covalent linkage of thioesterase domains through a disulfide bond, revealing structural similarities with ADP regulation in the human ACOT12 thioesterase.


Pretreatment of spiramycin fermentation residue using hyperthermophilic digestion: quick startup and performance.
This study aimed to evaluate the feasibility of hyperthermophilic anaerobic digestion at 70 °C in the pretreatment of spiramycin fermentation residue. By feeding municipal excess sludge under a solid retention time of 5 days, the hyperthermophilic digester was successfully started up within 3 days from mesophilic digestion by a one-step temperature increase from 35 to 70 °C. MiSeq sequencing showed the fast establishment of thermophilic fermenting bacterial communities in 3 days immediately after the temperature increase, with increases in abundance of Coprothermobacter, Spirochaetaceae_uncultured and Fervidobacterium from <0.001%, 1.06% and <0.001% to 33.77%, 11.65% and 3.42%, respectively. The feasibility of hyperthermophilic digestion for spiramycin residue was evaluated in batch experiments for 7 days. Hyperthermophilic digestion considerably reduced antibiotic concentrations, with removal efficiencies of 55.3% and 99.0% for the spiramycin residue alone and its mixture with hyperthermophilic sludge, respectively. At the same time, the abundances of four macrolide-lincosamide-streptogramin resistance genes were also reduced within 7 days, due to the decrease of their corresponding hosts. These results suggest that hyperthermophilic digestion could easily be started up from mesophilic digestion and might be a suitable pretreatment approach for spiramycin residue.


Bleeding peptic ulcer: An evolving role for surgical intervention.
Early surgical intervention was previously advocated in patients > 60 years with bleeding peptic ulcer presenting with haemodynamic instability or ongoing transfusion requirements. It is, however, well recognized that emergency surgical intervention with its inherent risks must be reserved for highly selected patients in whom endoscopy initially fails to control exsanquinating haemorrhage or in whom life-threatening bleeding recurs. Therapeutic endoscopy for bleeding ulcer has led to a remarkable decline in rebleeding rates, the need for emergency surgery and mortality. Octogenarians are at risk, particularly when ulcer size exceeds 2 cm. Poor surgical candidates make up two-thirds of patients with major ulcer bleeding and operation is to be avoided if at all possible. Medical therapy with proton pump inhibitor and subsequent eradication of Helicobacter pylori following endoscopic treatment has been shown to be beneficial to outcomes. Should surgery be deemed necessary, it is likely that laparoscopic techniques to control bleeding, with or without the addition of an acid-reducing procedure, will find a role in haemodynamically stable patients undergoing operation on an early elective basis.


Long Non-coding RNAs: Regulators of the Activity of Myeloid-Derived Suppressor Cells.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous cell population with potent immunosuppressive functions. They play major roles in cancer and many of the pathologic conditions associated with inflammation. Long non-coding RNAs (lncRNAs) are untranslated functional RNA molecules. The lncRNAs are involved in the control of a wide variety of cellular processes and are dysregulated in different diseases. They can participate in the modulation of immune function and activity of inflammatory cells, including MDSCs. This mini review focuses on the emerging role of lncRNAs in MDSC activity. We summarize how lncRNAs modulate the generation, recruitment, and immunosuppressive functions of MDSCs and the underlying mechanisms.


[A case of compression of the posterior tibial nerve by a synovial cyst with impact on the superior tibiofibular joint].
The authors report a case of compression of the posterior tibial nerve by a cyst originating from the superior tibio-fibular joint. The clinical signs were dysesthesia of the sole of the foot and paresis of the toe flexors. The diagnosis was obtained by electromyographic studies. The patient recovered completely after surgical excision of the cyst, which had developed beneath the tendinous arch of origin of the soleus muscle.


Hospital-acquired dysmagnesemia and mortality in critically ill patients: data from MIMIC-III database.
This study aimed to determine the relationship between hospital-acquired dysmagnesemia and in-hospital mortality in critically ill patients. A retrospective cohort study was conducted on critically ill patients who had normal serum magnesium levels on admission. Data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care III database. The normal range of serum magnesium was 1.6-2.6 mg/dL. In-hospital serum magnesium levels were categorized based on the occurrence of hospital-acquired hypomagnesemia and hypermagnesemia. Hospital-acquired hypomagnesemia and hypermagnesemia in the same patient were defined as a patient with the lowest level of serum magnesium of <1.6 mg/dL and the highest level of serum magnesium of >2.6 mg/dL, respectively. The in-hospital outcomes were collected. The findings revealed that 27.2% of patients developed hospital-acquired dysmagnesemia. In-hospital mortalities were 8.8% in patients with persistently normal serum magnesium levels, 12.2% in patients with hospital-acquired hypomagnesemia only, 18.4% in patients with hospital-acquired hypermagnesemia only, and 20.6% in patients with both hospital-acquired hypomagnesemia and hypermagnesemia. Compared to patients with persistently normal serum magnesium in hospital, those with hospital-acquired hypermagnesemia only [odds ratio (OR) = 1.346, P < 0.001] and those with both hospital-acquired hypomagnesemia and hypermagnesemia (OR = 1.333, P = 0.001) were significantly associated with higher in-hospital mortality. Hospital-acquired dysmagnesemia was common among critically ill patients. Hospital-acquired dysmagnesemia, especially hospital-acquired hypermagnesemia, was significantly associated with increased in-hospital mortality in critically ill patients.


Effects of specialty proteins as alternatives to bovine or porcine spray-dried plasma in non-medicated diets fed to weaned pigs housed in an unsanitary environment.
Two experiments were done to compare growth performance of pigs weaned at 21 ± 2 d of age that were housed in unsanitary pens and fed non-medicated diets containing alternative proteins versus spray-dried porcine (SDPP; Exp. 1) or bovine (SDBP; Exp. 2) plasma. Experiment 1 used 360 pigs fed 1 of 6 experimental diets from d 0 to 15, followed by a common diet fed to all pigs from d 15 to 28 post-weaning with 11 pens of 5 or 6 pigs/pen allotted per treatment. Experimental diets were based on 8.04% soy protein concentrate (SPC) as the control protein or a similar diet with either 2.50 or 5.00% SDPP or 0.17, 0.33, or 1.00% activated porcine plasma (APP) replacing SPC on an equal Lys basis. Experiment 2 used 300 pigs that were fed 1 of 6 experimental diets from d 0 to 14 post-weaning with 10 pens of 4 to 6 pigs/pen allotted per diet. Experiment 2 diets were based on 8.04% SPC as the control protein source or similar diets with the following specialty proteins replacing SPC on an equal Lys basis: 0.40% APP; 10.66% enzymatically hydrolyzed soy and yeast protein (EHSY); a combination (CB) of 6.36% EHSY, 0.40% APP, and 2.50% fish meal; 0.44% spray-dried whole egg from hyper-immunized hens (IEGG); or 5.00% SDBP. Results of Exp. 1 indicated pigs fed SDPP diets had greater (P < 0.05) ADG and ADFI at d 7 and 15 compared with pigs fed SPC or APP diets. Gain:feed at d 7 was higher (P < 0.05) for pigs fed diets with SDPP compared with other diets. Average BW at d 7 was greater (P < 0.05) for pigs fed diets with SDPP compared to other diets and pigs fed the 5.00% SDPP diet had greater BW at d 15 compared to diets without SDPP. At d 28 BW was greater (P < 0.05) for pigs fed the 2.50% SDPP diet compared with pigs fed diets with SPC, 0.33% APP, or 1.00% APP. Performance of pigs fed the SPC diet did not differ from APP diets at any period of the study. In Exp. 2, pigs fed the SDBP diet had greater (P < 0.05) BW, ADG, and ADFI at d 7 and 14 compared with pigs fed the other diets. Gain:feed did not differ significantly among diets. Average daily gain and ADFI of pigs did not differ among diets that did not contain SDBP. In conclusion, during the initial 2 wk post-weaning, pigs housed in unsanitary pens and fed non-medicated diets with APP in Exp. 1, or APP, EHSY, CB, or IEGG in Exp. 2 had equivalent performance to pigs fed SPC; however, performance of pigs fed diets with the alternatives was not equivalent to diets containing SDPP in Exp. 1 or SDBP in Exp. 2.


Modulation of T-cell activation through protein kinase C- or A-dependent signalling pathways synergistically increases human immunodeficiency virus long terminal repeat induction by cytomegalovirus immediate-early proteins.
By using human CD4+ lymphoblastoid T cells transiently cotransfected with human immunodeficiency virus (HIV) and cytomegalovirus (CMV), we tested whether modulation of T-cell activation through the protein kinase C (PKC) or the protein kinase A (PKA) pathway synergized with CMV immediate-early (IE) proteins in HIV long terminal repeat (LTR) transactivation. Stimulation with phorbol myristate acetate, tumor necrosis factor, or cross-linked antibodies to CD3 and CD28 resulted in modest enhancement (two- to fourfold) of the activity of a luciferase expression vector under control of the HIV LTR. Cotransfection of a vector expressing the CMV IE1 and IE2 proteins under the control of their own promoter enhanced HIV LTR activity 16- to 49-fold. Combination of any one of the above stimuli and CMV IE expression amplified HIV LTR activity 99- to 624-fold. Stimulation of PKA-dependent pathways with forskolin, 8-bromo cyclic AMP, or prostaglandin E2 had a minimal effect on HIV LTR activity, whereas such stimuli resulted in synergistic amplification in cells cotransfected with CMV IE (three- to fivefold increases over the effects of CMV IE alone). This synergism was independent of the NF-kappa B binding motifs within the HIV LTR. CMV IE2, but not IE1, protein induced HIV transactivation and synergized with signals modulating T-cell activation. The intense synergism observed was superior to the increase in IE protein expression following PKC activation by phorbol myristate acetate. Treatment of cells with PKC inhibitor GF109203X blocked most of the observed synergism.(ABSTRACT TRUNCATED AT 250 WORDS)


