Drug Repositioning of Metformin Encapsulated in PLGA Combined with Photothermal Therapy Ameliorates Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is a highly prevalent form of autoimmune disease that affects nearly 1% of the global population by causing severe cartilage damage and inflammation. Despite its prevalence, previous efforts to prevent the perpetuation of RA have been hampered by therapeutics' cytotoxicity and poor delivery to target cells. The present study exploited drug repositioning and nanotechnology to convert metformin, a widely used antidiabetic agent, into an anti-rheumatoid arthritis drug by designing poly(lactic-co-glycolic acid) (PLGA)-based spheres. Moreover, this study also explored the thermal responsiveness of the IL-22 receptor, a key regulator of Th-17, to incorporate photothermal therapy (PTT) into the nanodrug treatment. PLGA nanoparticles were synthesized using the solvent evaporation method, and metformin and indocyanine green (ICG) were encapsulated in PLGA in a dropwise manner. The nanodrug's in vitro anti-inflammatory properties were examined in J744 and FLS via real-time PCR. PTT was induced by an 808 nm near-infrared (NIR) laser, and the anti-RA effects of the nanodrug with PTT were evaluated in DBA/1 collagen-induced arthritis (CIA) mice models. Further evaluation of anti-RA properties was carried out using flow cytometry, immunofluorescence analysis, and immunohistochemical analysis. The encapsulation of metformin into PLGA allowed the nanodrug to enter the target cells via macropinocytosis and clathrin-mediated endocytosis. Metformin-encapsulated PLGA (PLGA-MET) demonstrated promising anti-inflammatory effects by decreasing the expression of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), increasing the expression of anti-inflammatory cytokines (IL-10 and IL-4), and promoting the polarization of M1 to M2 macrophages in J774 cells. The treatment of the nanodrug with PTT exhibited more potent anti-inflammatory effects than free metformin or PLGA-MET in CIA mice models. These results demonstrated that PLGA-encapsulated metformin treatment with PTT can effectively ameliorate inflammation in a spatiotemporal manner.


Use of 30-Hz Accelerated iTBS in Drug-Resistant Unipolar and Bipolar Depression in a Public Healthcare Setting: A Case Series.
Background: Depressive episodes, especially when resistant to pharmacotherapy, are a hard challenge to face for clinicians and a leading cause of disability worldwide. Neuromodulation has emerged as a potential therapeutic option for treatment-resistant depression (TRD), in particular transcranial magnetic stimulation (TMS). In this article, we present a case series of six patients who received TMS with an accelerated intermittent theta-burst stimulation (iTBS) protocol in a public healthcare setting. Methods: We enrolled a total number of six participants, affected by a treatment-resistant depressive episode, in either Major Depressive Disorder (MDD) or Bipolar Disorder (BD). Patients underwent an accelerated iTBS protocol, targeted to the left dorsolateral prefrontal cortex (DLPFC), 3-week-long, with a total of 6 days of overall stimulation. On each stimulation day, the participants received 3 iTBS sessions, with a 15-min pause between them. Patients were assessed by the Hamilton Rating Scale for Depression (HAM-D), the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Rating Scale for Anxiety (HAM-A), and the Mania Rating Scale (MRS). At baseline (T0), at the end of the second week (T1), and at the end of the cycle of stimulation (T2). Results: The rANOVA (repeated Analysis of Variance) statistics showed no significant effect of time on the rating scale scores, with a slight decrease in MADRS scores and a very slight increase in HAM-A and HAM-D scores. No manic symptoms emerged during the entire protocol. Conclusions: Although accelerated iTBS might be considered a less time-consuming strategy for TMS administration, useful in a public healthcare setting, our results in a real-word six-patient population with TRD did not show a significant effect. Further studies on wider samples are needed to fully elucidate the potential of accelerated iTBS protocols in treatment-resistant depression.


