Widespread membrane potential changes and cardiorespiratory synchronization involved in anxiety and sleep-wake transitions.
Located within the ascending reticular activating system are nuclei which release neurotransmitters such as acetylcholine, serotonin, dopamine, and norepinephrine. These nuclei have widespread projections that extend into the limbic system and throughout cortex. Activation of these neurotransmitters during awake states leads to arousal, while inhibition leads to the loss of consciousness experienced during slow-wave sleep. Previously, we proposed a mechanism in which cardiorespiratory synchronization may underlie the widespread hyperpolarization that occurs throughout the brain during slow-wave sleep. We further propose that a similar homeostatic mechanism may be involved in sleep-wake transitions and maintaining various arousal states including rapid eye movement sleep, waking, and anxiety. Widespread depolarization associated with more rapid, shallow breathing and desynchronized cardiorespiratory oscillatory activity may underlie waking, anxiety, and rapid eye movement sleep states. The exact voltage values of these widespread membrane potential changes remain unknown and possibly highly variable between different neural areas and cell types. Here, we place these consciousness states on a spectrum of approximated widespread membrane potential values with anxiety states being the most depolarized, followed by waking states, and rapid eye movement sleep. We propose that although these widespread membrane potential changes are minor, they may underlie transitions between and maintenance of varying levels of arousal. Further research on these mechanisms could provide insights into how the brain functions. This homeodynamic arousal mechanism involves the established feed-forward and feedback signaling between the ascending reticular activating system and the hypothalamus, as well as the modulation by cardiorespiratory oscillatory feedback from the body. Understanding the basic mechanisms responsible for the states of sleep, waking, and anxiety could lead to better treatment options in health and disease.


The Efficacy and Safety of Esmolol for Septic Shock: A Systematic Review and Meta-analysis of Randomized Controlled Trials.
Purpose: The meta-analysis aims to identify whether septic shock patients can benefit from esmolol. Materials and Methods: The relevant studies from MEDLINE, Cochrane Library, Embase were searched by two independent investigators using a variety of keywords. Stata software (version 12.0, Stata Corp LP, College Station, TX, United States)was used for statistical analysis. Results: A total of 14 studies were identified and incorporated into the meta-analysis. For overall analysis, the treatment of esmolol was associated with decreased 28-day mortality (RR = 0.66, 95% CI = 0.56-0.77, p < 0.001). Meanwhile, our analysis found that, esmolol could decrease HR (SMD: -1.70; 95% CI: [-2.24-(-1.17)], cTnI (SMD: -1.61; 95% CI: [-2.06-(-1.16)] compared with standard treatment. No significant differences between the two groups were found in MAP, Lac, CI, and SVI. Conclusion: The findings of this meta-analysis intend to demonstrate that septic shock patients with high heart beats rate might be benefit from esmolol treatment despite enough fluid resuscitation. While, dependent on the study published, with the further development of septic shock, the positive impact of esmolol varies. The appropriate heart rate change interval cannot be confirmed, further high-quality and large-scale RCTs should be performed to verify it and screening more suitable heart rate levels. Systematic Review Registration: CRD42021239513.


Down-regulation of brush border efflux transporter expression in the kidneys of pregnant mice.
Pregnancy increases the urinary excretion of chemicals in women and rodents. It is unknown whether the enhanced clearance of drugs during pregnancy involves changes in the expression of transporters that mediate chemical secretion and reabsorption. The purpose of this study was to quantify the mRNA and protein expression of efflux transporters in kidneys from virgin and pregnant mice on gestational days 7, 11, 14, and 17 and postnatal days 1, 15, and 30 with use of quantitative polymerase chain reaction, Western blot, and immunofluorescence. Multidrug resistance protein (Mdr) 1b mRNA, multidrug resistance-associated protein (Mrp) 4 mRNA, and protein levels decreased significantly by 25-75% throughout pregnancy and lactation. Similarly, Mrp2 and multidrug and toxin extrusion transporter (Mate) 1 mRNA expression were down-regulated 20-40% during mid to late gestation but returned to control levels by postnatal day 15. In contrast, Mrp3 mRNA and protein increased 225% and 31%, respectively, at gestational day 14. Coordinated down-regulation of brush border transporters Mate1, Mrp2, and Mrp4 and up-regulation of the basolateral Mrp3 transporter would reduce chemical secretion into urine.


Specific armadillo repeat sequences facilitate β-catenin nuclear transport in live cells via direct binding to nucleoporins Nup62, Nup153, and RanBP2/Nup358.
β-Catenin transduces the Wnt signal from the membrane to nucleus, and certain gene mutations trigger its nuclear accumulation leading to cell transformation and cancer. β-Catenin shuttles between the nucleus and cytoplasm independent of classical Ran/transport receptor pathways, and this movement was previously hypothesized to involve the central Armadillo (Arm) domain. Fluorescence recovery after photobleaching (FRAP) assays were used to delineate functional transport regions of the Arm domain in living cells. The strongest nuclear import/export activity was mapped to Arm repeats R10-12 using both in vivo FRAP and in vitro export assays. By comparison, Arm repeats R3-8 of β-catenin were highly active for nuclear import but displayed a comparatively weak export activity. We show for the first time using purified components that specific Arm sequences of β-catenin interact directly in vitro with the FG repeats of the nuclear pore complex (NPC) components Nup62, Nup98, and Nup153, indicating an independent ability of β-catenin to traverse the NPC. Moreover, a proteomics screen identified RanBP2/Nup358 as a binding partner of Arm R10-12, and β-catenin was confirmed to interact with endogenous and ectopic forms of Nup358. We further demonstrate that knock-down of endogenous Nup358 and Nup62 impeded the rate of nuclear import/export of β-catenin to a greater extent than that of importin-β. The Arm R10-12 sequence facilitated transport even when β-catenin was bound to the Arm-binding partner LEF-1, and its activity was stimulated by phosphorylation at Tyr-654. These findings provide functional evidence that the Arm domain contributes to regulated β-catenin transport through direct interaction with the NPC.


Genetic determinants of bone mass in adults. A twin study.
The relative importance of genetic factors in determining bone mass in different parts of the skeleton is poorly understood. Lumbar spine and proximal femur bone mineral density and forearm bone mineral content were measured by photon absorptiometry in 38 monozygotic and 27 dizygotic twin pairs. Bone mineral density was significantly more highly correlated in monozygotic than in dizygotic twins for the spine and proximal femur and in the forearm of premenopausal twin pairs, which is consistent with significant genetic contributions to bone mass at all these sites. The lesser genetic contribution to proximal femur and distal forearm bone mass compared with the spine suggests that environmental factors are of greater importance in the aetiology of osteopenia of the hip and wrist. This is the first demonstration of a genetic contribution to bone mass of the spine and proximal femur in adults and confirms similar findings of the forearm. Furthermore, bivariate analysis suggested that a single gene or set of genes determines bone mass at all sites.


[Stepwise synthesis of oligonucleotides. XXXV. Native and immobilized polynucleotide phosphorylase from Thermus thermophilus in oligoribonucleotide synthesis].
A polynucleotide phosphorylase was isolated from the Thermus thermophilus protein fractions, obtained at different steps of purification of elongation factors, and immobilized on agarose activated with cyanogen bromide and macroporous glass modified with (3,3-diethoxypropyl)triethoxysilane. The preparations of the native and immobilized enzyme catalyzed rather efficiently the addition of adenylyl and guanylyl residues to oligonucleotide primers, in contrast to the E. coli and M. luteus polynucleotide phosphorylases. Tri-, tetra- and pentanucleotides with 3'-terminal guanosine and adenosine were obtained including structural analogues of the anticodon fragment 34-37 of yeast tRNA(Phe).


ROR1 expression is not a unique marker of CLL.
Recent studies have identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) on the surface of chronic lymphoid leukaemia (CLL) cells. In order to determine whether ROR1 expression is a suitable surrogate marker for the diagnosis of CLL we analysed the mRNA level of ROR1 in different types of non-Hodgkin lymphomas (NHL), and detected elevated levels of ROR1 compared to control peripheral mononuclear cells in several entities (CLL ≥ mantle cell lymphoma (MCL) > marginal zone lymphoma (MZL) >> diffuse large B-cell lymphoma > follicular lymphoma). ROR1 protein was expressed intensely on the cell surface of lymphoma cells with leukaemic blood count detected by three colour immunofluorescence. Our results indicate that ROR1 expression is not limited to CLL cases, but it is more prevalent in NHLs, mainly in MCL where it is expressed intensely and MZL where it is expressed moderately, suggesting a general role of ROR1 in lymphoma genesis and/or maintenance. Copyright © 2010 John Wiley & Sons, Ltd.


Clinical trial: oral colon-release parnaparin sodium tablets (CB-01-05 MMX) for active left-sided ulcerative colitis.
The administration of parnaparin sodium as oral colon-release tablets (CB-01-05 MMX) has been proposed as a novel approach for the treatment of ulcerative colitis (UC). To assess the efficacy and the tolerability of 8 weeks' oral daily administration of 210 mg of parnaparin sodium compared with placebo in subjects treated with stable-doses of oral aminosalicylates. This multicenter, randomized, double-blind proof of concept trial compared the efficacy of CB-01-05 MMX 210 mg tablets to placebo in 141 subjects with mild to moderately active left-sided UC treated with stable-doses of aminosalicylates. The efficacy was assessed by clinical activity index (CAI), endoscopic index (EI) and histological score (HS). A total of 121 subjects (61 in test group and 60 in control group) formed the per protocol (PP) population. After 8 weeks of treatment, clinical remission was achieved in 83.6% of the CB-01-05 MMX group, and in 63.3% in the comparator group (P = 0.011). This effect was also significantly evident in the test group at week 4 (P = 0.028). A significant difference was also detected in rectal bleeding, (disappeared respectively in 75.4% and 55.0%; P = 0.018), and in mucosal friability (recovered respectively in 80.3% and in 56.7%; P = 0.005). CB-01-05 MMX was safe and significantly effective in treating subjects with mild-to-moderate left-sided UC treated with stable-doses of aminosalicylates.