Electrical stimulation and electromagnetic field use in patients with diabetic neuropathy: systematic review and meta-analysis.
Painful diabetic neuropathy (PDN) is a common complication of diabetes mellitus, and pharmacological therapies are ineffective in many patients. Therefore, other treatment modalities should be considered, including electrical stimulation and electromagnetic fields. The research objective was to evaluate the effect of treatment with electrical stimulation and electromagnetic fields on pain and sensitivity in patients with painful diabetic neuropathy compared with placebo or another intervention. We searched the following electronic databases (from inception to April 2012): MEDLINE (accessed by PubMed), LILACS, Physiotherapy Evidence Database (PEDro), EMBASE and Cochrane CENTRAL. We included randomized trials that compared electrical stimulation or electromagnetic fields with control groups in which the objective was to assess pain and sensitivity in patients with PDN. Two reviewers independently extracted the data. A random-effects model was used for the main analysis. The search retrieved 1336 articles, of which 12 studies were included. Reductions in the mean pain score were significantly greater in the TENS (transcutaneous electrical nerve stimulation) group than in the placebo group [-0.44 (95% CI: -0.79 to -0.09; I2: 0%)]. There was no improvement in pain relief when electromagnetic fields were compared with the control group [-0.69 (95% CI: -1.86 to 0.48; I2: 63%)]. We found that TENS improved pain relief in patients with diabetic neuropathy, while no such improvement was observed with the use of electromagnetic field treatment. Due to the methodological differences between the studies, a meta-analysis for the outcome of sensitivity could not be performed.


Clozapine: strong antiaggressive effects with minimal motor impairment.
Clinical studies have shown clozapine to be effective in the treatment of schizophrenia and associated with an extremely low incidence of extrapiramidal side effects. Diverse studies indicate that clozapine is an atypical neuroleptic with a preferential activity on the mesolimbic structures and a lower affinity for striatal D2 receptors than the classical antipsychotics. The purpose of this study was to assess the behavioral properties of clozapine, especially its effects on aggressive and motor behaviors. Individually housed male mice of the OF1 strain were exposed to anosmic "standard opponents" 30 minutes after the last drug administration. One category of animals received a single IP dose of the compound (0.2, 0.5, 1 or 1.5 mg/kg). Another category received daily doses (0.5, 1 or 1.5 mg/kg) for 21 days. Encounters were videotaped and behavior evaluated using an ethologically based analysis. Clozapine, in the acute treatment condition, produced a significant decrease in "attack" and "threat" behaviors without "immobility" being significantly increased. These results suggest a rather specific antiaggressive action of the compound with little motor impairment. In the chronic administration, no significant change in aggressive behavior was observed which may be attributed to the development of some degree of tolerance.


[Gastric epithelial polyps. A retrospective study 1995-2000].
The analysis of the endoscopic and histological characteristics of all the gastric epithelial polyps diagnosed through endoscopy in our service during a period of 5 years, and the evaluation of the usefulness of the endoscopic monitoring after polypectomy. Between January 1995 and January 2000 5,314 high digestive system endoscopies were carried out in the Gastroenterology Service of the Santa María Madre Hospital. Sixty-four gastric epithelial polyps were detected in 18 patients (10 men and 8 women) with a median age of 61.7 years. Sixty-three polyps were removed through endoscopic polypectomy, and one was biopsied because of its size (5 cm), 30 (46.87%) were hyperplastic polyps, 24 (37.5%) presented normal histological characteristics, 8 (12.5%) were adenomas and 2 (3.12%) were polypoid adenocarcinomas. 56.2% measured less than 6 mm and only 6.2% measured more than 11 mm. No patient presented simultaenous gastric adenocarcinoma. Only one complication was observed after the polypectomy, a hemorrhage that was treated successfully with local injection of adrenaline. During the follow-up no case of cancer was detected and the recurrence of the polyp was observed in 2/8 patients with adenoma. Gastric epithelial polyps are infrequent (0.33% gastroscopies); most of them (93.75%) measure less than 1 cm and they can be removed through endoscopy with safety. In our series, the most frequent histological type was the hyperplastic polyp (43.75%); polypoid adenocarcinoma constituted 3.12% of the cases, one of them with less than 6 mm. Endoscopic follow-up is considered absolutely essential after the polypectomy, especially in adenomatous polyps.


When less is more: non-monotonic spike sequence processing in neurons.
Fundamental response properties of neurons centrally underly the computational capabilities of both individual nerve cells and neural networks. Most studies on neuronal input-output relations have focused on continuous-time inputs such as constant or noisy sinusoidal currents. Yet, most neurons communicate via exchanging action potentials (spikes) at discrete times. Here, we systematically analyze the stationary spiking response to regular spiking inputs and reveal that it is generically non-monotonic. Our theoretical analysis shows that the underlying mechanism relies solely on a combination of the discrete nature of the communication by spikes, the capability of locking output to input spikes and limited resources required for spike processing. Numerical simulations of mathematically idealized and biophysically detailed models, as well as neurophysiological experiments confirm and illustrate our theoretical predictions.


Experimental determination of the respiratory tract deposition of diesel combustion particles in patients with chronic obstructive pulmonary disease.
Air pollution, mainly from combustion, is one of the leading global health risk factors. A susceptible group is the more than 200 million people worldwide suffering from chronic obstructive pulmonary disease (COPD). There are few data on lung deposition of airborne particles in patients with COPD and none for combustion particles. To determine respiratory tract deposition of diesel combustion particles in patients with COPD during spontaneous breathing. Ten COPD patients and seven healthy subjects inhaled diesel exhaust particles generated during idling and transient driving in an exposure chamber. The respiratory tract deposition of the particles was measured in the size range 10-500 nm during spontaneous breathing. The deposited dose rate increased with increasing severity of the disease. However, the deposition probability of the ultrafine combustion particles (< 100 nm) was decreased in COPD patients. The deposition probability was associated with both breathing parameters and lung function, but could be predicted only based on lung function. The higher deposited dose rate of inhaled air pollution particles in COPD patients may be one of the factors contributing to their increased vulnerability. The strong correlations between lung function and particle deposition, especially in the size range of 20-30 nm, suggest that altered particle deposition could be used as an indicator respiratory disease.


Examining the Effects of Chromatic Aberration, Object Distance, and Eye Shape on Image-Formation in the Mirror-Based Eyes of the Bay Scallop Argopecten irradians.
The eyes of scallops form images using a concave spherical mirror and contain two separate retinas, one layered on top of the other. Behavioral and electrophysiological studies indicate that the images formed by these eyes have angular resolutions of about 2°. Based on previous ray-tracing models, it has been thought that the more distal of the two retinas lies near the focal point of the mirror and that the proximal retina, positioned closer to the mirror at the back of the eye, receives light that is out-of-focus. Here, we propose three mechanisms through which both retinas may receive focused light: (1) chromatic aberration produced by the lens may cause the focal points for longer and shorter wavelengths to fall near the distal and proximal retinas, respectively; (2) focused light from near and far objects may fall on the distal and proximal retinas, respectively; and (3) the eyes of scallops may be dynamic structures that change shape to determine which retina receives focused light. To test our hypotheses, we used optical coherence tomography (OCT), a method of near-infrared optical depth-ranging, to acquire virtual cross-sections of live, intact eyes from the bay scallop Argopecten irradians Next, we used a custom-built ray-tracing model to estimate the qualities of the images that fall on an eye's distal and proximal retinas as functions of the wavelengths of light entering the eye (400-700 nm), object distances (0.01-1 m), and the overall shape of the eye. When we assume 550 nm wavelength light and object distances greater than 0.01 m, our model predicts that the angular resolutions of the distal and proximal retinas are 2° and 7°, respectively. Our model also predicts that neither chromatic aberration nor differences in object distance lead to focused light falling on the distal and proximal retinas simultaneously. However, if scallops can manipulate the shapes of their eyes, perhaps through muscle contractions, we speculate that they may be able to influence the qualities of the images that fall on their proximal retinas and-to a lesser extent-those that fall on their distal retinas as well.


Using eHealth Data to Inform CPD for Medical Practitioners: A Scoping Review with a Consultation Exercise with International Experts.
eHealth data analytics is widely used in health care research. However, there is limited knowledge on the role of eHealth data analysis to inform continuing professional development (CPD). The aim of this study was to collate available research evidence on the use of eHealth data for the development of CPD programs and plans for medical practitioners. A scoping review was conducted using the six-stage Arksey and O'Malley Framework. A consultation exercise (stage 6) was performed with 15 international experts in the fields of learning and practice analytics to deepen the insights. Scoping review. The literature searches identified 9876 articles published from January 2010 to May 2022. After screening and full-text review, a total of nine articles were deemed relevant for inclusion. The results provide varied-and at times partial or diverging-answers to the scoping review research questions. Consultation exercise. Research rigor, field of investigation, and developing the field were the three themes emerged from analysis. Participants validated the scoping review methodology and confirmed its results. Moreover, they provided a meta-analysis of the literature, a description of the current CPD ecosystem, and clear indications of what is and should be next for the field. This study shows that there is no formal or well-established correlation between eHealth data and CPD planning and programming. Overall findings fill a gap in the literature and provide a basis for further investigation. More foundational work, multidisciplinary collaborations, and stakeholders' engagement are necessary to advance the use of eHealth data analysis for CPD purposes.