Recent data on the role of antiretroviral therapy in weight gain and obesity in persons living with HIV.
Antiretroviral therapy (ART) has long been implicated in fat alterations and weight variations leading to cardiometabolic consequences. Recent largely prescribed antiretrovirals (ARVs) from the integrase-strand-transfer-inhibitor (INSTI) class have been associated with excessive weight gain/obesity in a minority of persons with HIV (PWH). As well, in the nucleoside reverse transcriptase inhibitors (NRTI) class, tenofovir-alafenamide (TAF), often replacing tenofovir-disoproxil-fumarate (TDF), has been associated with weight gain, a worrying concern in the present worldwide obesogenic environment. The respective role of the different ARV, the risk factors and the mechanisms remain questionable. The INSTIs dolutegravir (DTG) and bictegravir (BIC) and TAF have a proper effect on weight gain, while efavirenz (EFV) and TDF inhibit it. These effects are reported in ART-naïve PWH, in addition to weight gain resulting from the return to health process, and in ART-controlled PWH. Also, INSTIs induce weight gain in adolescents and excessive weight gain during pregnancy. The effects of INSTIs and TAF are additive. Their trajectory differs. Most of the weight gain is observed during the initial 12-month period.The main risk factors are low CD4+ and high viral load (VL) in ART-naïve PWH, Black race or originating from some African countries and female gender. The role of age and BMI differs between studies. The reversibility of the effect of INSTI and TAF appears limited.Regarding the mechanisms, the INSTIs can directly alter adipose tissue in particular through inhibition of fat beiging, resulting in fat fibrosis and hypertrophy. Macrophage infiltration is decreased. The mechanisms explaining the opposite effects of TDF and TAF remain elusive. The specific impact of DTG, BIC and TAF on weight gain/obesity in PWH is confirmed in different populations independently of the weight limiting effect of EFV and TDF. ART-linked excessive weight gain is uncommon. African origin and female sex are risk factors that need to be considered. The mechanisms are better understood for INSTIs but unknown for TDF/TAF. The reversibility of weight gain/obesity when stopping INSTI or TAF remains limited.


Plasma clusterin and the risk of Alzheimer disease.
Variants in the clusterin gene are associated with the risk of Alzheimer disease (AD) and clusterin levels have been found to be increased in brain and cerebrospinal fluid of patients with AD. Plasma clusterin was reported to be associated with brain atrophy, baseline disease severity, and rapid clinical progression in patients with AD. To evaluate the potential of plasma clusterin as a biomarker of the presence, severity, and risk of AD. A case-cohort study nested within the Rotterdam Study, a prospective population-based cohort study conducted in Rotterdam, The Netherlands. Plasma levels of clusterin were measured at baseline (1997-1999) in 60 individuals with prevalent AD, a random subcohort of 926 participants, and an additional 156 participants diagnosed with AD during follow-up until January 1, 2007 (mean [SD], 7.2 [2.3] years). Prevalent AD, severity of AD measured by the Mini-Mental State Examination (MMSE) score, and the risk of developing AD during follow-up. The likelihood of prevalent AD increased with increasing plasma levels of clusterin (odds ratio [OR] per SD increase of plasma clusterin level, 1.63; 95% confidence interval [CI], 1.21-2.20; adjusted for age, sex, education level, apolipoprotein E status, diabetes, smoking, coronary heart disease, and hypertension). Among patients with AD, higher clusterin levels were associated with more severe disease (adjusted difference in MMSE score per SD increase in clusterin levels, -1.36; 95% CI, -2.70 to -0.02; P = .047). Plasma clusterin levels were not related to the risk of incident AD during total follow-up (adjusted HR, 1.00; 95% CI, 0.85-1.17; P for trend = .77) or within 3 years of baseline (adjusted HR, 1.09; 95% CI, 0.84-1.42; P for trend = .65). Plasma clusterin levels were significantly associated with baseline prevalence and severity of AD, but not with incidence of AD.