Bradykinin receptor number and sensitivity to ligand stimulation of mitogenesis is increased by expression of a mutant ras oncogene.
Bradykinin is a nine amino acid peptide of the kinin family believed to play a role in pain mediation and in the regulation of blood pressure, fluid balance and smooth muscle contraction. Here we demonstrate that bradykinin is also a potent mitogen for a mutant Ha-ras-transfected cell line, Rat 13. The Rat 13 cells display two binding sites for bradykinin: a moderate number (52,000) of high affinity sites (Kd = 4.9 nM) co-exist with a much smaller number (1100) of very high-affinity sites (Kd = 2.7 pM). Ligand binding stimulates mitogenesis through the lower affinity receptors, which are classified as B2. These receptors are down-regulated in response to ligand. In contrast, Rat 1 cells (the cell line from which Rat 13 was derived) have only 4000 receptors per cell in total and respond weakly to bradykinin as a mitogen. Thus, expression of a mutant ras protein in Rat 13 cells increases their expression of the bradykinin receptor and their sensitivity to ligand stimulation of mitogenesis. Additional binding studies demonstrate that human A431 epithelial cells and Swiss mouse 3T3 fibroblasts also possess high-affinity sites for bradykinin.


Longitudinal tracking of subpopulation dynamics and molecular changes during LNCaP cell castration and identification of inhibitors that could target the PSA-/lo castration-resistant cells.
We have recently demonstrated that the undifferentiated PSA-/lo prostate cancer (PCa) cell population harbors self-renewing long-term tumor-propagating cells that are refractory to castration, thus representing a therapeutic target. Our goals here are, by using the same lineage-tracing reporter system, to track the dynamic changes of PSA-/lo and PSA+ cells upon castration in vitro, investigate the molecular changes accompanying persistent castration, and develop large numbers of PSA-/lo PCa cells for drug screening. To these ends, we treated LNCaP cells infected with the PSAP-GFP reporter with three regimens of castration, i.e., CDSS, CDSS plus bicalutamide, and MDV3100 continuously for up to ~21 months. We observed that in the first ~7 months, castration led to time-dependent increases in PSA-/lo cells, loss of AR and PSA expression, increased expression of cancer stem cell markers, and many other molecular changes. Meanwhile, castrated LNCaP cells became resistant to high concentrations of MDV3100, chemotherapeutic drugs, and other agents. However, targeted and medium-throughput library screening identified several kinase (e.g., IGF-1R, AKT, PI3K/mTOR, Syk, GSK3) inhibitors as well as the BCL2 inhibitor that could effectively sensitize the LNCaP-CRPC cells to killing. Of interest, LNCaP cells castrated for >7 months showed evidence of cyclic changes in AR and the mTOR/AKT signaling pathways potentially involving epigenetic mechanisms. These observations indicate that castration elicits numerous molecular changes and leads to enrichment of PSA-/lo PCa cells. The ability to generate large numbers of PSA-/lo PCa cells should allow future high-throughput screening to identify novel therapeutics that specifically target this population.


Development of novel biocompatible thermosensitive anti-adhesive agents using human-derived acellular dermal matrix.
Postoperative adhesion is a natural phenomenon that occurs in damaged tissue cells. Several anti-adhesion agents are currently used, but there is no leading-edge product with excellent adhesion-preventive effects. The purpose of this study was to develop ideal anti-adhesive agents using human-derived acellular dermal matrix (ADM). We developed 5 new biocompatible thermosensitive anti-adhesion barriers (AABs) using micronized human-derived ADM, hyaluronic acid, and temperature-sensitive and biocompatible synthesized polymers. The biocompatibility, anti-adhesion effect, and biodegradability of these AABs were compared with those of commercial thermosensitive anti-adhesion agents. No cytotoxic effects were observed in vitro and in vivo. Animal testing of adhesion resistance confirmed that the adhesion area, strength, and grade of AAB03 were statistically superior to those of the control group. Factors related to adhesion formation, such as lymphocytes, macrophages, microvessels, and collagen fiber density, were observed using specific staining methods; the results confirmed that AAB03 group exhibited significantly lower macrophage counts, microvessel density, and collagen fiber density than the control groups. Furthermore, AAB03 was completely absorbed by 6 weeks. Thus, AAB03 has the potential to be used as a high-performance anti-adhesion agent.


3. Decrease of labeled DNA in cells of the adrenal medulla after intermittent exposure to cold.
Italico rats were injected with thymidine-(3)H 6 hr after the end of 300 hr of intermittent cold treatment. This plan of experiment ensured replacement in the adrenal medulla of lost DNA which is specifically sensitive to cold treatment and has a labeling index sufficiently high for statistical evaluation. The labeling index in the adrenal medulla decreases to one-half of the initial value within 10 days in animals subjected to further intermittent cold treatment and within 32 days in animals kept at room temperature. The very low mitotic index and the absence of doubling of the labeling index show that the observed labeling cannot be ascribed to pre-mitotic DNA synthesis. The concept of metabolic DNA adequately explains the findings.


[The "Appropriatezza ECO Milano" project. Assessment of appropriateness of indications, prescriptions and clinical utility of two-dimensional Doppler echocardiography among inpatients and outpatients of Milan, Italy].
The value of echocardiography in the diagnosis and follow-up of most cardiovascular diseases is well established, even though the ever-increasing demand for the use of this technique is not always justifiable. The "Appropriatezza ECO Milano" project was developed among hospitals in Milan (Italy) to foster a rational use of echocardiography. The aim of this study was to evaluate and improve appropriateness of requests for two-dimensional color Doppler echocardiography, considering indications, prescription behaviors and clinical utility in both the outpatient and inpatient settings. Following several meetings, a consensus was reached whereby a multicenter, observational study would be undertaken. We assessed the value of each request in agreement with the 2003 American College of Cardiology/American Heart Association/American Society of Echocardiography guidelines. An ad hoc Microsoft Access database was developed to collect study data, which refer to May 2007. Eleven hospitals participated in the study. 4130 echocardiographic examinations were considered (2300 performed in men and 1830 performed in women; mean age 64 +/- 16 years); 1701 examinations were performed in hospitalized patients and 2429 in outpatients. The incidence of pathological findings was higher in hospitalized patients (73%) than in outpatients (53%) (Pearson chi2 = 29, p<0.001). A higher additional clinical value was found in hospitalized vs non-hospitalized patients (48 vs. 35%, Pearson chi2 = 99; p <0.001). In both settings, the majority of echocardiographic examinations were requested by cardiologists (inpatients 36%, outpatients 54%). The most appropriate examinations were performed more frequently in class I or class IIA hospitalized patients (73%) than in outpatients (52%) (Pearson chi2 = 277, p<0.001). Furthermore, the least accurate the indication, the less the clinical utility found in examinations requested from hospitals and outpatient clinics (64 vs 61% in class I patients, Pearson chi2 = 413, p<0.001; 5 vs 11% in class III patients, Pearson chi2 = 584, p<0.001). Conclusions. Our data confirm an inadequate level of appropriateness of requests for two-dimensional color Doppler examinations in either inpatients or outpatients. After over 10 years of passively observing and recording this trend, a timely resolution of these issues is topical in order to improve the implementation of criteria and to guarantee cost-effective and high-quality cardiovascular care.


Indocyanine Green (ICG)-Guided One-Stage Delayed Bladder Closure and Radical Soft-Tissue Mobilization (Kelly Procedure) For Bladder Exstrophy Repair: The First Experience.
The vascular supply of the pelvic structures and the external genitalia can be easily injured during the one-stage delayed bladder closure and radical soft-tissue mobilization (Kelly procedure) for bladder exstrophy surgical repair. Aiming to help surgeons assessing and confirming tissue perfusion and viability, indocyanine green (ICG)-based laser angiography was incorporated into the operative approach to reduce the risk of ischemic injuries. The EleVision IR system (Medtronic Ltd) was adopted to confirm the identification of the vascular pedicles and assess the tissue perfusion in real-time in a 5-month-old with bladder exstrophy undergoing the one-stage delayed bladder closure and radical soft-tissue mobilization (Kelly procedure). ICG (0.15 mg/kg) was intravenously administered at 6 key steps during surgery with the ability to be re-dosed every 15 minutes. ICG-based laser angiography helped to confirm the correct identification of the vascular structures during surgery and to assess tissue perfusion in real-time. Blood flow did not change considerably after initial dissection or upon approximating the pubis symphysis. At the end of the procedure, good penile perfusion was shown, proving that no direct injury or substantial compression of the pudendal vessels had occurred following the mobilization and the reconstructive phase. ICG-based laser angiography proved to be safe, effective, and easy to employ and should be considered as a reasonable adjunct for tissue perfusion assessment and operative decision-making in patients undergoing bladder exstrophy Kelly repair.


[Mechanism of optic nerve congestive disk development during acute period of closed craniocerebral injury].
The mechanism of development of congestion on the fundus oculi in acute posttraumatic intraocular hypertension was studied. A total of 410 patients were examined during the acute period of closed craniocerebral injury of different severity. Pressure in the central retinal vein was tentatively measured by transpalpebral compression of the eyeball with monitoring venous pulsation by direct ophthalmoscopy. The presence of spontaneous pulsation of retinal veins was regarded as an indicator of normal intracranial pressure. Analysis of the severity and location of the intracranial focus of injury together with evaluation of pressure in the retinal vein suggest that congestion on the fundus oculi in closed craniocerebral injury is triggered by the reaction of cavernous sinus intramural baroreceptors to a sudden rise of intracranial pressure.


Prostaglandin F2 alpha and indomethacin in hepatogenic pulmonary angiodysplasia. Effects on pulmonary hemodynamics and gas exchange.
We treated a 68-year-old man with cirrhosis of the liver associated with moderate hypoxemia. Contrast-enhanced echocardiography revealed late opacification of the left ventricle, and pulmonary perfusion imaging with 99mTc macroaggregated albumin showed evidence of a significant uptake in both lungs and in the liver, spleen, and kidneys. Right cardiac catheterization revealed pulmonary hypotension, low pulmonary vascular resistance, and high cardiac output. We administered prostaglandin F2 alpha intravenously (0.2 microgram/kg/min for 30 minutes) and indomethacin orally (75 mg/day for three days). There was some degree of resolution of the hypoxemia and increases in both pulmonary arterial pressure and pulmonary vascular resistance. These findings suggest that the pathophysiology of hepatogenic pulmonary angiodysplasia is a reversible intrapulmonary vascular dilatation. These conditions can to some extent be modulated by vasoactive substances such as prostaglandins or other eicosanoids.


Accelerating progress in achieving the millennium development goal for children through community-based approaches.
The Millennium Development Goal 4 (MDG4) calls for the reduction in under-five mortality by two-thirds between 1990 and 2015. Only 16 of the 68 countries with 97% of the world's child deaths are on track to achieve this. This paper reviews the current evidence regarding proven interventions for reducing child mortality in high-mortality, resource-poor settings. All of these interventions require implementation within communities rather than implementation confined to only those attending health facilities with strong community participation in order to be effective. The evidence strongly suggests that facility-based interventions require a strong community-based component in order to improve child mortality in the surrounding population. We provide specific information about common community-based approaches used in the implementation of interventions with documented improvements in child mortality. A stronger emphasis on community-based approaches will be needed in order to accelerate progress in reaching MDG4. This report arises from an ongoing review of assessments of the effectiveness of community-based primary health care (CBPHC) in improving child health sponsored by the Working Group on CBPHC of the American Public Health Association.