Allogenic preserved costal cartilage in reconstructive surgery.
Allogenic, preserved cartilage is often used for reconstruction of face. This study was undertaken to analyze the effects of cartilage transplantation. In analyzed group of 437 patients after cartilage transplantation, 42.2% were operated because of posttraumatical changes, 29.0% because of congenital malformations. In 16.7% nonspecific inflammations were the cause of reconstructive operations. Malformations were mainly localised in nose 59%, ear concha 16.5% and mandible 10.9%. Human costal cartilage, preserved in 0.9% NaCl and radiation-sterilized was used for reconstruction. 24-190 months after surgery (in several clinical units) patients were examined and results were collected in special questionnaire by the team who performed surgery. The results of treatment were compared with age, diagnosis and localisation of changes. It was found that very good result of treatment was achieved in 33.5% of patients, in 41.8% result was satisfactory. In 19.9% of operated patients result of treatment was unsatisfactory. Correlation of some clinical and biological characteristics with the result of treatment is discussed.


Abdominal fluid collection secondary to acute pancreatitis: treated with percutaneous catheter drainage.
Complicated pancreatic inflammatory diseases are often life-threatening, multifocal, and multibacterial disorders. Untreated, these lesions often prove fatal. The purpose of the study is to describe interventional radiologic techniques for diagnosis and treatment of complicated peripancreatic fluid collections. Between January 1994 and December 1995, 17 patients with abdominal fluid collection from complicated acute pancreatitis underwent percutaneous drainage following initial diagnosis with computed tomography (CT). These patients required multiple CT examinations, multiple catheter insertions, multiple catheter manipulations, and long-term catheter drainage. Twenty-five infected fluid collections among these 17 patients were percutaneously drained. Sixteen (94%) patients were successfully treated with catheter drainage alone. Surgical treatment was necessary in one patient because of segmental stricture of transverse colon caused by inflammation and adhesion of transverse mesocolon. Catheter drainage duration averaged 31 days. Patients required an average of three catheter manipulations and four abdominal CT scans. Mean hospital stay was 42 days (range, 11-95 days), and mean ICU stay was 25 days (range, 1-70 days). The study confirms that complicated peripancreatic fluid collections can be safely and effectively treated in most patients with percutaneous catheter technique.


Cascade Reactions of Aryl-substituted Terminal Alkynes Involving in situ-Generated α-Imino Gold Carbenes.
An efficient, highly selective and divergent synthetic method to construct 2-substituted indoles and aryl-annulated carbazoles via the intermolecular generation of α-imino gold carbenes from terminal alkynes or diynes in combination with sulfilimines is disclosed. Importantly, the tandem reaction is proposed to proceed through an intermolecular gold carbene generation/ C-H annulation followed by the activation of a second alkyne leading to 6-endo-dig cyclization, which is significantly different from previous dual activation or 1,6-carbene shift approaches for diyne systems. In the case of ortho-alkynylaniline as starting material, an unexpected regioselective formation of the indole moiety via the intermolecular path, instead of intramolecular hydroamination was discovered. This reactivity paved the way for a one-pot synthesis of the 11H-indolo [3,2-c] quinoline scaffold by exploiting the formed amino indole for a subsequent Pictet-Spengler reaction with aldehydes. The photophysical properties of the carbazoles indicated good violet-blue emission with quantum yields up to 40%.


Higher social cue utilisation improves communication, reduces perceived workload, and improves performance amongst ad hoc dyads in simulated rail control.
The objective was to examine whether ad hoc dyads with different collective social cue utilisation would record differences in performance and perceptions of workload during a simulated rail control task that incorporated distinct levels of demand. The frequency of two types of communicative statements was also examined as mediating factors: closing the loop and informative responding. A quasi-experimental design was employed using 40 dyadic teams. The results indicated that ad hoc teams whose members comprised higher social cue utilisation recorded relatively faster response times and perceived lower levels of workload, and engaged in a greater frequency of communicative statements that involved 'closing the loop' and 'informative responses'. Social cue utilisation also exerted an indirect effect on perceived workload through informative responding. The outcomes have theoretical implications for models of ad hoc team performance, and practical implications for the selection and training of teams that operate on an ad hoc basis. Practitioner summary: This study indicates that, in the context of simulation tasks requiring teamwork, higher social cue utilisation amongst ad hoc team members is associated with communication, workload perception, and overall performance.


Do cognitively normal children with epilepsy have a higher rate of injury than their nonepileptic peers?
The objective of this study was to determine if cognitively normal children with epilepsy have higher accidental injury rates than their age- and sex-matched friends without epilepsy and what factors may predict this. Patients 5 to 16 years old, with a developmental quotient >70, without major motor or sensory impairments, with a 1-year history of epilepsy and who either had a seizure or had been on antiepileptic drugs within the past year, were identified from the pediatric neurology database of the Royal University Hospital. Twenty-five of 31 cases and their best friend controls agreed to participate. Seizure-related factors including type, duration, frequency, timing, date of diagnosis, antiepileptic drug initiation and discontinuation, and specific types and total antiepileptic drugs used were assessed by interview. Questionnaires about accidental injury including type, number, severity, and, if applicable, injuries resulting from seizures, as well as general safety practices, activity restrictions, and presence of attention-deficit hyperactivity disorder, were completed by cases and controls. No significant differences in injury numbers (specific types or total) or severity were found, although a small number of epileptic children were very predisposed to injury. Seizure-related factors did not predict injury in cases. Safety practices were similar, and restrictions in cases were not excessive. Children with attention-deficit hyperactivity disorder had a higher injury rate, both in cases and controls. Cognitively normal children with epilepsy do not have a higher injury rate than their nonepileptic peers. If consciousness is impaired in seizures, extra supervision for swimming and bathing and restricted climbing heights are suggested. All other safety restrictions for epileptic children should follow those appropriate to nonepileptic children to allow a normal lifestyle.


Isolation of human cytomegalovirus from peripheral blood T cells of renal transplant patients.
Previous reports have demonstrated that human CMV can be isolated from the mononuclear leukocyte fraction of peripheral blood taken from patients excreting CMV. Many renal transplant patients show evidence of an active CMV infection, and in these patients T cell responses are often impaired. Thus the purpose of the current study was to determine whether the virus could be isolated from either the T and/or B lymphocytes of viruric patients 3 months after renal transplantation. The virus was recovered from a small percentage of T cells (3 per 10(6) cells), but not from B cells. Thus it would appear that virus infection of T cells cannot explain the depressed cell-mediated immunity observed in these transplant patients unless a specific regulatory subset of T cells is infected. However, the isolation of CMV from T cells implies that they must be considered as one of the possible cells for virus persistence in vivo.


Multiple sclerosis-from probable to definite diagnosis: a 7-year prospective study.
To investigate the rate of progression from probable to clinically definite multiple sclerosis (MS) and to define patients who had rapidly (within 1 year) progressed to a definite diagnosis. A 7-year prospective study. A group of 163 patients experiencing their first episode of neurologic symptoms suggestive of MS. All patients had brain magnetic resonance imaging that demonstrated at least 3 demyelinating lesions at onset. Within the follow-up period (mean, 42 months; range, 13-84 months), 136 patients (83.4%) had an additional relapse and were thus defined as having clinically definite MS, whereas 27 patients (16.6%) were defined as having clinically probable MS. Most of the 136 patients with clinically definite MS (57.6%, 94 patients) experienced the additional relapse within 1 year. Demographic and clinical parameters at presentation were analyzed to identify variables predictive of rapid progression (within 1 year) to clinical definite MS. Motor involvement at onset was the only clinical parameter associated with rapid progression to a definite diagnosis. Survival curves demonstrated that polysymptomatic involvement and higher Extended Disability Status Scale score at presentation correlated with rapid progression to definite diagnosis. Most patients with a diagnosis of probable MS and positive brain magnetic resonance imaging will progress rapidly to clinically definite MS.


Spontaneous Escherichia coli meningitis in an adult.
Spontaneous meningitis due to gram-negative bacilli (excluding Hemophilus influenzae) is an infrequent infection in adult patients. It usually occurs in patients with underlying immunosuppressive conditions. Most of the cases are due to Escherichia coli and represent a complication of bacteraemia. The infection has a high mortality rate which may be as high as 90%, especially if associated with septicaemia. We report the case of a 53-y-old man with spontaneous, community-acquired Escherichia coli meningitis who was admitted with an unusual presentation. Blood and urine cultures were negative.


Altered expression of the lymphocyte activation markers CD30 and CD27 in patients with pouchitis.
The mechanism underlying the development of ileal pouch inflammation in ulcerative colitis patients (pouchitis) after restorative proctocolectomy is unclear. Persistent systemic T cell activation or expansion of specific memory cell populations could predispose certain patients to develop local inflammation within the neo-rectum. Therefore, the aim was to study the expression of the lymphocyte activation markers CD27, CD30, CD25 and CD69 on the CD45RO+ memory cell subset of isolated peripheral blood mononuclear cells (PBMC), soluble CD30 levels and mucosal CD30 expression in patients with pouchitis and in controls. Flow cytometry was performed on PBMC isolated from patients with pouchitis (n = 9), without pouchitis (n = 10) and normal controls (n = 9). Serum CD30 was measured in patients with pouchitis (n = 25), without pouchitis (n = 26) and normal controls (n = 20) by ELISA. CD30 expression was quantified in pouchitis (n = 15) and normal pouch (n = 15) mucosa using a three-stage immunoperoxidase method. Naive CD45RO-CD27+ PBMC were significantly decreased in pouchitis (25.6%) compared to normal controls (34.4%), (P = 0.03). CD30, CD25 and CD69 subsets did not differ between the groups. Serum CD30 was increased in pouchitis patients 58 (1-380) U/ml compared to non-pouchitis 16.5 (1-290) U/ml, P=0.007, and normal controls 11 (2-80) U/ml, P = 0.0005. In the mucosa, the numbers of CD30+ cells were increased in pouchitis compared to non-inflamed pouches (P = 0.02). Increased sCD30 in pouchitis is associated with elevated mucosal expression. Of the activation markers studied, only the circulating naïve CD27+ population differed in pouchitis patients compared with controls. The observed decrease in this cell type may reflect antigen priming and subsequent loss of CD27 implying that antigen driven activation of specific T cell subsets may occur in pouchitis.