The role of movement errors in modifying spatiotemporal gait asymmetry post stroke: a randomized controlled trial.
Current rehabilitation to improve gait symmetry following stroke is based on one of two competing motor learning strategies: minimizing or augmenting symmetry errors. We sought to determine which of those motor learning strategies best improves overground spatiotemporal gait symmetry. Randomized controlled trial. Rehabilitation research lab. In all, 47 participants (59 ± 12 years old) with chronic hemiparesis post stroke and spatiotemporal gait asymmetry were randomized to error augmentation, error minimization, or conventional treadmill training (control) groups. To augment or minimize asymmetry on a step-by-step basis, we developed a responsive, "closed-loop" control system, using a split-belt instrumented treadmill that continuously adjusted the difference in belt speeds to be proportional to the patient's current asymmetry. Overground spatiotemporal asymmetries and gait speeds were collected prior to and following 18 training sessions. Step length asymmetry reduced after training, but stance time did not. There was no group × time interaction. Gait speed improved after training, but was not affected by type of asymmetry, or group. Of those who trained to modify step length asymmetry, there was a moderately strong linear relationship between the change in step length asymmetry and the change in gait speed. Augmenting errors was not superior to minimizing errors or providing only verbal feedback during conventional treadmill walking. Therefore, the use of verbal feedback to target spatiotemporal asymmetry, which was common to all participants, appears to be sufficient to reduce step length asymmetry. Alterations in stance time asymmetry were not elicited in any group.


Photoelectron spectra of CeO(-) and Ce(OH)2 (-).
The photoelectron spectrum of CeO(-) exhibits what appears to be a single predominant electronic transition over an energy range in which numerous close-lying electronic states of CeO neutral are well known. The photoelectron spectrum of Ce(OH)2 (-), a molecule in which the Ce atom shares the same formal oxidation state as the Ce atom in CeO(-), also exhibits what appears to be a single transition. From the spectra, the adiabatic electron affinities of CeO and Ce(OH)2 are determined to be 0.936 ± 0.007 eV and 0.69 ± 0.03 eV, respectively. From the electron affinity of CeO, the CeO(-) bond dissociation energy was determined to be 7.7 eV, 0.5 eV lower than the neutral bond dissociation energy. The ground state orbital occupancies of both CeO(-) and Ce(OH)2 (-) are calculated to have 4f 6s(2) Ce(+) superconfigurations, with open-shell states having 4f5d6s superconfiguration predicted to be over 1 eV higher in energy. Low-intensity transitions observed at higher electron binding energies in the spectrum of CeO(-) are tentatively assigned to the (1)Σ(+) (Ω = 0) state of CeO with the Ce+26s2 superconfiguration.


Overcoming the difficulties in collecting apoplastic fluid from rice leaves by the infiltration-centrifugation method.
Physiological and biochemical studies on the leaf apoplast have been facilitated by the use of the infiltration-centrifugation technique to collect intercellular washing fluid (IWF). However, this technique has been difficult to implement in rice (Oryza sativa L.) for various reasons. We compared the collection efficiency of leaf IWF between two types of rice varieties (Indica and Japonica), as well as between rice and other species (spinach, snap bean and wheat). Although the extraction of IWF in most species took only 2-3 min, it took up to 35 min in rice. The difficulty in infiltration with rice was ascribed to the small stomatal aperture and hydrophobicity of the leaves. In this study, we have established an improved method for collecting IWF and determining the apoplastic air and water volumes in rice leaves. We have shortened the infiltration time to 8 min via the following improvements: (i) infiltration under outdoor shade in the daytime to prevent stomatal closure and a rise in temperature of the infiltration medium; (ii) soaking of leaves in a surfactant solution to decrease the leaf hydrophobicity; and (iii) continuous pressurization using a sealant injector to facilitate the infiltration. The rapid collection of IWF achieved using this technique will facilitate study of the leaf apoplast in rice.