Short-term treatment of RAW264.7 macrophages with adiponectin increases tumor necrosis factor-alpha (TNF-alpha) expression via ERK1/2 activation and Egr-1 expression: role of TNF-alpha in adiponectin-stimulated interleukin-10 production.
Adiponectin is an adipokine with potent anti-inflammatory properties. However, the mechanisms by which adiponectin suppresses macrophage function are not well understood. Treatment of RAW264.7 macrophages with adiponectin for 18 h decreased lipopolysaccharide (LPS)-stimulated tumor necrosis factor-alpha (TNF-alpha) production. Here we demonstrate that globular adiponectin (gAcrp) initially increased TNF-alpha expression in RAW264.7 macrophages; this TNF-alpha then contributed to increased expression of interleukin-10, which in turn was required for the development of tolerance to subsequent LPS exposure. gAcrp-mediated increases in TNF-alpha mRNA accumulation were associated with increased TNF-alpha promoter activity. gAcrp increased the DNA binding activity of both Egr-1 and NFkappaB; mutation of either the Egr-1 or NFkappaB binding sites in the TNF-alpha promoter decreased gAcrp-stimulated promoter activity. Further, co-transfection with either dominant negative Egr-1 or the IkappaB super-repressor prevented gAcrp-stimulated TNF-alpha promoter activity. gAcrp also increased Egr-1 promoter activity, mRNA accumulation, and DNA binding activity. Inhibition of ERK1/2 with U0126 potently suppressed gAcrp-stimulated Egr-1 promoter activity, as well as TNF-alpha promoter activity. In summary, these data demonstrate that adiponectin initially increases TNF-alpha production by macrophages via ERK1/2-->Egr-1 and NFkappaB-dependent mechanisms; these increases in TNF-alpha in turn lead to increased expression of interleukin-10 and an eventual dampening of LPS-mediated cytokine production in macrophages.


Association of Telomere Length With Chromosomal Damage Among Chinese Workers Exposed to Vinyl Chloride Monomer.
To explore the relationship between relative telomere length (RTL) and chromosomal damage represented by micronucleus (MN) frequencies among vinyl chloride monomer (VCM) -exposed workers. A group of 126 VCM-exposed workers, 60 internal controls, and 25 external controls were examined for RTL by Quantitative polymerase chain reaction and MN frequencies by cytokinesis-block micronucleus test. Cumulative exposure dose was used to estimate the exposure of VCM-exposed workers. The RTL were significantly shorter in exposed workers and internal controls than in external controls. The exposed workers had significantly increased MN frequencies than both control groups. Additionally, MN frequencies were negatively associated with RTL in VCM-exposed group. VCM exposure may alter telomere length, which could be a potential biomarker of susceptibility to chromosomal damage.


Analysis of Regional Right Ventricular Function by Tissue Doppler Imaging and Three-Dimensional Echocardiography in Highly Trained Athletes.
Regional right ventricular (RV) function has not yet been characterized in highly trained athletes, and the effects of increased RV volumes on resting changes of regional RV deformation are unknown. The aim of the study was to analyze global and regional RV function by a multisegmental approach using tissue Doppler imaging (TDI) and to determine whether higher RV volumes evaluated by three-dimensional echocardiography (3DE) had an impact on the RV mechanics assessed by resting regional TDI parameters. We enrolled prospectively 25 professional soccer players and 25 age- and sex-matched nonathletic controls. Transthoracic echocardiography including additional views of the RV was performed. The TDI sample volume was placed in the basal region of the anterior, inferior, and RV free wall to assess the following parameters: isovolumic contraction time (IVCTRV), isovolumic relaxation time (IVRTRV), ejection time (ETRV), and myocardial performance index (MPIRV). Furthermore, conventional left ventricular (LV) and RV parameters at two-dimensional (2D) and 3DE were determined. In athletes, LV mass index/body surface area (BSA), left atrial volume index, 2D LV volumes/BSA were significantly increased in comparison with controls. Moreover, athletes had higher 2D LV and RV stroke volume (SV), lower values for A wave and E/e' ratio, higher basal RV diameter, and right atrial (RA) area (P < 0.0001). Moreover, athletes showed significantly increased LV and RV volumes and SV indexed for BSA (P < 0.0001) evaluated at 3DE. In athletes, ETRV-free wall, ETRV-anterior, IVCTRV-inferior, and IVCTRV-anterior were statistically increased (P < 0.0001). Conversely, IVRTRV-anterior was reduced in comparison with controls. A significant positive correlation between IVRTRV-inferior and three-dimensional (3D) RV end-diastolic volume (EDV), end-systolic volume, and SV was observed in athletes. Finally, a good positive correlation was observed between 3D RV EDV and 3D LV SV indexed for BSA. In athletes, the higher 3D RV volumes are proportionally related to an increase of IVRTRV-inferior and 3D LV SV. Further studies on the resting changes of regional RV deformation for screening and follow-up in these participants are needed.


[Lyme borreliosis. The manifestations of the disease from the internal medicine and rheumatology viewpoints].
Lyme disease is an infectious syndrome transmitted by tick bites. Of the multiple manifestations, cardiac and joint involvement are of primary interest for internists and rheumatologists. Up to 10% of patients develop cardiac symptoms, most frequently a disturbance of atrioventricular conduction. The characteristic presentation of the disease, however, are of symptoms of arthritis in one or several large joints. This review summarizes Lyme disease with emphasis on presenting symptoms important to internists and rheumatologists.


Analysis of interobserver variability for endomicroscopy of the gastrointestinal tract.
Endomicroscopy allows in vivo microscopic investigation of enteral mucosa during endoscopic examinations. The aim of this study was to determine interobserver variability in the evaluation of endomicroscopic pictures of several organs by groups of investigators composed of confocal experts, pathologists and students. Twenty-five selected representative endomicroscopic pictures of the colon, stomach and oesophagus (total number, 75) were evaluated based on tissue, inflammatory and neoplastic changes (secondary endpoints). The endomicroscopic presence of neoplastic features was the primary endpoint and correlated with the final histological diagnosis. The kappa values for experts examining colon, stomach, and oesophagus pictures were 0.80, 0.91, and 0.488, respectively; for students 0.74, 0.684, and 0.527 and for pathologists 0.749, 0.633, and 0.346, respectively. Neoplasia was accurately diagnosed in 67-97% of patients with no significant differences between the 3 groups. Tissue differentiation was determined best by pathologists, whereas the degree of inflammation was better diagnosed by experts and students. In all 3 groups the diagnosis of oesophageal diseases was the most difficult. Endomicroscopic images can be interpreted with high concordance. In our study, the diagnostic reliability was not different between students, endomicroscopic experts, and pathologists. Thus, endomicroscopy could be an additional and reliable imaging modality for diagnosing mucosal neoplasia of the gut.


Correlation of manual semi-quantitative and automated quantitative Ki-67 proliferative index with OncotypeDXTM recurrence score in invasive breast carcinoma.
Ki-67 immunohistochemistry (IHC) staining is a widely used cancer proliferation assay; however, its limitations could be improved with automated scoring. The OncotypeDXTM Recurrence Score (ORS), which primarily evaluates cancer proliferation genes, is a prognostic indicator for breast cancer chemotherapy response; however, it is more expensive and slower than Ki-67. To compare manual Ki-67 (mKi-67) with automated Ki-67 (aKi-67) algorithm results based on manually selected Ki-67 "hot spots" in breast cancer, and correlate both with ORS. 105 invasive breast carcinoma cases from 100 patients at our institution (2011-2013) with available ORS were evaluated. Concordance was assessed via Cohen's Kappa (κ). 57/105 cases showed agreement between mKi-67 and aKi-67 (κ 0.31, 95% CI 0.18-0.45), with 41 cases overestimated by aKi-67. Concordance was higher when estimated on the same image (κ 0.53, 95% CI 0.37-0.69). Concordance between mKi-67 score and ORS was fair (κ 0.27, 95% CI 0.11-0.42), and concordance between aKi-67 and ORS was poor (κ 0.10, 95% CI -0.03-0.23). These results highlight the limits of Ki-67 algorithms that use manual "hot spot" selection. Due to suboptimal concordance, Ki-67 is likely most useful as a complement to, rather than a surrogate for ORS, regardless of scoring method.


Barriers and facilitators related to COVID-19 vaccine acceptance and uptake among people living with HIV.
This review reports on the myriad barriers and facilitators related to COVID-19 vaccine hesitancy and factors contribution to uptake among people living with HIV (PLWH) globally published over the past year (2021-2022). Across the literature, participants indicated concerns about the safety, efficacy and overall rapid development of the COVID-19 vaccine as a reason for delaying or not being vaccinated. Medical mistrust and perceptions about the risk of COVID-19 immune response and severity also played a role in COVID-19 vaccine hesitancy among PLWH. Almost every study examined different sociodemographic characteristics associated with COVID-19 vaccination acceptance and uptake, and although strong themes emerged around race/ethnicity, sex and educational attainment, the results were mixed across other characteristics, including age. Some studies also examined medical factors specifically related to PLWH including CD4 + cell count and adherence to antiretroviral therapy. The findings highlight individual, structural and social differences in COVID-19 vaccine acceptance and uptake among PLWH, which are varied throughout the world. We call on researchers and interventionists to not just consider the role of medical mistrust and disinformation, but also how emotional, financial and political vulnerability plays into making decisions around COVID-19 vaccine uptake and overall healthcare.


Studies on insulin-like substances in Korean red ginseng.
Korean red ginseng powder was found to contain adenosine and an acidic substance which inhibited epinephrine-induced lipolysis and stimulated insulin-mediated lipogenesis from glucose (3, 4). In the present experiment, the chemical structure of this acidic substance is determined to be pyro-glutamic acid. Pyroglutamic acid exhibits selective modulations toward the opposite metabolic pathways in rat adipocytes; it inhibits the lipolysis but rather stimulates the lipogenesis. Based on these results, we suggest to call these substances (adenosine and pyro-glutamic acid) "selective modulators".