Genome construction between bacterial species in vitro: replication and expression of Staphylococcus plasmid genes in Escherichia coli.
Genes carried by EcoRI endonuclease-generated fragments of Staphylococcus plasmid DNA have been covalently joined to the E. coli antibiotic-resistance plasmid pSC101, and the resulting hybrid molecules have been introduced into E. coli by transformation. The newly constructed plasmids replicate as biologically functional units in E. coli, and express genetic information carried by both of the parent DNA molecules. In addition, electron microscope heteroduplex analysis of the recombinant plasmids indicate that they contain DNA sequences derived from E. coli and Staphylococcus aureus. Recombinant molecules can transform other E. coli cells for penicillin-resistance markers originally carried by the staphylococcal plasmid, and can be transferred among E. coli strains by conjugally proficient transfer plasmids.


[Unusual thrombus embolization during primary coronary angioplasty: a case report].
Embolization of thrombotic material during primary angioplasty may occur even if the procedure is performed with appropriate medication as well as in hospital centers having a high volume of procedures. Over recent years the introduction of mechanical devices for thromboaspiration and/or distal protection have reduced the incidence of embolization thus improving myocardial reperfusion and survival. We report the case of a large thrombus migrated from the proximal left circumflex artery to the proximal left anterior descending artery during balloon inflation. In our opinion, the cause was retrograde expulsion of the thrombus by the deploying balloon.


Physicochemical Study of Viral Nanoparticles at the Air/Water Interface.
The assembly of most single-stranded RNA (ssRNA) viruses into icosahedral nucleocapsids is a spontaneous process driven by protein-protein and RNA-protein interactions. The precise nature of these interactions results in the assembly of extremely monodisperse and structurally indistinguishable nucleocapsids. In this work, by using a ssRNA plant virus (cowpea chlorotic mottle virus [CCMV]) as a charged nanoparticle we show that the diffusion of these nanoparticles from the bulk solution to the air/water interface is an irreversible adsorption process. By using the Langmuir technique, we measured the diffusion and adsorption of viral nucleocapsids at the air/water interface at different pH conditions. The pH changes, and therefore in the net surface charge of the virions, have a great influence in the diffusion rate from the bulk solution to the air/water interface. Moreover, assembly of mesoscopic and microscopic viral aggregates at this interface depends on the net surface charge of the virions and the surface pressure. By using Brewster's angle microscopy we characterized these structures at the interface. Most common structures observed were clusters of virions and soap-frothlike micron-size structures. Furthermore, the CCMV films were compressed to form monolayers and multilayers from moderate to high surface pressures, respectively. After transferring the films from the air/water interface onto mica by using the Langmuir-Blodgett technique, their morphology was characterized by atomic force microscopy. These viral monolayers showed closed-packing nano- and microscopic arrangements.


Whole Genome Sequencing and Comparative Genomic Analysis of Chlamydia gallinacea Field Strains Isolated from Poultry in Poland.
Chlamydia gallinacea is an intracellular bacterium belonging to the Chlamydiaceae family. Poultry is considered to be the major reservoir of this agent, which has worldwide distribution and a particularly consistent worldwide occurrence in chicken flocks. The bacterium has been linked to respiratory disease in humans but without definitive confirmation; nevertheless, while it has not been proved to be the cause of human respiratory disease, a recent report from Italy verified its bird-to-human transmission. This aspect being significant for public health, more research is needed to gain insight into the infection biology of C. gallinacea. In this study, the genomes of eleven novel C. gallinacea field strains from different regions of Poland were analyzed comparatively. It was confirmed that C. gallinacea strains are closely related, with at least 99.46% sequence identity. They possess a conservative genome structure involving the plasticity zone with a complete cytotoxin, the type three secretion system, inclusion membrane proteins, polymorphic membrane proteins, hctA and hctB histone-like proteins, and the chlamydial protease-like activating factor exoenzyme, as well as plasmids. Genetic diversity seems to be restricted. However, some genetic loci, such as ompA and multi-locus sequence typing target genes, are diverse enough to enable high-resolution genotyping and epidemiological tracing.


The effects of sevoflurane and ketamine on intraocular pressure in children during examination under anesthesia.
We studied the effects on intraocular pressure (IOP) of anesthesia administered during examination under anesthesia (EUA) in children. Randomized clinical trial. This randomized trial compared IOP after inhaled sevoflurane gas to that after intramuscular ketamine hydrochloride in children undergoing EUA. IOP was measured in 30 eyes with TonoPen XL (Mentor, Inc, Norwell, Massachusetts, USA) as soon as possible after anesthesia induction (T1) and two, four, six, and eight minutes thereafter. At the same times, we recorded systolic and diastolic blood pressure (SBP, DBP) and heart rate (HR). Compared with the mean IOP at T1, IOP in the sevoflurane group was significantly lower for all measurements from two to eight minutes thereafter (mean decrease in IOP: two minutes = 12%, four minutes = 19%; six minutes = 19%; eight minutes = 17%, all P < or = .01). In the ketamine group, mean IOP was not significantly changed from T1 through six minutes, whereas at eight minutes, it was 7% lower (P = .03). SBP and DBP were significantly lower for sevoflurane than for ketamine at all measurements from two minutes onward, and HR was lower for sevoflurane than for ketamine at two, four, and six minutes. IOP measured after ketamine sedation is more likely to represent the awake IOP than that after sevoflurane anesthesia. Changes in SBP, DBP, and HR caused by sevoflurane suggest that hemodynamic alterations may underlie its effects on IOP.


Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs.
Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B.


The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain.
GPIHBP1 is a glycolipid-anchored membrane protein of capillary endothelial cells that binds lipoprotein lipase (LPL) within the interstitial space and shuttles it to the capillary lumen. The LPL•GPIHBP1 complex is responsible for margination of triglyceride-rich lipoproteins along capillaries and their lipolytic processing. The current work conceptualizes a model for the GPIHBP1•LPL interaction based on biophysical measurements with hydrogen-deuterium exchange/mass spectrometry, surface plasmon resonance, and zero-length cross-linking. According to this model, GPIHBP1 comprises two functionally distinct domains: (1) an intrinsically disordered acidic N-terminal domain; and (2) a folded C-terminal domain that tethers GPIHBP1 to the cell membrane by glycosylphosphatidylinositol. We demonstrate that these domains serve different roles in regulating the kinetics of LPL binding. Importantly, the acidic domain stabilizes LPL catalytic activity by mitigating the global unfolding of LPL's catalytic domain. This study provides a conceptual framework for understanding intravascular lipolysis and GPIHBP1 and LPL mutations causing familial chylomicronemia.


Socioeconomic inequality in unmet outpatient healthcare needs among people living in urban informal settlements in Sanandaj city, Iran.
The growing trend of informal settlements is a serious humanitarian crisis. Unmet need for health care services is an indicator to measure the state of equality and access to healthcare services. This study, for the first time in Iran, examined the prevalence of unmet needs for outpatient healthcare services and related socioeconomic inequalities among residents of informal settlements in Sanandaj city. This cross-sectional study was conducted on informal settlements of Sanandaj city with a sample size of 1345 people. Data were collected using a questionnaire. Multivariate logistic regression was used to determine significant predictors of unmet needs for healthcare services. Concentration index (C) and concentration curve (CC) were calculated to measure inequality in the prevalence of unmet needs for healthcare services. The prevalence of unmet needs for outpatient healthcare services was 31.7%. Financial and physical barriers were the most common reasons for not using the needed services. The highest unmet need was related to dental (80.6%) and rehabilitation services (78.8%). Being elderly with about 2.3 times (OR: 2.37, 95% CI: 1.19-4.75), not having a job with about 1.7 times (OR: 1.70, 95% CI: 1.13-2.57) and having a low economic status with about 4 times (OR: 4.46, 95% CI: 2.39-9.70) increased the odds of experiencing unmet need for outpatient healthcare services. The value of concentration index showed that unmet need for outpatient healthcare services was significantly concentrated among people with lower economic status (C= -0.330, 95% CI: -0.432 to -0.227). The unmet need is high among people living in informal settlements of Sanandaj city and a significant part of the residents of these settlements does not have access to required healthcare services. Regardless of the needs of people living in these settlements, who constitute a large population of Iran, access to universal health coverage is not possible in such areas. Removing the identified obstacles and causes behind the unmet needs requires the interdisciplinary participation of all actors, including the government, the nation, and civil society.


[Changes in the cytochemical properties of chromatin after stimulating proliferation in a stationary culture of Chinese hamster cells].
The first part of the prereplicative period in stimulated for cell proliferation steady-state culture of Chinese hamster cells was studied cytochemically. Investigation of the binding pattern of basic dye Acridine orange and Actinomycin D with cell nuclei and the melting profile of chromatin in situ suggests that one of the early events occurring in the course of stimulation of cell proliferation in steady-state culture is chromatin activation, i.e. changes in its physicochemical properties resulting in augmentation of transcription.