Comparative outcomes of catheter-directed thrombolysis plus anticoagulation versus anticoagulation alone in the treatment of inferior vena caval thrombosis.
The contemporary practice patterns and role of catheter-directed thrombolysis (CDT) in the treatment of inferior vena cava thrombosis is unknown. The Nationwide Inpatient Sample database was used to identify patients with a principal discharge diagnosis of inferior vena cava thrombosis (International Classification of Diseases-Ninth Revision-Clinical Modification, 453.2) from 2005 to 2011. We compared patients treated with CDT plus anticoagulation with patients treated with anticoagulation alone. We used propensity scores to construct 2 matched groups of 563 patients for comparative outcomes analysis. Among 2674 patients admitted with inferior vena cava thrombosis, 718 (26.9%) underwent CDT. The national CDT utilization rates increased from 16.0% in 2005 to 34.7% in 2011 (P<0.001). Based on the propensity-matched comparison, the inhospital mortality was not significantly different between the CDT and the anticoagulation groups (2.0% versus 1.4%; P=0.49). The rates of pulmonary embolism (12.1% versus 7.8%; P=0.02), intracranial hemorrhage (1.6% versus 0.2%; P=0.03), and acute renal failure (13.9% versus 9.4%; P=0.02) were significantly higher in the CDT group. The CDT group had longer length of stay and higher hospital charges compared with the anticoagulation group. There has been a steady increase in the use of CDT in the treatment of patients with inferior vena cava thrombosis in the United States. This observational study showed no significant difference in mortality between CDT versus anticoagulation alone; however, the bleeding events and resource utilization were higher in the CDT group. Adequately powered randomized controlled trials are needed in this area.


Transgenerational effects of cyanobacterial toxins on a tropical micro-crustacean Daphnia lumholtzi across three generations.
Climate change and human activities induce an increased frequency and intensity of cyanobacterial blooms which could release toxins to aquatic ecosystems. Zooplankton communities belong to the first affected organisms, but in tropical freshwater ecosystems, this issue has yet been poorly investigated. We tested two questions (i) if the tropical Daphnia lumholtzi is capable to develop tolerance to an ecologically relevant concentration of purified microcystin-LR and microcystins from cyanobacterial extract transferable to F1 and F2 generations? And (ii) would F1 and F2 generations recover if reared in toxin-free medium? To answer these questions, we conducted two full factorial mutigenerational experiments, in which D. lumholtzi was exposed to MC-LR and cyanobacterial extract at the concentration of 1 μg L-1 microcystin continuously for three generations. After each generation, each treatment was spit into two: one reared in the control (toxin free) while the other continued in the respective exposure. Fitness-related traits including survival, maturity age, body length, and fecundity of each D. lumholtzi generation were quantified. Though there were only some weak negative effects of the toxins on the first generation (F0), we found strong direct, accumulated and carried-over impacts of the toxins on life history traits of D. lumholtzi on the F1 and F2, including reductions of survival, and reproduction. The maturity age and body length showed some inconsistent patterns between generations and need further investigations. The survival, maturity age (for extract), and body length (for MC-LR) were only recovered when offspring from toxin exposed mothers were raised in clean medium for two generations. Chronic exposure to long lasting blooms, even at low density, evidently reduces survival of D. lumholtzi in tropical lakes and reservoirs with ecological consequences.


The formation and biotransformation of cysteine conjugates of halogenated ethylenes by rabbit renal tubules.
The nephrotoxicity of chlorotrifluoroethylene ( CTFE ) was examined using isolated rabbit renal tubules suspensions. Exposure of the tubules to CTFE resulted in consumption of CTFE , formation of a glutathione conjugate and inhibition of active organic acid transport. Synthetic cysteine, N-acetylcysteine or glutathione conjugates of CTFE inhibited transport indicating S-conjugation as a possible toxic pathway. 1,2-dichlorovinyl glutathione ( DCVG ), a model synthetic glutathione conjugate, was used to examine the degradation and toxicity of these conjugates. DCVG inhibited rabbit renal tubule transport in vivo and in vitro. The DCVG was found to be degraded with the evolution of glutamine and glycine to produce the ultimate nephro-toxicant, dichlorovinyl cysteine. Dichlorovinyl cysteine is then bioactivated with the release of ammonia. This sequential degradation explains the latency of DCVG -induced renal transport inhibition relative to dichlorovinyl cysteine. It is now evident that certain halogenated ethylenes are capable of being biotransformed to glutathione conjugates in the kidney with their subsequent hydrolysis to nephrotoxic cysteine conjugates.