Why we should sample sparsely and aim for a higher target: Lessons from model-based therapeutic drug monitoring of vancomycin in intensive care patients.
To explore the optimal data sampling scheme and the pharmacokinetic (PK) target exposure on which dose computation is based in the model-based therapeutic drug monitoring (TDM) practice of vancomycin in intensive care (ICU) patients. We simulated concentration data for 1 day following four sampling schemes, Cmin , Cmax + Cmin , Cmax + Cmid-interval + Cmin , and rich sampling where a sample was drawn every hour within a dose interval. The datasets were used for Bayesian estimation to obtain PK parameters, which were used to compute the doses for the next day based on five PK target exposures: AUC24 = 400, 500, and 600 mg·h/L and Cmin = 15 and 20 mg/L. We then simulated data for the next day, adopting the computed doses, and repeated the above procedure for 7 days. Thereafter, we calculated the percentage error and the normalized root mean square error (NRMSE) of estimated against "true" PK parameters, and the percentage of optimal treatment (POT), defined as the percentage of patients who met 400 ≤ AUC24 ≤ 600 mg·h/L and Cmin ≤ 20 mg/L. PK parameters were unbiasedly estimated in all investigated scenarios and the 6-day average NRMSE were 32.5%/38.5% (CL/V, where CL is clearance and V is volume of distribution) in the trough sampling scheme and 27.3%/26.5% (CL/V) in the rich sampling scheme. Regarding POT, the sampling scheme had marginal influence, while target exposure showed clear impacts that the maximum POT of 71.5% was reached when doses were computed based on AUC24 = 500 mg·h/L. For model-based TDM of vancomycin in ICU patients, sampling more frequently than taking only trough samples adds no value and dosing based on AUC24 = 500 mg·h/L lead to the best POT.


Local collaborations for physical activity promotion: a network analysis.
This study aims to describe a local network for physical activity promotion and identify factors associated to collaboration or partnership ties between its actors. The study was carried out in a district of São Paulo, Brazil. Thirty-two actors responsible for policies, programs, and initiatives to promote physical activity within the district were interviewed from June to December 2012. Interviews included information about the actors' attributes and their relationships with the other actors. Network analysis techniques were used to describe and analyze the structure of the network. Thirty-two actors maintained 179 relationships among themselves (density = 0.18), of which 46% were reciprocal. Four in 10 relationships did not extend beyond information exchange. Forty-six relationships were classified as collaborations or partnerships (density = 0.09), of which 40% were concentrated on one actor of the public sector. To perceive institutional structure and bureaucracy as limiting factors to networking has been positively associated with new collaboration or partnership ties (OR = 2.37; 95%CI: 1.2-5.50). Understanding the structure of the network may empower the actors and foster self-management, facilitating the identification and decision, in a collaborative way, in which new relationships may have greater impact in the physical activity promotion within the district.


[SUBUNITS OF MAMMAL DNA DEPENDENT RNA POLYMERASE III MODIFIED IN VIVO].
In subfractions of DNA-dependent RNA polymerase isolated from nuclei of 3T3 mouse fibroblasts, A431 epidermoid carcinoma cells and mature human placenta, we have identified three subunits modified by both phosphorylation and O-N-acetylglucosamine glucosilation. The subfractions of the human enzyme contained modified subunits with molecular weight of 60 and 45 kDa and a subunit of 52 kDa probably belonging to one of the basal factors of RNA Polymerase III transcription. The subfractions of 3T3 mouse cells RNA Polymerase III consisted of modificated subunits with molecular weight 49, 45 and 42 kDa, however, the 45 kDa subunit might be a component of the basal transcription factor of RNA Polymerase III, since it was not identified in mouse enzyme composition.


Pathogenesis of Hantaan virus in mice.
The virulence of two virus clones (HV cl-1 and HV cl-2) of Hantaan virus, which were plaque-purified on Vero E6 cells, were compared in suckling mice infected by the intraperitoneal or intracerebral route. HV cl-1 increased the mortality of the mice whereas HV cl-2 did not. Furthermore, virus of high titre was isolated from various organs of mice infected with HV cl-1 and high titres were maintained, whereas after infection with HV cl-2, virus was isolated from various organs only in low titre and only temporarily. HV cl-1 strongly induced cell-to-cell fusion, but the cell fusion activity was at a minimum level in cells infected with HV cl-2. However these two clones induced similar titres of antibodies in mice. Cytotoxic T lymphocyte assays against macrophages infected with homologous and heterologous virus showed that cytotoxic T cell activity was induced in mice infected with HV cl-2, but suppressed in mice infected with HV cl-1. These results suggest that an alteration in the cell fusion function and the cytotoxic T cell activity are important in the pathogenesis of Hantaan virus infection in newborn mice.


HIV-1 promonocytic and lymphoid cell lines: an in vitro model of in vivo mitochondrial and apoptotic lesion.
To characterize mitochondrial/apoptotic parameters in chronically human immunodeficiency virus (HIV-1)-infected promonocytic and lymphoid cells which could be further used as therapeutic targets to test pro-mitochondrial or anti-apoptotic strategies as in vitro cell platforms to deal with HIV-infection. Mitochondrial/apoptotic parameters of U1 promonocytic and ACH2 lymphoid cell lines were compared to those of their uninfected U937 and CEM counterparts. Mitochondrial DNA (mtDNA) was quantified by rt-PCR while mitochondrial complex IV (CIV) function was measured by spectrophotometry. Mitochondrial-nuclear encoded subunits II-IV of cytochrome-c-oxidase (COXII-COXIV), respectively, as well as mitochondrial apoptotic events [voltage-dependent-anion-channel-1(VDAC-1)-content and caspase-9 levels] were quantified by western blot, with mitochondrial mass being assessed by spectrophotometry (citrate synthase) and flow cytometry (mitotracker green assay). Mitochondrial membrane potential (JC1-assay) and advanced apoptotic/necrotic events (AnexinV/propidium iodide) were measured by flow cytometry. Significant mtDNA depletion spanning 57.67% (P < 0.01) was found in the U1 promonocytic cells further reflected by a significant 77.43% decrease of mitochondrial CIV activity (P < 0.01). These changes were not significant for the ACH2 lymphoid cell line. COXII and COXIV subunits as well as VDAC-1 and caspase-9 content were sharply decreased in both chronic HIV-1-infected promonocytic and lymphoid cell lines (<0.005 in most cases). In addition, U1 and ACH2 cells showed a trend (moderate in case of ACH2), albeit not significant, to lower levels of depolarized mitochondrial membranes. The present in vitro lymphoid and especially promonocytic HIV model show marked mitochondrial lesion but apoptotic resistance phenotype that has been only partially demonstrated in patients. This model may provide a platform for the characterization of HIV-chronicity, to test novel therapeutic options or to study HIV reservoirs.


Monocular retinopathy of prematurity-like retinal vasculopathy in a dog.
To describe a case of monocular retinopathy of prematurity (ROP)-like vasculopathy without oxygen supplementation in the dog. Fundus photographs (RetCam), spectral-domain optical coherence tomography (sdOCT), confocal scanning laser ophthalmoscopy (cSLO), and fluorescein angiography (FA), as well as postmortem histology and immunohistochemistry (Collagen IV and anti-vWF antibodies), were carried out to characterize the vascular abnormalities. Ophthalmic examination showed peripheral and mid-temporal avascular areas in the tapetal region, neovascularization and abnormally dilated and tortuous retinal vessels in the left eye. sdOCT demonstrated not only cross-sectional views of preretinal fibrovascular proliferation but also extensive proliferation extraretinally into the vitreous. FA emphasized demarcation of vascular and avascular zones with neovascular tufts "popcorns." Histology and immunohistochemistry confirmed presence of abnormally dilated vessels and the intravitreal blood vessels. ROP is a disease of abnormally developed retinal vascularization associated with oxygen supplementation therapy, potentially causing blindness in premature infants. Although the mechanism of ROP-like vasculopathy in our case is unclear, it is important to appreciate that the abnormal vascular pattern seen in ROP in premature infants can occur in canines without oxygen administration.


Endothelial nitric oxide synthase increases in left atria of dogs with pacing-induced heart failure.
In congestive heart failure (CHF) the alterations in cardiac NO synthase (NOS) isoforms activity and expression are incompletely documented and the chamber specificity of these changes is unknown. We studied plasma nitrate-nitrite (NO-x), atrial, and ventricular NOS activities and protein expression (Western blot and densitometric analysis) in nonpaced control dogs and in dogs paced for 2 or 21 days into CHF. Plasma NO-x rose significantly after 7 and 21 days of pacing, whereas creatinine levels remained unchanged. In control dogs Ca2+-dependent NOS activity in left atria was double that of right or left ventricular activity. In paced animals the activity increased only in the atria after 21 but not 2 days of pacing. Levels of endothelial NOS (eNOS) protein were enhanced in the left atria but not ventricles after 21 days of pacing because of a greater quantity of the 150-kDa but not the 135-kDa eNOS. Ca2+-independent NOS activity was undetectable in any cardiac tissue. The specific upregulation of eNOS in the left atria suggests that NO production may be enhanced to counterbalance hypertrophy that develops during pacing-induced CHF.


Glucocorticoid exposure predicts survival in female baboons.
Are differences in hypothalamic-pituitary-adrenal (HPA) axis activation across the adult life span linked to differences in survival? This question has been the subject of considerable debate. We analyze the link between survival and fecal glucocorticoid (GC) measures in a wild primate population, leveraging an unusually extensive longitudinal dataset of 14,173 GC measurements from 242 adult female baboons over 1634 female years. We document a powerful link between GCs and survival: Females with relatively high current GCs or high lifelong cumulative GCs face an elevated risk of death. A hypothetical female who maintained GCs in the top 90% for her age across adulthood would be expected to lose 5.4 years of life relative to a female who maintained GCs in the bottom 10% for her age. Hence, differences among individuals in HPA axis activity provide valuable prognostic information about disparities in life span.


Changes in extracellular matrix and in transforming growth factor beta isoforms after coronary artery ligation in rats.
Extensive myocardial remodeling occurs after transmural myocardial infarction (MI). The infarcted myocardium is being replaced by scar tissue after gradual resorption of the necrotic tissue. The remodeling process involves both synthesis and degradation of collagens as major components of the extracellular matrix (ECM). In the present study we have analyzed the time-dependent changes of the processes related to this fibrosis in the infarct area and in the non-infarcted left ventricle (LV) six hours to 82 days after occlusion of the left anterior descending coronary artery (LAD) in rats. We also examined whether changes occurred in the expression pattern of the transforming growth factor (TGF) beta isoforms, since this cytokine is known as powerful inductor of fibrosis. Elevation in colligin expression preceded the pronounced increase in mRNA expression of both type I and type III collagen after MI from day three onwards. The maximal increase in colligin protein in the infarct area coincided with the most pronounced expression of collagen I and collagen III mRNA expression. Also, the expression and activity of matrix metalloproteinases (MMPs) and of tissue inhibitor of matrix metalloproteinase (TIMP)-2 mRNA were increased predominantly in the infarct area. TGF beta(1)and TGF-beta(2)expression increased within the first days after MI, whereas TGF-beta(3)expression was elevated predominantly in the infarct area. This pronounced increase in TGF-beta(3)persisted up to 82 days and correlated positively with the parameters of ECM metabolism. Thus, the scar formation is an ongoing dynamic process in which TGF-beta(3)seems to play an active role in the complex ventricular remodeling.