Efficacy and Safety of Abicipar in Neovascular Age-Related Macular Degeneration: 52-Week Results of Phase 3 Randomized Controlled Study.
To compare the efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) versus ranibizumab every 4 weeks in treatment-naïve patients with neovascular age-related macular degeneration (AMD). Two randomized, multicenter, double-masked, parallel-group, active-controlled, phase 3 clinical trials (CEDAR, SEQUOIA) with identical protocols were conducted. Data from both trials were pooled for analysis. Patients with active choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) of 24-73 Early Treatment Diabetic Retinopathy Study letters in the study eye were enrolled. Patients (n = 1888) were randomized in a 1:1:1 ratio to study eye treatment with abicipar 2 mg every 8 weeks after 3 initial doses at baseline and weeks 4 and 8 (Q8), abicipar 2 mg every 12 weeks after 3 initial doses at baseline and weeks 4 and 12 (Q12), or ranibizumab 0.5 mg every 4 weeks (Q4). The primary efficacy end point was proportion of patients with stable vision (defined as <15-letter loss in BCVA from baseline) in the study eye at week 52. Secondary end points included change from baseline in BCVA and central retinal thickness (CRT) at week 52. Safety measures included adverse events (AEs). The proportion of patients with stable vision at week 52 was 93.2%, 91.3%, and 95.8% in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively, with both abicipar Q8 and Q12 noninferior to ranibizumab Q4. Week 52 mean change from baseline in BCVA was 7.5, 6.4, and 8.4 letters and in CRT was -144, -145, and -144 μm in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. Incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3%, respectively. The IOI AEs were typically mild or moderate in severity and treated with topical corticosteroids; 62 of 192 patients (32.3%) received oral and/or injectable corticosteroids. Abicipar Q8 and Q12 were both noninferior to ranibizumab Q4 in the primary end point of stable vision at week 52. Intraocular inflammation was more frequent with abicipar. Quarterly and Q8 abicipar reduce nAMD disease and treatment burden compared with monthly treatment.


Relations among heart failure severity, left ventricular loading conditions, and repolarization length in advanced heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.
In patients with heart failure (HF), low peak oxygen consumption (VO(2)) and prolonged QT interval or enhanced QT variability are associated with poor prognosis. Whether HF severity or left ventricular (LV) loading conditions can influence repolarization length is unknown. Survival, QTc interval, peak VO(2), clinical, laboratory, echocardiographic, and invasive hemodynamic data were analyzed in 154 transplant candidates; mortality was examined after a mean follow-up of 4.3 +/- 1.8 years. The relation between the QTc interval and other variables was examined using multivariate analysis and multiple correlation coefficients. Patients were stratified by peak VO(2) to study its relation with peak VO(2), mortality, loading conditions, and QTc intervals. Mean ejection fraction was 10 +/- 9%; mean cardiac index was 2.06 +/- 0.7 L/min/m(2). Seventy-one patients (47%) were dead at the end of study. Mortality and nonfatal ventricular arrythmias were higher (p <0.01) in patients with lower peak VO(2) and longer QTc intervals (p <0.001). An inverse correlation was found between QTc interval length and peak VO(2) (r = -0.790, p <0.0001). No correlation was found between QTc interval and LV loading conditions or the other analyzed variables. Thus, repolarization length measured by the QTc interval is inversely correlated with HF severity measured by peak VO(2) and is independent of LV loading conditions in patients with severe HF.


Rationale for the use of contrast media in MR imaging.
Understanding the rationale of contrast media use in MR imaging is based on knowledge of the blood brain barrier (BBB) and the pathophysiology of infectious agents attacking the central nervous system. This article focuses on the relationship between BBB structures and functions in healthy and unhealthy conditions and contrast media in patients with acquired immunodeficiency syndrome.


[Protocol of preventing perioperative strokes in reconstructions of carotid artery bifurcation].
Presented herein is a protocol of preventing perioperative strokes in reconstructions of bifurcation of the carotid artery, used at the Department of Vascular Surgery of the Institute of Surgery named after A.V. Vishnevsky. The authors analysed the results of 630 primary carotid endarterectomies performed for atherosclerosis under general anaesthesia over the period from 2008 to 2010. Tolerance of the brain to carotid clamping was determined by measuring cerebral retrograde arterial pressure. Of the 630 operations, 65 (10.3%) interventions were carried out under temporal internal bypass. It was shown that the incidence rate of perioperative neurological complications among those tolerating carotid artery clamping was slightly lower than in the non-tolerating patients, with the incidence rate of strokes amounting to 1.8 and 3.1%, and that of "stroke + stroke-related mortality" amounting to 2.1 and 3.1%, respectively, but the differences were not statistically significant (p>0.5). Perioperative strokes in the absence of thrombosis of the reconstruction zone were observed in 0.6% of cases.


Relationship of alterations in splenic clearance function and microcirculation to host defense in acute rodent malaria.
During the course of Plasmodium berghei malaria in the rat, splenic clearance of damaged uninfected erythrocytes (heated or Heinz body-containing) underwent changes strikingly similar to those of infected erythrocytes. Splenic trapping of abnormal erythrocytes was impaired during the period of rising parasitemia but became supernormal just before the onset of resolution of the acute infection. These changes could be related to the development of splenomegaly and alterations in splenic cordal microcirculation during infection. The relative distribution of flow through the cords was decreased during rising parasitemia and was restored before the onset of resolution. Together, our observations support the hypothesis that altered rheologic properties of infected erythrocytes are a major determinant of their removal by the spleen. These data suggest that the alterations in splenic microcirculation that occur during malaria may have important implications for host defense.


Targeting lentiviral vectors to antigen-specific immunoglobulins.
Gene transfer into B cells by lentivectors can provide an alternative approach to managing B lymphocyte malignancies and autoreactive B cell-mediated autoimmune diseases. These pathogenic B cell populations can be distinguished by their surface expression of monospecific immunoglobulin. Development of a novel vector system to deliver genes to these specific B cells could improve the safety and efficacy of gene therapy. We have developed an efficient method to target lentivectors to monospecific immunoglobulin-expressing cells in vitro and in vivo. We were able to incorporate a model antigen CD20 and a fusogenic protein derived from the Sindbis virus as two distinct molecules into the lentiviral surface. This engineered vector could specifically bind to cells expressing surface immunoglobulin recognizing CD20 (alphaCD20), resulting in efficient transduction of target cells in a cognate antigen-dependent manner in vitro, and in vivo in a xenografted tumor model. Tumor suppression was observed in vivo, using the engineered lentivector to deliver a suicide gene to a xenografted tumor expressing alphaCD20. These results show the feasibility of engineering lentivectors to target immunoglobulin- specific cells to deliver a therapeutic effect. Such targeting lentivectors also could potentially be used to genetically mark antigen-specific B cells in vivo to study their B cell biology.


American Academy of Pediatrics. Behavioral and cognitive effects of anticonvulsant therapy. Committee on Drugs.
Behavioral disturbances associated with the use of anticonvulsant therapy may be readily apparent and easily diagnosed. They are most commonly reported with the use of barbiturates and usually include hyperactivity, disturbed sleep, irritability, and emotional lability. But, subtle behavioral disturbances may also adversely affect performance and learning. Behavioral changes resulting from therapy with barbiturates and benzodiazepines tend to be idiosyncratic as opposed to the dose-related affects seen with phenytoin and valproate therapy. Carbamazepine and valproate can affect mood and behavior negatively, but, generally, this occurs less frequently than when several other anticonvulsants are used; this is especially true in patients without CNS damage. The suspicion that there may be a causal relationship between anticonvulsant therapy and impairment of cognitive skills in nonintoxicated patients is gaining increasing support. Neuropsychologic studies in acutely exposed normal volunteers, studies in epileptic patients receiving monotherapy, and crossover studies between drugs have incriminated barbiturates and hydantoin drugs. Memory/cognitive dysfunction, although affected to a greater extent with higher drug dosages, has been reported with levels within the therapeutic range. Thus, serum drug levels cannot be considered good predictors of which patients will have subtle side effects. Carbamazepine and valproate seem to be relatively free of many adverse neuropsychologic effects, although additional studies need to be performed. The complete separation of seizure effects from drug effects remains on ongoing goal. Similarly, in comparative studies to date, the issues of whether the differences between the drugs are due to negative effects of one or positive psychotropic effects of the other, or both, are not adequately addressed.(ABSTRACT TRUNCATED AT 250 WORDS)


Prevalence and correlates of repeat mammography among women aged 55-79 in the Year 2000 National Health Interview Survey.
Utilization of mammography has increased steadily since the early 1990s. It is now important to expand the attention given to obtaining repeat examination. This study examines the prevalence and cross-sectional correlates of repeat mammography, among women aged 55-79, using a 12-month (N = 3,502) and a 24-month interval (N = 3,491). Data were from the Year 2000 Cancer Control Module of the National Health Interview Survey (NHIS-CCM). The NHIS-CCM asked about the most recent mammogram and the total number of mammograms over the prior 6 years. An algorithm estimated repeat mammography for the two intervals. Prevalence estimates were 49% for the 12-month interval, and 64.1% for the 24-month interval. Correlates of lower likelihood of repeat mammography for both indicators were: no regular source of care, having public or no health insurance, less than a college education, household income less than $45K, not being married, current or never smoking, age 65-79, and lower absolute risk of breast cancer (Gail Model score). A substantial percentage of women do not receive repeat mammography. The correlates of repeat mammography were similar to those often found for ever-had and recent mammography. There is probably some imprecision in the prevalence estimates due to the nature of NHIS-CCM questions. Issues pertinent to the definition of repeat examination are addressed.