Evidence for positive selection of taurine genes within a QTL region on chromosome X associated with testicular size in Australian Brahman cattle.
Previous genome-wide association studies have identified significant regions of the X chromosome associated with reproductive traits in two Bos indicus-influenced breeds: Brahman cattle and Tropical Composites. Two QTL regions on this chromosome were identified in both breeds as strongly associated with scrotal circumference measurements, a reproductive trait previously shown to be useful for selection of young bulls. Scrotal circumference is genetically correlated with early age at puberty in both male and female offspring. These QTL were located at positions 69-77 and 81-92 Mb respectively, large areas each to which a significant number of potential candidate genes were mapped. To further characterise these regions, a bioinformatic approach was undertaken to identify novel non-synonymous SNP within the QTL regions of interest in Brahman cattle. After SNP discovery, we used conventional molecular assay technologies to perform studies of two candidate genes in both breeds. Non-synonymous SNP mapped to Testis-expressed gene 11 (Tex11) were associated (P < 0.001) with scrotal circumference in both breeds, and associations with percentage of normal sperm cells were also observed (P < 0.05). Evidence for recent selection was found as Tex11 SNP form a haplotype segment of Bos taurus origin that is retained within Brahman and Tropical Composite cattle with greatest reproductive potential. Association of non-synonymous SNP presented here are a first step to functional genetic studies. Bovine species may serve as a model for studying the role of Tex11 in male fertility, warranting further in-depth molecular characterisation.


Passive exchanges during water vapour absorption in mealworms (Tenebrio molitor): a new approach to studying the phenomenon.
The weights of single mealworms were continuously recorded at 20 degrees C during exposure to periods of constant humidity and to abrupt changes in atmospheric vapour pressure. Two exchange stages were recognized in each animal. Weight changes were either limited to slow losses, suggesting transpiration through the external cuticle, or showed more rapid humidity-dependent gains as well as losses. Rapid exchanges indicated that water was gained or lost through permeable barriers, from a fluid compartmet of significantly lower vapour pressure than the haemolymph, equivalent to about 90% R.H. Weight gains and losses during humidity changes provided evidence of a significant, passively exchanging fluid compartment located between the exchange surface and absorbing mechanism. Weight changes in faecal pellets following their elimination provide further support for a rectal site of atmospheric absorption.


Reversible changes in diffusion- and perfusion-based imaging in cerebral venous sinus thrombosis.
Diffusion- and perfusion-based imaging studies are regularly used in patients with ischemic stroke. Cerebral venous sinus thrombosis (CVST) is a rare cause of stroke and is primarily treated by systemic anticoagulation. Endovascular intervention can be considered in cases of failed medical therapy, yet the prognostic value of diffusion- and perfusion-based imaging for CVST has not been clearly established. We present a patient with CVST whose abnormal findings on MRI and CT perfusion images were largely reversed after endovascular treatment.


Influence of somatostatin and bombesin on plasma enteroglucagon and cell proliferation after intestinal resection in the rat.
The possible relationship between enteroglucagon and cellular proliferation in a rat model of intestinal adaptation after suppression and stimulation of enteroglucagon by somatostatin and bombesin has been investigated. Forty eight rats were divided into three groups of 16 animals, each group being further sub-divided into eight animals having intestinal resection and eight having intestinal transection. Group 1 was given somatostatin to suppress enteroglucagon, group 2 was given bombesin to stimulate enteroglucagon and group 3 (control group) had neither peptide. All animals were killed 12 days after operation. Circulating enteroglucagon and crypt cell production rate (CCPR) in the terminal ileum were measured. After administration of somatostatin (group 1) both CCPR and plasma enteroglucagon were lower after resection than controls (group 3) (p less than 0.001). Transected rats receiving somatostatin showed a reduction in both plasma enteroglucagon and CCPR, but only the fall in enteroglucagon was statistically significant (p less than 0.001). Transected rats receiving bombesin (group 2) had raised plasma enteroglucagon and CCPR compared with the control group (group 3) (P less than 0.005) but there was no significant further rise in these already raised parameters in resected animals. This study indicates that cell proliferation in the rat small bowel after surgery can be influenced by regulatory peptides. The changes in enteroglucagon corresponded closely with changes in CCPR, and this peptide remains a favoured candidate for the humorally mediated trophic influence on the small bowel.