[Effectiveness of Mitral Natural Folding Plasty for Minimally Invasive Cardiac Surgery Mitral Valve Plasty (MICS MVP)].
We performed 45 cases of Natural folding plasty without leaflet resection for degenerative mitral regurgitation (MR) between September 2005 and July 2014. Twenty cases of 45 were operated by right small intercostal approach (MICS). There was no operative mortality. No patient had greater than mild MR intraoperative transesophageal echocardiography. The median follow-up was 847 (19~1,747) days. One case needed a second pump run performed without complication. One patient had a reoperation performed for recurrent MR 20 months later. Natural folding plasty for degenerative MR with favorable long term out come in our results. This technique is simple and reproducible for most surgeons. Furthermore, with its simplicity and reversibility, we considered it to be suitable for MICS approach.


Time-Resolved SAXS Studies of the Kinetics of Thermally Triggered Release of Encapsulated Silica Nanoparticles from Block Copolymer Vesicles.
Silica-loaded poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) diblock copolymer vesicles are prepared in the form of concentrated aqueous dispersions via polymerization-induced self-assembly (PISA). As the concentration of silica nanoparticles present during the PISA synthesis is increased up to 35% w/w, higher degrees of encapsulation of this component within the vesicles can be achieved. After centrifugal purification to remove excess non-encapsulated silica nanoparticles, SAXS, DCP, and TGA analysis indicates encapsulation of up to hundreds of silica nanoparticles per vesicle. In the present study, the thermally triggered release of these encapsulated silica nanoparticles is examined by cooling to 0 °C for 30 min, which causes in situ vesicle dissociation. Transmission electron microscopy studies confirm the change in diblock copolymer morphology and also enable direct visualization of the released silica nanoparticles. Time-resolved small-angle X-ray scattering is used to quantify the extent of silica release over time. For an initial silica concentration of 5% w/w, cooling induces a vesicle-to-sphere transition with subsequent nanoparticle release. For higher silica concentrations (20 or 30% w/w) cooling only leads to perforation of the vesicle membranes, but silica nanoparticles are nevertheless released through the pores. For vesicles prepared in the presence of 30% w/w silica, the purified silica-loaded vesicles were cooled to 0 °C for 30 min, and SAXS patterns were collected every 15 s. A new SAXS model has been developed to determine both the mean volume fraction of encapsulated silica within the vesicles and the scattering length density. Satisfactory data fits to the experimental SAXS patterns were obtained using this model.


Computer assistive technology and associations with quality of life for individuals with spinal cord injury: a systematic review.
Systematic review. The purpose of the study was to identify and organize evidence regarding quality of life influenced by assistive technology related to computers for people with traumatic and non-traumatic spinal cord injury (SCI). Distrito Federal, Brazil. A search strategy was conducted on the PubMed, PEDro, LILACS, PsycINFO, and SCIELO. All types of study designs considering assistive technology to improve quality of life for individuals with SCI were included. After search strategy procedures, ten references were included to review. The methodologic quality of each study was evaluated using the Level of Evidence proposed by the Oxford Centre for Evidence-based Medicine. Most of the studies showed that devices for computer access improve the quality of life of people with SCI, regardless of the level of injury and type of resource. However, the positive outcomes in the quality of life should be interpreted with caution, as several methodological limitations were observed in the articles. Despite the scarcity of studies and their methodological limitations, there is evidence that assistive technology for computer access favors the quality of life of people with tetraplegia due to SCI, since it improves participation, independence, and self-esteem.


The activity of disease-causative STING variants can be suppressed by wild-type STING through heterocomplex formation.
Stimulator of interferon genes (STING) is essential for the type I interferon response induced by microbial DNA from viruses or self-DNA from mitochondria/nuclei. Recently, gain-of-function mutations in STING have been identified in patients with STING-associated vasculopathy with onset in infancy (SAVI). The SAVI patients exhibit complex systemic vascular inflammation and interstitial lung disease, resulting in pulmonary fibrosis and respiratory failure. SAVI mouse models have recently developed, harbouring common SAVI mutations, such as N153S and V154M, which correspond to the human N154S and V155M, respectively. Interestingly, crosses of heterozygous SAVI mice did not yield homozygous SAVI mice as of embryonic day 14, indicating that homozygous SAVI embryos were not viable and that wild-type (WT) allele would function dominantly over SAVI alleles in terms of viability. However, the molecular mechanism underlying the dominance has not been understood. In the present study, we show that STING (WT) and STING (SAVI) can form heterocomplex. The heterocomplex localized primarily in the endoplasmic reticulum (ER) and failed to reach the trans-Golgi network (TGN), where STING activates the downstream kinase TBK1. SURF4 is the essential protein functioning in the retrieval of STING from the Golgi to the ER. The amount of SURF4 bound to STING (SAVI) significantly increased in the presence of STING (WT). These results suggest that STING (WT) can suppress the activity of STING (SAVI) by tethering STING (SAVI) to the ER through heterocomplex formation. The dormant heterocomplex formation may underlie, at least in part, the dominance of STING WT allele over SAVI alleles in the STING-triggered inflammatory response.


Development and validation of an in vitro model system to study peripheral sensory neuron development and injury.
The ability to discriminate between diverse types of sensation is mediated by heterogeneous populations of peripheral sensory neurons. Human peripheral sensory neurons are inaccessible for research and efforts to study their development and disease have been hampered by the availability of relevant model systems. The in vitro differentiation of peripheral sensory neurons from human embryonic stem cells therefore provides an attractive alternative since an unlimited source of biological material can be generated for studies that specifically address development and injury. The work presented in this study describes the derivation of peripheral sensory neurons from human embryonic stem cells using small molecule inhibitors. The differentiated neurons express canonical- and modality-specific peripheral sensory neuron markers with subsets exhibiting functional properties of human nociceptive neurons that include tetrodotoxin-resistant sodium currents and repetitive action potentials. Moreover, the derived cells associate with human donor Schwann cells and can be used as a model system to investigate the molecular mechanisms underlying neuronal death following peripheral nerve injury. The quick and efficient derivation of genetically diverse peripheral sensory neurons from human embryonic stem cells offers unlimited access to these specialised cell types and provides an invaluable in vitro model system for future studies.


Magnetic resonance imaging of the thorax in the evaluation of asbestosis.
The purpose of the study was to evaluate the accuracy of magnetic resonance imaging (MRI) in detecting subclinical morphological changes caused by asbestos exposure. Conventional chest radiographs according to the International Labour Organisation (ILO) categories 0-11 and spirometric data were compared with MRI in 17 men with mean (+/-2SD) asbestos exposure time of 24.6+/-13.0 yrs. Mean age was 62.0+/-9.4 yrs. The inclusion criterion was an ILO score of 2 or more. Electrocardiographic registrations and antirespiratory movement artefact techniques were used in all MRI examinations to avoid movement artefacts. Mean ILO grading was found to be 7.7+/-3.8 on chest radiography and 9.8+/-2.0 with MRI (p=0.01). Five patients had a higher ILO stage as evaluated by MRI, but in nine patients the staging remained unchanged. MRI revealed mediastinal adenopathy in four patients. Forced expiratory volume in one second (expressed as a percentage of the predicted value) was negatively correlated with ILO score as assessed by MRI (r=-0.4, p=0.032). Magnetic resonance imaging seems to be more sensitive than conventional radiographs in detecting subclinical fibrosis as well as the extent of pleural asbestosis.


Long-term Outcomes of a Telementoring Program for Distant Teaching of Endovascular Aneurysm Repair.
To prospectively evaluate the long-term outcomes after a telementoring program for distant teaching of endovascular aneurysm repair (EVAR) and the degree of EVAR procedure assimilation into routine practice. A telementoring protocol using stepwise introduction of EVAR was implemented between a university care center and a remote vascular health care site; from March 1999 to October 2003, 49 EVAR patients (mean age 72 years; 48 men) were treated during telementoring at the remote center. After the telementoring period, 86 patients (mean age 71 years; 77 men) underwent EVAR procedures carried out at the secondary care center from November 2003 to July 2011. The long-term outcomes were compared between the EVAR procedures performed during telementoring with the procedures performed independently thereafter. No significant difference was appreciated between telementored and not telementored procedures either in 30-day mortality (4.1% vs 2.3%, p=0.621) or in the initial technical success (93.9% vs 97.7%, p=0.353). The telementored group showed no significant difference in overall aneurysm-related mortality (6.1% vs 2.3%, p=0.353) or in the overall complication rates (p=0.985). The reintervention rate was significantly lower among the unmentored procedures (11.6% vs 32.7%, p=0.004). In particular, significantly fewer patients underwent late endovascular procedures (1.2% vs 12.2%, p=0.009) and late percutaneous interventions (7.0% vs 20.4%, p=0.027) after telementoring ceased. The telementoring program followed here allowed excellent EVAR skill assimilation into the routine practice of a remote health care site. Telementoring is a feasible strategy to support skill introduction in remote medical facilities.


Glut9 is a major regulator of urate homeostasis and its genetic inactivation induces hyperuricosuria and urate nephropathy.
Elevated plasma urate levels are associated with metabolic, cardiovascular, and renal diseases. Urate may also form crystals, which can be deposited in joints causing gout and in kidney tubules inducing nephrolithiasis. In mice, plasma urate levels are controlled by hepatic breakdown, as well as, by incompletely understood renal processes of reabsorption and secretion. Here, we investigated the role of the recently identified urate transporter, Glut9, in the physiological control of urate homeostasis using mice with systemic or liver-specific inactivation of the Glut9 gene. We show that Glut9 is expressed in the basolateral membrane of hepatocytes and in both apical and basolateral membranes of the distal nephron. Mice with systemic knockout of Glut9 display moderate hyperuricemia, massive hyperuricosuria, and an early-onset nephropathy, characterized by obstructive lithiasis, tubulointerstitial inflammation, and progressive inflammatory fibrosis of the cortex, as well as, mild renal insufficiency. In contrast, liver-specific inactivation of the Glut9 gene in adult mice leads to severe hyperuricemia and hyperuricosuria, in the absence of urate nephropathy or any structural abnormality of the kidney. Together, our data show that Glut9 plays a major role in urate homeostasis by its dual role in urate handling in the kidney and uptake in the liver.