A novel alternate anaplerotic pathway to the glyoxylate cycle in streptomycetes.
ccr encoding crotonyl coenzyme A (CoA) reductase (CCR), which catalyzes the conversion of crotonyl-CoA to butyryl-CoA in the presence of NADPH, was previously cloned from Streptomyces collinus. We now report that a complete open reading frame, designated meaA, is located downstream from ccr. The predicted gene product showed 35% identity with methylmalonyl-CoA mutases from various sources. In addition, the predicted amino acid sequences of S. collinus ccr and meaA exhibit strong similarity to that of adhA (43% identity), a putative alcohol dehydrogenase gene, and meaA (62% identity) of Methylobacterium extorquens, respectively. Both adhA and meaA are involved in the assimilation of C1 and C2 compounds in an unknown pathway in the isocitrate lyase (ICL)-negative Methylobacterium. We have demonstrated that S. collinus can grow with acetate as its sole carbon source even though there is no detectable ICL, suggesting that in this organism ccr and meaA may also be involved in a pathway for the assimilation of C2 compounds. Previous studies with streptomycetes provided a precedent for a pathway that initiates with the condensation of two acetyl-CoA molecules to form butyryl-CoA, which is then transformed to succinyl-CoA with two separate CoB12-mediated rearrangements and a series of oxidations. The biological functions of ccr and meaA in this process were investigated by gene disruption. A ccr-blocked mutant showed no detectable crotonyl-CoA reductase activity and, compared to the wild-type strain, exhibited dramatically reduced growth when acetate was the sole carbon source. An meaA-blocked mutant also exhibited reduced growth on acetate. However, both methylmalonyl-CoA mutase and isobutyryl-CoA mutase, which catalyze the two CoB12-dependent rearrangements in this proposed pathway, were shown to be present in the meaA-blocked mutant. These results suggested that both ccr and meaA are involved in a novel pathway for the growth of S. collinus when acetate is its sole carbon source.


A smartphone client-server teleradiology system for primary diagnosis of acute stroke.
Recent advances in the treatment of acute ischemic stroke have made rapid acquisition, visualization, and interpretation of images a key factor for positive patient outcomes. We have developed a new teleradiology system based on a client-server architecture that enables rapid access to interactive advanced 2-D and 3-D visualization on a current generation smartphone device (Apple iPhone or iPod Touch, or an Android phone) without requiring patient image data to be stored on the device. Instead, a server loads and renders the patient images, then transmits a rendered frame to the remote device. Our objective was to determine if a new smartphone client-server teleradiology system is capable of providing accuracies and interpretation times sufficient for diagnosis of acute stroke. This was a retrospective study. We obtained 120 recent consecutive noncontrast computed tomography (NCCT) brain scans and 70 computed tomography angiogram (CTA) head scans from the Calgary Stroke Program database. Scans were read by two neuroradiologists, one on a medical diagnostic workstation and an iPod or iPhone (hereafter referred to as an iOS device) and the other only on an iOS device. NCCT brain scans were evaluated for early signs of infarction, which includes early parenchymal ischemic changes and dense vessel sign, and to exclude acute intraparenchymal hemorrhage and stroke mimics. CTA brain scans were evaluated for any intracranial vessel occlusion. The interpretations made on an iOS device were compared with those made at a workstation. The total interpretation times were recorded for both platforms. Interrater agreement was assessed. True positives, true negatives, false positives, and false negatives were obtained, and sensitivity, specificity, and accuracy of detecting the abnormalities on the iOS device were computed. The sensitivity, specificity, and accuracy of detecting intraparenchymal hemorrhage were 100% using the iOS device with a perfect interrater agreement (kappa=1). The sensitivity, specificity, and accuracy of detecting acute parenchymal ischemic change were 94.1%, 100%, and 98.09% respectively for reader 1 and 97.05%, 100%, and 99.04% for reader 2 with nearly perfect interrater agreement (kappa=.8). The sensitivity, specificity, and accuracy of detecting dense vessel sign were 100%, 95.4%, and 96.19% respectively for reader 1 and 72.2%, 100%, and 95.23% for reader 2 using the iOS device with a good interrater agreement (kappa=.69). The sensitivity, specificity, and accuracy of detecting vessel occlusion on CT angiography scans were 94.4%, 100%, and 98.46% respectively for both readers using the iOS device, with perfect interrater agreement (kappa=1). No significant difference (P<.05) was noted in the interpretation time between the workstation and iOS device. The smartphone client-server teleradiology system appears promising and may have the potential to allow urgent management decisions in acute stroke. However, this study was retrospective, involved relatively few patient studies, and only two readers. Generalizing conclusions about its clinical utility, especially in other diagnostic use cases, should not be made until additional studies are performed.


The experiences of family members of persons with intellectual disabilities who used residential care homes during the COVID-19 pandemic.
The global COVID-19 pandemic has shown the vulnerability of some population groups, including persons with intellectual and developmental disabilities (IDD). The present paper will provide more clarity and understanding of the experiences of family members of persons with IDD housed in residential facilities in Catalonia within the period of maximum restrictions during the COVID-19 pandemic. Semi-structured interviews were conducted using an interpretive phenomenological qualitative approach. Study participants consisted of 14 relatives of IDD individuals who were institutionalized in residence facilities or homes. The guiding questions emerged from group discussions with relatives of those with IDD who did not participate in the subsequent interviews. Drawing from this group, the factors that were identified to have had the greatest impact on their lives were later used to guide the interviews. Data collection was carried out in face-to-face individual interviews that were recorded together with the observations of two researchers between February and October 2022. Our analysis identified 4 main themes that developed into additional factors: the decision to stay at home or in the residence, fear, illness, and protocol. Individuals with IDD lost their daily routines, suffered from social isolation, and did not understand the situation. The results of this study allow for a better understanding of the experiences of families of persons with IDD in residential centres during the lockdown by identifying their needs and how to better support them in the future. Knowledge and understanding of these events should allow for better management of similar situations in the future.


Anti-FcepsilonRIalpha serum autoantibodies in different subtypes of urticaria.
In recent years, a histamine-releasing anti-FcepsilonRIalpha autoantibody has been demonstrated in about one-third of patients with chronic urticaria. However, its clinical significance is still unclear. The objective was to detect a possible correlation between the occurrence of the anti-FcepsilonRIalpha autoantibody and the clinical type or cause of urticaria. Sera from 66 consecutively seen in- and outpatients with various types of urticaria and five healthy controls were examined for the presence of anti-FcepsilonRIalpha autoantibodies with a sandwich ELISA technique. In addition, basophil histamine release was studied in 13 autoantibody-positive sera. Anti-FcepsilonRIalpha autoantibodies were found in 17/48 patients with chronic urticaria, in 2/4 with angioedema, in 1/2 with urticarial vasculitis, and in 2/11 with dermographic urticaria. However, no anti-FcepsilonRIalpha autoantibodies were detected in acute, cold, or delayed-pressure urticaria; in urticaria pigmentosa; or in normal controls. Of all chronic urticaria patients, 22 were classified as idiopathic since no underlying cause could be found. Of this group, seven were seropositive for anti-FcepsilonRIalpha. However, anti-FcepsilonRIalpha was also found in patients who went into remission after treatment of identified causes; namely, in one with type I allergy, one with drug intolerance, one with Helicobacter infection, and six with food intolerance. The autoantibody was also detected in 2/4 patients with associated autoimmune diseases. Functional activity was shown in basophil histamine release in 3/4 autoantibody-positive sera of patients with chronic idiopathic urticaria and in 4/6 autoantibody-positive sera of patients who went into remission after the treatment of underlying causes. These data confirm that anti-FcepsilonRIalpha autoantibodies in urticaria are mostly found in chronic urticaria. Furthermore, their detection independently of the apparent cause of the urticaria suggests that as yet unidentified mechanisms must be operative, possibly related to the chronic inflammatory process and/or individual predispositions that favor their induction.


[Efficacy of rifaksimin in excessive bacterial growth syndrome after cholecystectomy].
OBJECTIVE. To determine the frequency of the syndrome of excessive bacterial growth in patients with cholecystectomy and PL, justify the need for correction of intestinal microflora and to assess the effectiveness of rifaksimin decontamination. The study involved 35 patients with gallstone disease (GSD) (3 men, 32 women, average age--59 +/- 9 years) and 50 patients who underwent cholecystectomy at the cholecystolithiasis (4 men, 46 women, average age--60 +/- 9 years). Inclusion criteria were the complaints that are characteristic for the syndrome of excessive bacterial growth in the small intestine (EBG). All the patients underwent clinical, laboratory and instrumental examinations and hydrogen breath test. In identifying the EBG was a rifaksimin treatment at a dose of 800 mg/day for 7 days. Treatment efficacy was determined by the dynamics of clinical symptoms and indicators of the hydrogen breath test at the 8 th and 30th day of observation. Patients who was underwent cholecystectomy, EBG was detected in 58%, and among patients with gallstone disease--in 28%. The rifaksimin treatment to 8 th day was declining intensity of clinical symptoms correlated with the dynamics of the hydrogen breath test. On day 30 the majority of patients clinical symptoms of EBD disappeared (from 56 to 75% depending on the symptoms), but in some patients it persisted, despite the reduction in their severity. These data also correlated with the dynamics of the hydrogen breath test. At cholecystolithiasis and in patients with removal of the gallbladder detected EBG in 28 and 52% respectively, which requires corrective therapy. The rifaksimin therapy have positive dynamics in relieving clinical symptoms and the decline in the hydrogen breath test. However, some patients with therapy at a dose of 800 mg/day uncropped pain and dyspeptic symptoms and hadn't accompanied by normalization of pH test.