Hospital nurses' lived experience of power.
The purpose of this study was to explore hospital nurses' lived experience of power. A hermeneutic phenomenological approach informed by Merleau-Ponty's philosophy of the phenomenology of perception was used to further an understanding of nurses' embodiment of power. Fourteen hospital clinical nurses employed in intensive care units and on medical floors in two major medical centers in the northeastern United States participated in 1-hr semistructured interviews about their lived experience of power. A hermeneutic analytic approach and reflexive (cultural) bracketing produced three relational themes of power: (a) knowing my patients and speaking up for them; (b) working to build relationships that benefit patients; and (c) identifying my powerful self. Hospital clinical nurses develop a sense of power. Nurses believe power develops through acquisition of knowledge, experience, and self-confidence; this process is enhanced by exposure to good mentors. Nurses use their power to build relationships and advocate for patients. They consciously use power to improve patient care. Nurses' voices need to be heard and acknowledged. To do this in the clinical setting and beyond, hospital nurses must invite themselves or find ways to be invited into the authoritative discourse of hospital organizations. Nurses use their power to advocate for positive outcomes for patients and families. The satisfaction that comes from these positive relationships may improve nurses' perceptions of their work environment. Nurses' understanding and use of sociopolitical knowing needs further study, so that nurses may understand how to participate in current and future debates and decisions about our changing healthcare delivery systems and services.


Accuracy, efficacy, and clinical applications of the Radionics Operating Arm System.
The aim of this study was to evaluate the accuracy and efficacy of the Radionics Operating Arm System (OAS; Radionics Applications Software, Burlington, MA) in a routine clinical setup. The OAS is a frameless stereotactic articulated arm that can be used in conjunction with computed tomography (CT) or magnetic resonance (MR) imaging to provide image-based intraoperative navigation. The system was used in 130 consecutive cases. It failed or was considered unreliable in 4.6% of patients. Among the remaining patients, 103 had OAS-guided craniotomies, 11 had frameless stereotactic biopsies, and 10 had OAS-guided anterior cervical surgery. Patients were imaged 3-12 hours prior to surgery. Skin markers were used in all cases. The OAS accuracy was evaluated by measuring the difference between the actual probe position and its analogous position on the images. Frameless stereotactic biopsies were performed using the OAS, a modified probe, and a twist-drill. Anterior cervical surgery was performed using the OAS, MRI images, and a rigid cervical collar. The duration of the procedure was recorded for the first 50 patients, and the value of the OAS in localizing the site of craniotomy, the margin of the lesion, and the extent of the resection was also recorded. The system was associated with insignificant prolongation of procedure setup and was sufficiently reliable and achieved a useful registration in 124 (95.4%) patients. The mean accuracy of the system, using skin markers, was 2.5 mm. The OAS was also adaptable for performing other tasks, such as an interactive needle biopsy without a frame. Its use in conjunction with a hollow probe, to perform biopsy or aspiration of 11 brain lesions, produced 100% positive results. Its use in conjunction with MRI and a cervical collar fiducial system, to perform anterior cervical surgery in 10 patients, localized the level in all patients. Overall, the Radionics OAS was sufficiently reliable and accurate in a wide range of routine neurosurgical procedures. Therefore, we integrated it into our routine neurosurgical practice.


Comparative efficacy of antiherpes drugs in different cell lines.
A selection of antiherpes compounds including bromovinyldeoxyuridine (BVDU), acyclovir (ACV), and fluoroiodoaracytosine (FIAC) were compared for their inhibitory effects on herpes simplex virus type 1 (strain KOS) replication in a wide variety of human, simian, feline, and murine cell lines. The 50% inhibitory doses of the compounds varied considerably from one cell line to another, i.e., from 0.01 to 2 micrograms/ml for ACV and from 0.004 to 0.2 micrograms/ml for BVDU and FIAC. However, the relative order of antiviral potency remained constant, thus (in order of decreasing potency) BVDU greater than FIAC greater than ACV, for all cell lines studied except for the murine embryo cells, in which the order of decreasing potency was BVDU greater than ACV greater than FIAC, and for the feline lung cells, in which the order of decreasing potency was FIAC greater than ACV greater than BVDU.