Clinical research challenges posed by difficult-to-treat depression.
Approximately one-third of individuals in a major depressive episode will not achieve sustained remission despite multiple, well-delivered treatments. These patients experience prolonged suffering and disproportionately utilize mental and general health care resources. The recently proposed clinical heuristic of 'difficult-to-treat depression' (DTD) aims to broaden our understanding and focus attention on the identification, clinical management, treatment selection, and outcomes of such individuals. Clinical trial methodologies developed to detect short-term therapeutic effects in treatment-responsive populations may not be appropriate in DTD. This report reviews three essential challenges for clinical intervention research in DTD: (1) how to define and subtype this heterogeneous group of patients; (2) how, when, and by what methods to select, acquire, compile, and interpret clinically meaningful outcome metrics; and (3) how to choose among alternative clinical trial design options to promote causal inference and generalizability. The boundaries of DTD are uncertain, and an evidence-based taxonomy and reliable assessment tools are preconditions for clinical research and subtyping. Traditional outcome metrics in treatment-responsive depression may not apply to DTD, as they largely reflect the only short-term symptomatic change and do not incorporate durability of benefit, side effect burden, or sustained impact on quality of life or daily function. The trial methodology will also require modification as trials will likely be of longer duration to examine the sustained impact, raising complex issues regarding control group selection, blinding and its integrity, and concomitant treatments.


[Ischemic colitis in patients submitted to aortic replacement surgery. Risk factors].
Ischemic colitis (IC) is an important clinical problem, and may present after aortic surgical procedures. The aim of this work was to establish risk factors for IC presentation in aortic surgical replacement patients. A retrospective study of patients with aortic surgical replacement in a 3-year period was carried out. Patients were divided into two groups: patients without IC and patients with IC, the later group subdivided into patients with gangrenous ischemic colitis and without gangrenous ischemic colitis. Multiple logistic regressions was used to obtain the variables for possible risk factor for IC. We included 101 patients in the study; ischemic colitis was present in 16.8% of all cases, with 47.1% of gangrenous type. Metabolic acidosis was the most frequent alteration. Diagnosis was made by endoscopy in 94.1%. Mortality in IC group was 18.2% with an increase in the gangrenous group to 62.5%. Identified risk factors were disrupted aneurysm, previous colonic surgery, emergency surgery, and hemodynamic instability. Ischemic colitis is most frequent in emergency surgery for disrupted aneurysm in the hemodynamically unstable patient with retroperitoneal hematoma. We must entertain a high suspicion index for IC in all patients with aortic surgical procedures for early detection and adequate treatment.


Design challenges of implantable pressure monitoring system.
Pressure in various organs and body parts, such as blood vessels, heart, brain, eyes, bladder and GI tracts, is an important indication of health. Long term, continuous pressure monitoring is critically needed for a number of applications. When combined with existing neuro-prosthetics devices, they may provide better solutions to many neural disorders. First efforts toward a long-term implantable pressure monitoring system were initiated more than 40 years ago. However, a reliable, safe and implantable pressure sensor for long-term applications is not yet commercially available. This paper attempts to reveal the design challenges associated with the development of a long-term implantable pressure sensor.


Outcomes in a large series of minipercs: analysis of consecutive 318 patients.
The purpose of this study is to evaluate the outcomes of miniperc at our center. This is a retrospective review of consecutive 318 minipercs done in a single tertiary urological center. The Miniperc system used was either Wolf (Richard Wolf) 14F with 20F Amplaz sheath or Storz (Karl Storz) nephroscope 12F with 15/18F sheath or 16.5/19.5F sheath. Data about the demography of patients, comorbidities, stone size, number and size of the tract, size of nephroscope, energy source used, total operative time, exit strategy, hospital stay, clearance of stones, total analgesic requirement, visual analogue pain score at 6 and 24 hours, hemoglobin drop and complications were analyzed by the chi-square test and analysis of variance test. The average age of patients, stone size, operative time, hemoglobin drop and hospital stay were 41.9±17.0 years, 15.26±6.35 mm, 60±19 minutes,1.0±0.6 g/dL and 2.8±1 day, respectively. Complete clearance rate was 98.7%. Fourteen (4.4%) patients had Clavien-Dindo level 1 complications and 1 (0.31%) patient had Clavien-Dindo level 2 complications. The size of the stone treated by miniperc did not affect the hemoglobin drop (p-value=0.26) or hospital stay (p-value=0.924). There is no significant increase in hemoglobin drop (p-value=0.064) or hospital stay (p-value=0.627) with increasing number of miniperc tracts. An increase in operative time is associated with the increase in hemoglobin drop (p-value=0.041). Different energy sources did not significantly affect the operative time (p-value=0.184). Placement of only ureteral catheter is associated with less analgesic requirement (p-value=0.000). Miniperc is a safe alternative to standard percutaneous nephrolithotomy. In carefully selected patients, the best exit strategy would be a tubeless procedure with ureteral catheter drainage.


Biocontrol of gray mold disease on strawberry fruit by integration of Lactobacillus plantarum A7 with ajwain and cinnamon essential oils.
This study was conducted to evaluate the efficacy of the Lactobacillus plantarum A7 (L. Plantarum), ajwain and cinnamon essential oils (AO and CO, respectively) in suppressing gray mold rot in strawberry fruit. AO and CO showed over 90% inhibition of radial mycelia growth with lower concentration of the oils per plate for all tested pathogens. Combined application of L. plantarum with AO and CO was tested to assess the possible synergistic effects of these 3 elements on the control of tested plant pathogens. In this case both combinations of L. plantarum + AO and L. plantarum + CO inhibited the mycelia growth of the pathogens completely. Results showed that the combined treatment of strawberry fruits with L. plantarum + AO (50 μL) and L. plantarum + CO (100 μL) resulted in remarkably improved control of Botrytis infections, in comparison with application of L. plantarum or essential oils alone. Quality attributes (that is pH, acidity, vitamin C, and total soluble solid) of the strawberry fruits did not change significantly (P < 0.01) when combination of Lactobacillus and essential oils was used. To the best of our knowledge, this is the first report on the effects of combination of a Lactobacillus as an antagonist bacterium with essential oils to increase the shelf life of strawberry.


Inhibition of N-ethylmaleimide-sensitive factor protects against myocardial ischemia/reperfusion injury.
Exocytosis of endothelial granules promotes thrombosis and inflammation and may contribute to the pathophysiology of early reperfusion injury following myocardial ischemia. TAT-NSF700 is a novel peptide that reduces endothelial exocytosis by inhibiting the ATPase activity and disassembly activity of N-ethylmaleimide-sensitive factor (NSF), a critical component of the exocytic machinery. We hypothesized that TAT-NSF700 would limit myocardial injury in an in vivo murine model of myocardial ischemia/reperfusion injury. Mice were subjected to 30 minutes of ischemia followed by 24 hours of reperfusion. TAT-NSF700 or the scrambled control peptide TAT-NSF700scr was administered intravenously 20 minutes before the onset of ischemia. Myocardial ischemia/reperfusion caused endothelial exocytosis, myocardial infarction, and left ventricular dysfunction. However, TAT-NSF700 decreased von Willebrand factor levels after myocardial ischemia/reperfusion, attenuated myocardial infarct size by 47%, and preserved left ventricular structure and function. These data suggest that drugs targeting endothelial exocytosis may be useful in the treatment of myocardial injury following ischemia/reperfusion.


Nucleus Accumbens Cholinergic Interneurons Oppose Cue-Motivated Behavior.
Environmental reward-predictive stimuli provide a major source of motivation for adaptive reward pursuit behavior. This cue-motivated behavior is known to be mediated by the nucleus accumbens (NAc) core. The cholinergic interneurons in the NAc are tonically active and densely arborized and thus well suited to modulate NAc function. However, their causal contribution to adaptive behavior remains unknown. Here we investigated the function of NAc cholinergic interneurons in cue-motivated behavior. We used chemogenetics, optogenetics, pharmacology, and a translationally analogous Pavlovian-to-instrumental transfer behavioral task designed to assess the motivating influence of a reward-predictive cue over reward-seeking actions in male and female rats. The data show that NAc cholinergic interneuron activity critically opposes the motivating influence of appetitive cues. Chemogenetic inhibition of NAc cholinergic interneurons augmented cue-motivated behavior. Optical stimulation of acetylcholine release from NAc cholinergic interneurons prevented cues from invigorating reward-seeking behavior, an effect that was mediated by activation of β2-containing nicotinic acetylcholine receptors. NAc cholinergic interneurons provide a critical regulatory influence over adaptive cue-motivated behavior and therefore are a potential therapeutic target for the maladaptive cue-motivated behavior that marks many psychiatric conditions, including addiction and depression.


[Bone mineral density as a sign of age-related involution of human bones].
This review of the literature analyzes the current state of a problem of application of various morphological methods for the investigation of age-related involution of human bone system and their use in the course of forensic personality identification. The difficulties of the application of the available methods of quantitative morphology in determination of biological age, are emphasized. The possibilities of the practical use of radiological methods to study the skeleton, including the determination of the bone mineral density as an indicator of age-related changes of bone tissue, are analyzed. An ambiguity of the research results obtained is noted, and the possible reasons for and the factors contributing to the results variability are considered. It is concluded that the application of computer tomogram densitometry to the various regions of the bone skeleton in complex with some other methods, is promising for the determination of age interval in forensic identification examinations.


Cadmium and atherosclerosis: A review of toxicological mechanisms and a meta-analysis of epidemiologic studies.
Cadmium has been proposed to be the one of the factors of atherosclerosis development, although the existing data are still controversial. The primary objective of the present study is the review and the meta-analysis of studies demonstrating the association between Cd exposure and atherosclerosis as well as review of the potential mechanisms of such association. We performed a systematic search in the PubMed-Medline database using the MeSH terms cadmium, cardiovascular disease, atherosclerosis, coronary artery disease, myocardial infarction, stroke, mortality and humans up through December 20, 2017. Elevated urinary Cd levels were associated with increased mortality for cardiovascular disease (HR = 1.34, 95% CI: 1.07-1.67) as well as elevated blood Cd levels (HR = 1.78, 95% CI: 1.24-2.56). Analysis restricted to never smokers showed similar, though more imprecise, results. Consistently, we also observed an association between Cd exposure markers (blood and urine) and coronary heart disease, stroke, and peripheral artery disease. Moreover, Cd exposure was associated with atherogenic changes in lipid profile. High Cd exposure was associated with higher TC levels (OR = 1.48, 95% CI: 1.10-2.01), higher LDL-C levels (OR = 1.31, 95% CI 0.99-1.73) and lower HDL-C levels (OR = 1.96, 95% CI: 1.09-3.55). The mechanisms of atherogenic effect of cadmium may involve oxidative stress, inflammation, endothelial dysfunction, enhanced lipid synthesis, up-regulation of adhesion molecules, prostanoid dysbalance, as well as altered glycosaminoglycan synthesis.