Axl receptor blockade protects from invasive pulmonary aspergillosis in mice.
Aspergillus fumigatus is a sporulating fungus found ubiquitously in the environment, which is quickly contained in the immunocompetent host but can cause lethal invasive aspergillosis in the immunocompromised host. We have recently demonstrated that Axl (one member of the Tyro3, Axl, Mertk receptor family) is a key regulator of antiviral immune responses in the lung. In this study, we investigated the role of Axl in antifungal immunity in a model of invasive pulmonary aspergillosis (IPA). In this model, Aspergillus fumigatus conidia were administered into the lungs of neutrophil-depleted mice, and the mice were monitored for survival, lung inflammatory response, and fungal clearance. The lethal effect of IPA was significantly reduced in anti-Axl mAb-treated mice compared with IgG control-treated mice. Targeting Axl significantly inhibited pulmonary inflammation, including the expression of IL-1β, IL-6, TNF-α, and chitinase-like proteins in whole lung. Further, anti-Axl mAb treatment significantly increased M1 macrophages that highly expressed inducible NO synthase and decreased M2 macrophages that expressed Arginase 1 and were found in inflammatory zone protein (Fizz1). More importantly, anti-Axl mAb treatment significantly increased the number of IFN-γ-producing T cells and NK cells compared with the IgG control group during IPA. Together, our results demonstrate that the Axl mAb treatment is protective during invasive aspergillosis in neutropenic mice. Collectively, these data suggest a potential deleterious role for Axl during primary immune responses directed against A. fumigatus and novel therapeutic strategy for IPA.


[Comparative cytoenzymatic study of infectious and vaccinal processes in experimental brucellosis].
In experiments on 240 guinea-pigs metabolic changes were found to occur in peripheral blood cells in the process of the development of brucellosis infection and after immunization. The degree and character of the activity of lysosomal enzymes depended on the time of infection and immunity formation. In comparison with the vaccinal culture of Br. abortus 19, the virulent culture of Br. abortus 544 induced greater changes in the activity of esterase, acidic and alkaline phosphatase in neutrophils, in the activity of acidic phosphatase in lymphocytes, as well as in the number of lymphocytes containing this enzyme. The data on enzymatic activity are recommended for use as a differential test for evaluating the character of the infectious and vaccinal processes.


TaDIR1-2, a Wheat Ortholog of Lipid Transfer Protein AtDIR1 Contributes to Negative Regulation of Wheat Resistance against Puccinia striiformis f. sp. tritici.
Very few LTPs have been shown to act through plasma membrane receptors or to be involved in the hypersensitive response (HR). DIR1, a new type of plant LTP interacts with lipids in vitro, moves to distant tissues during systemic acquired resistance (SAR) and therefore is thought to be involved in long-distance signaling during SAR. However, the exact functions of DIR1 orthologs in cereal species under biotic and abiotic stresses have not been thoroughly defined. In this study, a novel wheat ortholog of the DIR1 gene, TaDIR1-2, was isolated from Suwon11, a Chinese cultivar of wheat and functionally characterized. Phylogenetic analysis indicated that TaDIR1-2 is clustered within the nsLTP-Type II group and shows a closer relationship with DIR1 orthologs from monocots than from eudicots. TaDIR1-2 was localized in the cytoplasm and the cell membrane of wheat mesophyll protoplast. Transcription of TaDIR1-2 was detected in wheat roots, stems and leaves. TaDIR1-2 transcript was significantly induced during the compatible interaction of wheat with the stripe rust pathogen, Puccinia striiformis f. sp. tritici (Pst). Treatments with salicylic acid (SA) and low temperature significantly up-regulated the expression of TaDIR1-2. Transient overexpression of TaDIR1-2 did not induce cell death or suppress Bax-induced cell death in tobacco leaves. Knocking down the expression of TaDIR1-2 through virus-induced gene silencing increased wheat resistance to Pst accompanied by HR, increased accumulation of H2O2 and SA, increased expression of TaPR1, TaPR2, TaPAL, and TaNOX, and decreased expression of two reactive oxygen species (ROS) scavenging genes TaCAT and TaSOD. Our results suggest that TaDIR1-2 acts as a negative regulator in wheat resistance to Pst by modulating ROS and/or SA-induced signaling.


Discovery of 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors.
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.


Punicalagin, a polyphenol in pomegranate juice, downregulates p53 and attenuates hypoxia-induced apoptosis in cultured human placental syncytiotrophoblasts.
Oxidative stress is associated with placental dysfunction and suboptimal pregnancy outcomes. Therapeutic interventions to limit placental injury from oxidative stress are lacking. Punicalagin is an ellagitannin and a potent antioxidant in pomegranate juice. We showed that both pomegranate juice and punicalagin decrease oxidative stress and apoptosis in cultured syncytiotrophoblasts. p53 is involved in the oxidative stress-induced apoptosis in trophoblasts. We now test the hypothesis that punicalagin limits trophoblast injury in vitro by regulating the levels of p53. We examined the expression of p53, mouse double minute 2 homolog, p21, hypoxia-inducible factor (HIF) α, and selected members of the B cell lymphoma 2 (BCL2) family of proteins in cultured syncytiotrophoblasts exposed to ≤1% oxygen in the absence or presence of punicalagin. We found that punicalagin attenuated hypoxia-induced apoptosis in syncytiotrophoblasts, as quantified by levels of cleaved poly-ADP ribose polymerase. This protective effect was in part mediated by reduced p53 activity shown by decreased expression of p21, lower HIF1α expression, and limited activity of caspases 9 and 3. There was no change in expression of proteins in the BCL2 family, which are also important in apoptosis. The data support a role for downregulation of p53 in the protection of human trophoblasts by punicalagin.


Evolution of the Neurosurgeon's Role in Clinical Trials for Glioblastoma: A Systematic Overview of the Clinicaltrials.Gov Database.
The therapeutic challenge of glioblastoma (GBM) has catalyzed the development of clinical trials to evaluate novel interventions. With increased understanding of GBM biology and technological advances, the neurosurgeon's role in neuro-oncology has evolved. To evaluate the current landscape of procedure-based clinical trials for GBM to characterize this evolution, gain insight into past failures, and accordingly outline implications for future research and practice that may inform future studies. The ClinicalTrials.gov database was searched for surgical/procedural trials in individuals with GBM. Demographics, specific intervention, trial phase, and main outcome measures were abstracted. A total of 224 of 2311 GBM trials (9.7%) were identified as procedural, with the majority being based in the United States (155/224, 69.2%), single-center (155/224, 69.2%), and not randomized (176/224, 78.6%). Primary and recurrent GBMs were evenly addressed. The leading interventions were local delivery of therapeutics (50.0%), surgical techniques (33.9%), such as image-guided surgery, and novel device applications (14.3%). Phase I designs predominated (82/224, 36.6%). The top primary outcome was safety/tolerability/feasibility (88/224, 39.3%), followed by survival (46/224, 20.5%). Approximately 17% of studies were terminated, withdrawn, or suspended. Fifty-two linked publications were identified, among which 42 were classified as having a positive result. Procedural interventions comprised ∼10% of all registered GBM trials. Local delivery of therapeutics, use of surgical imaging techniques and novel device applications, predominantly through phase I designs, represent the evolved role of the neurosurgeon in neuro-oncology. Improved reporting of trial designs, outcomes, and results are needed to better inform the field and increase efficiency.


Methamphetamine-induced structural plasticity in the dorsal striatum.
Repeated exposure to psychostimulant drugs produces long-lasting changes in dendritic structure, presumably reflecting a reorganization in patterns of synaptic connectivity, in brain regions that mediate the psychomotor activating and incentive motivational effects of these drugs, including the nucleus accumbens and prefrontal cortex. However, repeated exposure to psychostimulant drugs also facilitates a transition in the control of some behaviors from action-outcome associations to behavior controlled by stimulus-response (S-R) habits. This latter effect is thought to be due to increasing engagement and control over behavior by the dorsolateral (but not dorsomedial) striatum. We hypothesized therefore that repeated exposure to methamphetamine would differentially alter the density of dendritic spines on medium spiny neurons (MSNs) in the dorsolateral vs. dorsomedial striatum. Rats were treated with repeated injections of methamphetamine, and 3 months later dendrites were visualized using Sindbis virus-mediated green fluorescent protein (GFP) expression in vivo. We report that prior exposure to methamphetamine produced a significant increase in mushroom and thin spines on MSNs in the dorsolateral striatum, but a significant decrease in mushroom spines in the dorsomedial striatum. This may be due to changes in the glutamatergic innervation of these two subregions of the dorsal striatum. Thus, we speculate that exposure to psychostimulant drugs may facilitate the development of S-R habits because this reorganizes patterns of synaptic connectivity in the dorsal striatum in a way that increases control over behavior by the dorsolateral striatum.


Novel platinum-catalyzed tandem reaction: an efficient approach to construct naphtho[1,2-b]furan.
An efficient approach to synthesize naphtho[1,2-b]furan has been developed via platinum-catalyzed tandem reaction. This new tandem catalysis induces a cycloisomerization of allenyl ketone, followed by a 6pi-electrocyclization-type reaction of carbene intermediate. The metal carbene proved to be an effective intermediate in the 6pi-electrocyclization-type reaction.


On the interaction of seryl-tRNA synthetase with tRNA Ser. A contribution to the problem of synthetase-tRNA recognition.
By following the tryptophan fluorescence of yeast seryl-tRNA synthetase on addition of tRNA Ser it was observed that the number of binding sites for tRNA decreases from two to one with increasing temperature, ATP or KCl concentration. Concomitantly a considerable decrease of the apparent binding constant was observed. The variation in the number of binding sites is explained by the presence of at least one temperature and ionic strength sensitive binding site and one temperature and ionic strength independent binding site. Relaxation kinetic experiments revealed two binding processes: a fast one depending on tRNA concentration and ionic strength and a slow one, which appeared to be independent of tRNA concentration and ionic strength. Enzyme kinetic studies showed that the activity of seryl-tRNA synthetase strongly depends on the KCl concentration and exhibits a maximum at 0.2 M KCl. Based on the data from relaxation and enzyme kinetic experiments a model is suggested for the recognition process involving a first unspecific step where all tRNAs, cognate and non-cognate, are bound to the synthetase (scanning step). The identification of the cognate tRNA is then performed at the recognition site by a conformational transition of the tRNA . synthetase complex (identification step).