A missense mutation in NR5A1 causing female to male sex reversal: A case report.
Testicular disorder of sex development (TDSD) is a rare condition, characterised by a female karyotype, male phenotype, small testes and cryptorchidism. Only a few studies have investigated the genetic causes of male sex reversal. This is the clinical report of an Iranian 46,XX patient presented with TDSD and associated with hypospadias. Whole-exome sequencing (WES) of the patient ascertained the heterozygous missense variant (c.274C>T) in the NR5A1 gene, resulting in a substitution of arginine with tryptophan. The arginine 92 residue was located in a highly conserved region of steroidogenic factor 1 (SF1), which is crucial for its interaction with DNA. Our finding is in line with previous reports, which highlighted the role of p.(Arg92Trp) variant in TDSD individuals. As far as we are aware, this is the first report of TDSD with p.(Arg92Trp) variant in the Iranian population.


Quantitative benefit and risk assessment of arsenic and nutrient levels in tilapia products sold on Chinese e-commerce platforms.
E-commerce platforms have become a significant sales channel for processed tilapia products such as frozen tilapia fillets, pickled tilapia, and canned tilapia in China. As food safety issues are worldwide concerned, the imbalance between the nutritional benefits of fish and the risk of contamination has become a major constraint on fish consumption. Therefore, it is necessary to assess the safety of tilapia products sold on e-commerce platforms. We conducted a quantitative benefit-risk assessment of arsenic and nutrient levels for tilapia products sold on Chinese e-commerce platforms using the hazard quotient (HQ). A total of 147 tilapia products were collected from the central Chinese e-commerce platforms Tmall, Taobao, and Jingdong for arsenic determination. Arsenic concentrations in tilapia products ranged from 0.004 to 0.820 mg·kg-1. The inorganic arsenic content of tilapia products was lower than the national limit (0.1 mg·kg-1). One-way analysis of variance revealed that there was no significant difference in arsenic levels in tilapia products among different regions (p > 0.05), while there was a significant difference in product form, with canned tilapia containing significantly higher arsenic levels than frozen tilapia fillets and pickled tilapia fillets (p < 0.05). We conducted an aquaculture experiment to analyze the nutrient levels of tilapia. The mean value of EPA + DHA content of tilapia was 20.634 mg·100 g-1. The HQ values of tilapia products ranged from 0.004 to 0.736. In a word, the nutritional benefits of consuming tilapia products exceed the risk of arsenic exposure. These data can help demonstrate that tilapia products are low-risk, high-yield nutritious food and provide relevant safety recommendations for consumers purchasing processed tilapia products online.


Influence of dentin conditioning and contamination on the marginal integrity of sandwich Class II restorations.
This study investigated the influence of dentin conditioning and contamination on the marginal adaptation of Class II sandwich restorations. Large butt-joint MOD cavities with cervical margins located 1 mm below the CEJ were cut into 72 extracted human molars. Nine groups were filled using a total-bond technique with Z100 or a sandwich technique with either Vitremer or F2000 in combination with Z100. For all three material combinations three different pretreatments were compared: total etch, selective etch and dentin contamination with saliva and blood prior to primer/adhesive application. After water storage for 21 days and thermocycling (2000x, 5-55 degrees C) replicas were produced for quantitative marginal analysis in the SEM. Teeth were immersed in 0.5% basic fuchsin for 24 hours and dried. Percent dye penetration over the total marginal length was analyzed in three layers using a sequential grinding technique. Statistical analysis was performed using a two-way ANOVA. Post-hoc analyses were carried out with univariate Mann-Whitney-U-tests adjusting for multiple comparisons by a sequentially rejective test procedure (Bonferroni-Holm) at p < 0.05. Both F2000 and Vitremer sandwich restorations showed better marginal adaptation than Z100 total-bond restorations with all pretreatments. Acid etching of the dentin significantly influenced the marginal adaptation of Z100 total-bond restorations and Vitremer sandwich restorations. All types of restorations showed considerable microleakage. On contaminated dentin, sandwich restorations showed better marginal integrity than total-bond restorations. Marginal adaptation did not correspond with microleakage in all groups. In conclusion, F2000/Z100 and Vitremer/Z100 sandwich restorations show better marginal adaptation than Z100 total-bond restorations in large Class II cavities with cervical margins in dentin. Microleakage cannot predictably be prevented with the sandwich technique. Sandwich restorations seem to be less sensitive to contamination with saliva and blood.