[Survival analysis of acute pyogenic meningitis in children].
In order to determine the survival curves of lethality in acute bacterial meningitis (ABM) in children, we reviewed the charts of all patients admitted to the Hospital Couto Maia from January 1990 to December 1992. The Kaplan-Meir analysis was used to compare the survival rate and hospitalar permanence of patients with identified pathogens with those whose bacteria were not determined. The same analysis was used to compare the curves of the three most frequent agents. Statistical difference between the identified and nonidentified groups was not observed. The analysis of the three curves shows that the first 24 hours were responsible for the most elevated lethality rate. When the curves are compared, it is clear that S. pneumoniae has the most important intrahospitalar lethality and N. meningitidis the most benign evolution. We conclude that efforts have to be made to determine which variables are related to prognosis of ABM at the first day of hospital admission.


Neurotherapeutics in multiple sclerosis: novel agents and emerging treatment strategies.
New insights into the complex immunopathogenesis of multiple sclerosis have led to a proliferation of promising new therapeutic strategies. While the current armamentarium of immunomodulatory medications has demonstrated beneficial effects on the disease, more effective and tolerable therapies are needed. Several novel therapeutic strategies under investigation include oral therapies, monoclonal antibodies, symptomatic treatments, insights into neuroprotection and repair as well as combination regimens. New therapies may prove more efficacious and tolerable than the available arsenal of treatments; however, decisions regarding first-line therapies will expectedly become more complicated, with greater influence if risk-to-benefit ratios in light of premature safety data. Biomarker profiles may help elucidate disease subtypes as well as therapeutic response in an effort to individualize treatment choice. This review will highlight recent promising therapeutic strategies under investigation in the field of MS.


Preoperative serum CA125 levels do not predict suboptimal cytoreductive surgery in epithelial ovarian cancer.
The objective is to assess the ability of preoperative serum CA125 levels to identify patients at high risk of suboptimal cytoreductive surgery for epithelial ovarian cancer (EOC). One hundred and thirty-two women diagnosed with EOC between 1998 and 2004, who had serum CA125 levels measured preoperatively and received primary cytoreductive surgery, were retrospectively evaluated. The value of CA125 and patient and disease characteristics to predict suboptimal cytoreduction were determined, and a prognostic scoring system, based on statistically significant variables, was created. Optimal cytoreduction was achieved in 42.7% of the women with FIGO stage III/IV EOC. The optimal cutoff point of preoperative CA125 to predict surgical outcome in this group was 330 U/mL (sensitivity 80.0%; specificity 41.5%). The area under the receiver-operating characteristic curve (AUC) for preoperative CA125 predicting suboptimal surgery in FIGO stage III/IV was 0.576 (P = 0.617). Preoperative radiologic amount of ascites and weight loss (ie, >or=10% in the last 6 months before diagnosis) were independent prognostic factors for suboptimal cytoreduction, showing an AUC of 0.76 (P < 0.001) in women with FIGO stage III/IV. A prognostic scoring system showed that the chance of suboptimal surgery was 84.6% in FIGO stage III/IV when both these factors are present preoperatively. The role of CA125 levels predicting suboptimal cytoreduction seems questionable. Instead, women with considerable weight loss and a gross amount of ascites have a higher risk of suboptimal cytoreduction. These patients may be candidates for neoadjuvant chemotherapy.


Reduction in the plasma clearance rate of warfarin induced by cimetidine.
The interaction between the histamine H-2 receptor antagonist, cimetidine, and warfarin sodium was prospectively studied in 14 patients who were previously anticoagulated for five years. The patients received warfarin and cimetidine concomitantly for a minimum of ten days. Seven of the patients experienced increases in plasma warfarin concentrations. This correspondingly resulted in abnormal prolongation of their prothrombin times. In these patients the elevation in the steady-state warfarin concentration demonstrates that coadministration of cimetidine significantly reduces the plasma clearance rate of warfarin. The serum and urine metabolite levels of warfarin were not qualitatively different in the absence in contrast to the presence of cimetidine. It is apparent that cimetidine can act as an inhibitory influence on the catabolic degradation of warfarin.


Analysis of the apo E/apo C-I, angiotensin converting enzyme and methylenetetrahydrofolate reductase genes as candidates affecting human longevity.
Genetic factors are likely to affect human survival, since twin studies have shown greater concordance for age of death in monozygotic compared to dizygotic twins. Coronary artery disease is an important contributor to premature mortality in the UK. Accordingly, we have chosen genes associated with cardiovascular risk, apo E/apo C-I, angiotensin converting enzyme (ACE) and methylenetetrahydrofolate reductase (MTHFR), as candidates which may affect longevity/survival into old age. An association study was performed by comparing allele and genotype frequencies at polymorphic loci associated with these genes in 182 women and 100 men aged 84 years and older with 100 boys and 100 girls younger than 17 years. MTHFR allele and genotype frequencies were similar in the elderly and young populations. Apo C-I allele and genotype frequencies were significantly different in the elderly women compared to the younger sample (P < 0.05). No difference was observed in the elderly men. At the neighbouring apo E gene, we only observed a difference between genotypes in the elderly women and the young sample; however, this did not retain significance when the genotype frequencies of the young sample were adjusted to values expected from the allele frequencies on the basis of Hardy-Weinberg equilibrium and compared to observed genotypes in elderly men and women. In contrast to previous studies, apo E2 was not overrepresented in the elderly men or women. Thus, the proposition that apo E2, E3 and E4 protein isoforms are themselves functionally associated with increasing risks for early death, may be too simplistic. The I/I ACE was depleted in the elderly males but not the elderly females. Furthermore, significant differences were observed between ACE genotypes in elderly men and elderly women. These data suggest that the penetrance of loci which influence survival may vary according to sex. The depletion of the ACE I/I genotype in elderly men is generally consistent with a previous study which found decreased frequencies of the I allele in French centenarians compared to younger controls. However, these results are apparently paradoxical, since others have suggested that the I allele is associated with increased cardiovascular risk. Clarification of the overall effect of a genotype on survival will be vital if therapies are to be considered which target specific genetic variants.


alpha-1-syntrophin mutation and the long-QT syndrome: a disease of sodium channel disruption.
Long-QT syndrome (LQTS) is an inherited disorder associated with sudden cardiac death. The cytoskeletal protein syntrophin-alpha(1) (SNTA1) is known to interact with the cardiac sodium channel (hNa(v)1.5), and we hypothesized that SNTA1 mutations might cause phenotypic LQTS in patients with genotypically normal hNa(v)1.5 by secondarily disturbing sodium channel function. Mutational analysis of SNTA1 was performed on 39 LQTS patients (QTc> or =480 ms) with previously negative genetic screening for the known LQTS-causing genes. We identified a novel A257G-SNTA1 missense mutation, which affects a highly conserved residue, in 3 unrelated LQTS probands but not in 400 ethnic-matched control alleles. Only 1 of these probands had a preexisting family history of LQTS and sudden death with an additional intronic variant in KCNQ1. Electrophysiological analysis was performed using HEK-293 cells stably expressing hNa(v)1.5 and transiently transfected with either wild-type or mutant SNTA1 and, in neonatal rat cardiomyocytes, transiently transfected with either wild-type or mutant SNTA1. In both HEK-293 cells and neonatal rat cardiomyocytes, increased peak sodium currents were noted along with a 10-mV negative shift of the onset and peak of currents of the current-voltage relationships. In addition, A257G-SNTA1 shifted the steady-state activation (V(h)) leftward by 9.4 mV, whereas the voltage-dependent inactivation kinetics and the late sodium currents were similar to wild-type SNTA1. SNTA1 is a new susceptibility gene for LQTS. A257G-SNTA1 can cause gain-of-function of Na(v)1.5 similar to the LQT3.


Sex-Specific Differences in Glioblastoma.
Sex differences have been well identified in many brain tumors. Even though glioblastoma (GBM) is the most common primary malignant brain tumor in adults and has the worst outcome, well-established differences between men and women are limited to incidence and outcome. Little is known about sex differences in GBM at the disease phenotype and genetical/molecular level. This review focuses on a deep understanding of the pathophysiology of GBM, including hormones, metabolic pathways, the immune system, and molecular changes, along with differences between men and women and how these dimorphisms affect disease outcome. The information analyzed in this review shows a greater incidence and worse outcome in male patients with GBM compared with female patients. We highlight the protective role of estrogen and the upregulation of androgen receptors and testosterone having detrimental effects on GBM. Moreover, hormones and the immune system work in synergy to directly affect the GBM microenvironment. Genetic and molecular differences have also recently been identified. Specific genes and molecular pathways, either upregulated or downregulated depending on sex, could potentially directly dictate GBM outcome differences. It appears that sexual dimorphism in GBM affects patient outcome and requires an individualized approach to management considering the sex of the patient, especially in relation to differences at the molecular level.


Diagnostic performance of preoperative ultrasound for traumatic brachial plexus root injury: A comparison study with an electrophysiology study.
Accurate preoperative assessment for traumatic brachial plexus injury (BPI) is critical for clinicians to establish a treatment plan. The objective of this study was to investigate the diagnostic performance of preoperative ultrasound (US) through comparison with an electrophysiology study (EPS) in the assessment of traumatic brachial plexus (BP) root injury. We performed a retrospective study in patients with traumatic BPI who had preoperative US and EPS, excluding obstetric palsy and other nontraumatic neuropathies. US examination was performed on an EPIQ 5 color Doppler equipment. EPS was performed on a Keypoint 9033A07 Electromyograph/Evoked Potentials Equipment, testing electromyography (EMG), nerve conduction studies (NCS), and somatosensory evoked potentials (SEP). Each BP root of all patients was assessed by US and EPS as completely injured or incompletely injured, respectively. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated based on the correlation with intraoperative findings. The accuracy of US and EPS were compared using the McNemar test. The added benefit of US was evaluated by comparing the sensitivity and specificity between the combined tests with EPS using the McNemar test. This study included 49 patients with traumatic BPI who underwent BP surgeries from October 2018 to September 2022. Surgical exploration confirmed 89 completely injured BP roots in 28 patients. US correctly detected 80 completely injured BP roots (sensitivity, 0.899; specificity, 0.981; PPV, 0.964; NPV, 0.944; accuracy, 0.951). EPS correctly detected 75 completely injured BP roots (sensitivity, 0.843; specificity, 0.929; PPV, 0.872; NPV, 0.912; accuracy, 0.898). US showed significantly higher accuracy than EPS (p = 0.03). When combining US and EPS for completely injured BP root detection, the sensitivity of the inclusive combination (0.966) was significantly higher than EPS alone (p = 0.000977), and the specificity of the exclusive combination (1.000) was significantly higher than EPS alone (p = 0.000977). Preoperative US is an effective diagnostic tool in the assessment of traumatic BP root injury. US had higher accuracy than EPS in this study. Sensitivity and specificity were significantly higher than EPS when US was combined with EPS.