Effect of the aqueous extract of Rumex patientia on xylol and hyaluronidase induced capillary permeability compared to indomethacin.
In this study, the effect of an aqueous extract of Rumex patientia L. (Polygonaceae) (D-1) on capillary permeability which was induced by xylol and hyaluronidase was investigated. Experiments were conducted on rabbits according to Monakova and Matusis methods. The effects of D-1 were compared to those of indomethacin, which was used as a control throughout the experiment. Both D-1 (100 mg/kg) and indomethacin (10 mg/kg) were administered orally. As a result, D-1 inhibited capillary permeability, which was induced by xylol and hyaluronidase, and it was found that it was as effective as indomethacin.


Cohort study protocol to characterize the incidence and severity of neuropathic pain in patients with severe acute respiratory syndrome coronavirus 2 infection.
The coronavirus disease 2019 (COVID-19) pandemic has resulted in patients experiencing symptoms that include neurological dysfunction. As many viral infections are associated with neuropathy, the aim of the study is to characterize the incidence and severity of neuropathic pain in patients with COVID-19. A cohort study will be conducted in adult (≥18 years) patients who were tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at Washington University/Barnes-Jewish Hospital. Participants who are deceased, with incomplete test results, or who cannot be contacted will be excluded. Approximately 1320 participants will be recruited in a 1:2 ratio of those with a positive-to-negative SARS-CoV-2 test result. Each participant will be invited to complete a survey to assess their symptoms related to neuropathy, 30 to 90 days after their initial SARS-CoV-2 test. Survey responses, demographics, and clinical data from the electronic health record will be used for analysis. The primary outcome is the incidence of new symptoms of neuropathic pain. The self-reported DN4 and Neuropathic Pain Symptom Inventory questionnaires (Appendix 1, http://links.lww.com/PR9/A103) will be used for neuropathic pain screening and severity assessment, respectively. Exploratory analyses will be performed to investigate other potential clinical endpoints and trends. Similar to previous coronavirus infections, an increased incidence of new-onset neuropathic pain after COVID-19 disease is expected, along with an increase in the severity experienced by patients with COVID-19 with pre-existing chronic pain. Comprehensive understanding of how COVID-19 affects the nervous system can provide a better framework for managing pain in this disease.


Phenotypic modulation of human urinary tract stroma-derived fibroblasts by transforming growth factor beta3.
Animal models have described critical roles for transforming growth factor beta (TGFbeta) isoforms in modulating urinary tract stroma phenotype. TGFbeta3 is of particular interest because it may regulate TGFbeta1 and TGFbeta2 expression, but its modulatory affect has not been so well characterized in human cells. In this study, we aim to determine whether TGFbeta3 treatment induced differentiation of human urinary tract stroma-derived fibroblasts to a smooth muscle-like phenotype. We established cultures of human urinary tract stroma-derived fibroblasts and studied the effects of TGFbeta3 treatment using proliferation assays, cell cycle analysis, immunocytochemistry, and Western blotting for expression of differentiation marker and downstream regulators, and fura-2 fluorescence to study the effects on intracellular calcium. TGFbeta3 treatment induced proliferation that peaked at 72 hours, followed by enhanced expression of alpha-smooth muscle actin (alpha-SMA) with a maximal 3.4-fold increase at 168 hours. TGFbeta3 treatment decreased resting [Ca(2+)](i) by 70% and caused a 95% decrease in stimulated internal Ca(2+) release regulated by the sarcoplasmic/endoplasmic calcium-ATPase pump. These effects were associated with upregulation of nuclear activator of T cells -1 (NFAT), a known regulator of cell differentiation. TGFbeta3 treatment causes a time-specific response in the presence of serum, whereby fibroblasts initially proliferate and subsequently differentiate to a smooth muscle-like phenotype. This sequence was associated with stabilization of [Ca(2+)](i) stores, suggesting a role in the induction of hyperplasia and reduction of contractility; phenomena associated with a number of urinary tract pathologies.


Effects of peripheral nonlinearity on psychometric functions for forward-masked tones.
Psychometric functions (PFs) for forward-masked tones were obtained for conditions in which signal level was varied to estimate threshold at several masker levels (variable-signal condition), and in which masker level was varied to estimate threshold at several signal levels (variable-masker condition). The changes in PF slope across combinations of masker frequency, masker level, and signal delay were explored in three experiments. In experiment 1, a 2-kHz, 10-ms tone was masked by a 50, 70 or 90 dB SPL, 20-ms on-frequency forward masker, with signal delays of 2, 20, or 40 ms, in a variable-signal condition. PF slopes decreased in conditions where signal threshold was high. In experiments 2 and 3, the signal was a 4-kHz, 10-ms tone, and the masker was either a 4- or 2.4-kHz, 200-ms tone. In experiment 2, on-frequency maskers were presented at 30 to 90 dB SPL in 10-dB steps and off-frequency maskers were presented at 60 to 90 dB SPL in 10-dB steps, with signal delays of 0, 10, or 30 ms, in a variable-signal condition. PF slopes decreased as signal level increased, and this trend was similar for on- and off-frequency maskers. In experiment 3, variable-masker conditions with on- and off-frequency maskers and 0-ms signal delay were presented. In general, the results were consistent with the hypothesis that peripheral nonlinearity is reflected in the PF slopes. The data also indicate that masker level plays a role independent of signal level, an effect that could be accounted for by assuming greater internal noise at higher stimulus levels.


Electrochemically Triggered Self-Adaptive Reconstruction of an all-Purpose Electrode for Photothermally Enhanced Capacitors.
Large-capacity energy storage devices are attracting widespread research attention. However, the decreased capacity of these devices due to cold weather is a huge obstacle for their practical use. In this study, an electrochemical self-adaptive reconstructed Cux S/Cu(OH)2 -based symmetric energy storage device is proposed. This device provides a satisfactorily enhanced photothermal capacity under solar irradiation. After electrochemical reconstruction treatment, the morphological structure is rearranged and the Cux S component is partially converted to electrochemically active Cu(OH)2 with the introduction of a large number of active sites. The resulting Cux S/Cu(OH)2 electrode provides a significant capacitance of 115.2 F cm-2 at 5 mA cm-2 . More importantly, its wide working potential range and superior photo-to-thermal conversion ability endow Cux S/Cu(OH)2 with superb performance as full-purpose photothermally enhanced capacitance electrodes. Under solar irradiation, the surface temperature of Cux S/Cu(OH)2 is elevated by 76.6 °C in only 30 s, and the capacitance is boosted to 230.4% of the original capacitance at a low temperature. Furthermore, the assembled symmetric energy storage device also delivers a photothermal capacitance enhancement of 200.3% under 15 min solar irradiation.


Effectiveness of a Wii balance board-based system (eBaViR) for balance rehabilitation: a pilot randomized clinical trial in patients with acquired brain injury.
Acquired brain injury (ABI) is the main cause of death and disability among young adults. In most cases, survivors can experience balance instability, resulting in functional impairments that are associated with diminished health-related quality of life. Traditional rehabilitation therapy may be tedious. This can reduce motivation and adherence to the treatment and thus provide a limited benefit to patients with balance disorders. We present eBaViR (easy Balance Virtual Rehabilitation), a system based on the Nintendo® Wii Balance Board® (WBB), which has been designed by clinical therapists to improve standing balance in patients with ABI through motivational and adaptative exercises. We hypothesize that eBaViR, is feasible, safe and potentially effective in enhancing standing balance. In this contribution, we present a randomized and controlled single blinded study to assess the influence of a WBB-based virtual rehabilitation system on balance rehabilitation with ABI hemiparetic patients. This study describes the eBaViR system and evaluates its effectiveness considering 20 one-hour-sessions of virtual reality rehabilitation (n = 9) versus standard rehabilitation (n = 8). Effectiveness was evaluated by means of traditional static and dynamic balance scales. The final sample consisted of 11 men and 6 women. Mean ± SD age was 47.3 ± 17.8 and mean ± SD chronicity was 570.9 ± 313.2 days. Patients using eBaViR had a significant improvement in static balance (p = 0.011 in Berg Balance Scale and p = 0.011 in Anterior Reaches Test) compared to patients who underwent traditional therapy. Regarding dynamic balance, the results showed significant improvement over time in all these measures, but no significant group effect or group-by-time interaction was detected for any of them, which suggests that both groups improved in the same way. There were no serious adverse events during treatment in either group. The results suggest that eBaViR represents a safe and effective alternative to traditional treatment to improve static balance in the ABI population. These results have encouraged us to reinforce the virtual treatment with new exercises, so an evolution of the system is currently being developed.


A neurocomputational model of creative processes.
Creativity is associated with finding novel, surprising, and useful solutions. We argue that creative cognitive processes, divergent thinking, abstraction, and improvisation are constructed on different novelty-based processes. The prefrontal cortex plays a role in creative ideation by providing a control mechanism. Moreover, thinking about novel solutions activates the distant or loosely connected neurons of a semantic network that involves the hippocampus. Novelty can also be interpreted as different combinations of earlier learned processes, such as the motor sequencing mechanism of the basal ganglia. In addition, the cerebellum is responsible for the precise control of movements, which is particularly important in improvisation. Our neurocomputational perspective is based on three creative processes centered on novelty seeking, subserved by the prefrontal cortex, hippocampus, cerebellum, basal ganglia, and dopamine. The algorithmic implementation of our model would enable us to describe commonalities and differences between these creative processes based on the proposed neural circuitry. Given that most previous studies have mainly provided theoretical and conceptual models of creativity, this article presents the first brain-inspired neural network model of creative cognition.