Rapid Removal of Toxic Remazol Brilliant Blue-R Dye from Aqueous Solutions Using Juglans nigra Shell Biomass Activated Carbon as Potential Adsorbent: Optimization, Isotherm, Kinetic, and Thermodynamic Investigation.
Recently, the treatment of effluent by agricultural waste biomass has significantly attracted wide interest among researchers due to its availability, efficacy, and low cost. The removal of toxic Remazol Brilliant Blue-R (RBBR) from aqueous solutions using HNO3-treated Juglans nigra (walnut) shell biomass carbon as an adsorbent has been examined under various experimental conditions, such as initial pH, adsorbate concentration, adsorbent dosage, particle size, agitation speed, and type of electrolyte. The experiments are designed to achieve the maximum dye removal efficiency using the response surface methodology (RSM). The optimum pH, adsorbent dosage, and particle size were found to be 1.5, 7 g L-1, and 64 μm, respectively for maximum decolorization efficiency (98.24%). The prepared adsorbent was characterized by particle size, Brunauer-Emmett-Teller (BET) surface area, pore volume, zero-point charge (pHzpc), Fourier transform infrared spectroscopy (FT-IR), field emission scanning electron microscopy/energy dispersive X-ray spectroscopy (FE-SEM/EDX), X-ray diffraction (XRD), and thermogravimetric analysis (TGA). Based on fitting the experimental data with various models, the isotherm and kinetic mechanism are found to be more appropriate with Langmuir isotherm and pseudo-second-order kinetics. The adsorption mechanism can be described by the intra-particle diffusion model, Bangham, and Boyd plots. The overall rate of adsorption is controlled by the external film diffusion of dye molecules. The maximum monolayer adsorption capacity, (qmax) 54.38 mg g-1 for RBBR dye, was obtained at a temperature of 301 K. From a thermodynamic standpoint, the process is endothermic, spontaneous, and the chemisorption process is favored at high temperatures. Desorption studies were conducted with various desorbing reagents in various runs and the maximum desorption efficiency (61.78% in the third run) was obtained using the solvent methanol. Reusability studies demonstrated that the prepared adsorbent was effective for up to three runs of operation. The investigation outcomes concluded that walnut shell biomass activated carbon (WSBAC) is a cost-effective, eco-friendly, and bio-sustainable material that can be used for synthetic dye decolorization in aqueous media.


Computing the (1)H NMR spectrum of a bulk ionic liquid from snapshots of car-parrinello molecular dynamics simulations.
We have investigated the performance of several computational protocols in predicting the NMR spectrum of a molecular ion in a complex liquid phase such as an ionic liquid. To do this, we computed the proton NMR chemical shifts of the 1-ethyl-3-methylimidazolium cation [emim](+) in [emim][Cl]. Environmental effects on the imidazolium ring proton chemical shifts are quite significant and must be taken into account explicitly. Calculations performed on the isolated imidazolium cation as well as on the [emim][Cl] ion pair grossly fail to reproduce the correct spacing between proton signals. In contrast, calculations performed on clusters extracted from the trajectory of a Car-Parrinello molecular dynamics simulation yield very good results.


Exposure and mindfulness based therapy for irritable bowel syndrome--an open pilot study.
We conducted a study of a group therapy based on exposure and mindfulness in the treatment of irritable bowel syndrome (IBS). Out of 49 outpatients, most of whom were referred from gastroenterological clinics, 34 entered into the 10-week treatment. Patients were assessed before, immediately after and 6 months after treatment. The assessments consisted of a gastrointestinal symptom diary, self-report questionnaires covering quality of life, gastrointestinal specific anxiety, general functioning, and a psychiatric interview. At post-treatment, the mean reduction in symptoms was 41% and 50% of patients showed clinically significant improvement in symptom level. Patients also showed marked improvement on other outcome measures. Treatment gains were maintained at follow-up. The results support the use of exposure and mindfulness based strategies in the treatment of IBS, but further randomised studies are needed to confirm the efficacy of the treatment.


Nanofibers and their applications in tissue engineering.
Developing scaffolds that mimic the architecture of tissue at the nanoscale is one of the major challenges in the field of tissue engineering. The development of nanofibers has greatly enhanced the scope for fabricating scaffolds that can potentially meet this challenge. Currently, there are three techniques available for the synthesis of nanofibers: electrospinning, self-assembly, and phase separation. Of these techniques, electrospinning is the most widely studied technique and has also demonstrated the most promising results in terms of tissue engineering applications. The availability of a wide range of natural and synthetic biomaterials has broadened the scope for development of nanofibrous scaffolds, especially using the electrospinning technique. The three dimensional synthetic biodegradable scaffolds designed using nanofibers serve as an excellent framework for cell adhesion, proliferation, and differentiation. Therefore, nanofibers, irrespective of their method of synthesis, have been used as scaffolds for musculoskeletal tissue engineering (including bone, cartilage, ligament, and skeletal muscle), skin tissue engineering, vascular tissue engineering, neural tissue engineering, and as carriers for the controlled delivery of drugs, proteins, and DNA. This review summarizes the currently available techniques for nanofiber synthesis and discusses the use of nanofibers in tissue engineering and drug delivery applications.


Dual modality drainage for symptomatic walled-off pancreatic necrosis reduces length of hospitalization, radiological procedures, and number of endoscopies compared to standard percutaneous drainage.
Symptomatic walled-off pancreatic necrosis (WOPN) treated with dual modality endoscopic and percutaneous drainage (DMD) has been shown to decrease length of hospitalization (LOH) and use of radiological resources in comparison to standard percutaneous drainage (SPD). The aim of this study is to demonstrate that as the cohort of DMD and SPD patients expand, the original conclusions are durable. The database of patients receiving treatment for WOPN between January 2006 and April 2011 was analyzed retrospectively. One hundred two patients with symptomatic WOPN who had no previous drainage procedures were evaluated: 49 with DMD and 46 with SPD; 7 were excluded due to a salvage procedure. Patient characteristics including age, sex, etiology of pancreatitis, and severity of disease based on computed tomographic severity index were indistinguishable between the two cohorts. The DMD cohort had shorter LOH, time until removal of percutaneous drains, fewer CT scans, drain studies, and endoscopic retrograde cholangiopancreatography (ERCPs; p < 0.05 for all). There were 12 identifiable complications during DMD, which were successfully treated without the need for surgery. The 30-day mortality in DMD was 4% (one multi-system organ failure and one out of the hospital with congestive heart failure). Three patients receiving SPD had surgery, and three (7%) died in the hospital. DMD for symptomatic WOPN reduces LOH, radiological procedures, and number of ERCPs compared to SPD.


Internalization of Pseudomonas aeruginosa is mediated by lipid rafts in contact lens-wearing rabbit and cultured human corneal epithelial cells.
The internalization of Pseudomonas aeruginosa (PA) in nasal and tracheal epithelium has recently been shown to involve the formation of cholesterol- and sphingolipid-rich plasma membrane domains (lipid rafts). The purpose of this study was to investigate the role of lipid rafts in PA internalization by corneal epithelium in vivo, in vitro, and after contact lens wear. Lipid raft formation was evaluated in rabbit corneas with and without contact lens wear and a human corneal epithelial (hTCEpi) cell line before and after PA infection with cornea-pathogenic strains by staining with FITC-conjugated cholera toxin beta-subunit, known to bind the lipid raft component GM1. Bacterial internalization was assessed by gentamicin survival assay. The role of lipid rafts in PA internalization was evaluated by pretreatment of hTCEpi cells with cholesterol metabolism inhibitors. The interaction of PA with lipid rafts was confirmed by flow cytometry. Contact lens wear in rabbits induced lipid raft formation in occasional surface corneal epithelial cells. Subsequent PA exposure showed preferential binding to lipid raft-forming cells, leading to lipid raft aggregation and PA internalization. A similar sequence of lipid raft formation and PA internalization was also observed in hTCEpi for all PA strains. Internalization of all PA strains was blocked by three cholesterol metabolism inhibitors (P < 0.01). Flow cytometry showed an association of PA with rafts. These findings demonstrate that contact-lens-mediated PA internalization involves lipid raft formation. Also, hTCEpi cells may be used as an experimental model for studying further the molecular mechanism(s) of PA infection in the corneal epithelium.


Outcome of individualized dialysate sodium concentration for hemodialysis patients.
To evaluate the individualization of dialysate sodium (Na + ) concentration in hemodialysis (HD), we studied 40 stable chronic HD patients in a single-blind crossover design. They underwent 36 consecutive HD sessions with the dialysate Na + concentration set at 138 mmol/L, followed by 36 sessions of dialysate Na + set to match the patients average pre-HD plasma Na + levels. We multiplied the midweek pre-HD measured Na + by the Donnan coefficient of 0.95 (individualized Na + ). Pre-HD Na + dialysis sodium levels were nearly constant, with no variation between the two phases and a mean of 137.45 ± 2.04 mmol/L. Post-HD serum Na + was significantly higher during the standard phase (139.7 ± 2 mmol/L) than during the individualized phase (137.1 ± 1.6 mmol/L). Also, interdialytic weight gain (IDWG) was significantly more reduced during the individualized phase (3.25 ± 0.56%) than during the standard phase (3.94 ± 0.92%), P <0.001. Episodes of distressing symptoms including headache, muscle cramps and hypotension were significantly less frequent in the individualized phase. The mean of the pre-HD and post-HD systolic and diastolic blood pressures significantly decreased during the individualized phase, and we could reduce the doses of antihypertensive drugs in 10 (33.33%) patients. Individualized dialysate Na + concentration was associated with a decrease in IDWG and dialysis hypotension and related symptoms and better BP control in stable chronic HD patients.