Gastric acid secretion and gastrin production in the short bowel syndrome.
Excess gastric acid secretion and gastrin production may occur in patients with the short bowel syndrome but the two measurements have never been made simultaneously in man in response to a food stimulus. Using the technique of intragastric titration, this was carried out in eight patients after extensive small bowel resection resulting mainly from vascular occlusion and in eight matched normal control subjects. Basal acid output and peak acid output in response to pentagastrin was also measured separately. Although peak and integrated serum gastrin concentrations were significantly greater in patients (450 +/- SE 109 pg/ml; 113 +/- 2.9X10(-3) pg/ml/min) compared with control subjects (174 +/- 98 pg/ml; 6.1 +/- 2.0X10(-3) pg/ml/min p less than 0.05), no concomitant increase in acid secretion was shown either during intragastric titration or in response to pentagastrin. These findings indicate that there is no rationale for treating these patients with long term anti-ulcer therapy.


Lipid transport in the developing bovine follicle: messenger RNA expression increases for selective uptake receptors and decreases for endocytosis receptors.
Differences in rates of steroid production and secretion will, eventually, determine the developmental rates of ovarian follicles. The major supply of cholesterol, the precursor for steroid and androgen biosynthesis, to ovarian cells is from circulating lipoproteins via membrane receptors from the low density lipoprotein receptor (LDL) superfamily. This occurs by either endocytosis, which has been described for very low density lipoprotein receptors (VLDLr), for LDL receptors (LDLr), and by the selective uptake pathway described for the scavenger receptor class B type 1 receptor (SRB1) and the recently described ovarian receptor, lipoprotein receptor-related protein 8 (LRP8). In this study, the mRNA expression of these four cholesterol receptors in bovine ovarian cells was determined at different stages of follicular development. In small antral follicles, mRNA expression of the endocytosis receptors was higher than in large antral follicles. Expression of LRP8 mRNA increased linearly with follicular size together with an increase in LDL, VLDL, and cholesterol concentrations in the follicular fluid. SRB1 mRNA expression tended to increase with follicular diameter. Because different mRNA expression patterns were found for the two types of receptor, this may imply different regulation of cholesterol supply at different stages of follicular development. Accumulation of LDL and VLDL particles in the follicular fluid of large antral follicles may enhance cholesterol availability for the intense steroidogenic activity that is essential at these stages.


[What influences reconvalescence after lung resection?].
Reconvalescence after lung resections underlies several influences. The aim of this study was to outline the effect of patient and operative factors. Between 1/97 and 6/98 a cross sectional prospective study was undertaken at the University of Ulm. 125 patients with lung resections for various reasons via anterolateral thoracotomy were included. Variants thought to affect postoperative recovery were statistically analysed using uni- and multivariate analysis. A "good postoperative recovery" (GPR) was seen as at least two of the following criteria were fulfilled on the second postoperative day: Spitzer Index >/=6, FEV1 >40% of preoperative measurement, pain on LASA scale </=3. Chi-Square testing revealed a more frequent GPR for patients with benign diseases (61 vs 40%, p=0,0436), an atypical compared to anatomical resection (63 vs 40%, p=0,0157) and an opening of the retractor of not more than 13 cm (61 vs 34%, p=0,0033). Multivariate analysis demonstrated only the opening of the retractor as being of independent influence (p=0,0148). Age, sex, BMI, incision length, transsection of M. latissimus dorsi, number of accidental rib fractures, time of operation and routine of the surgeon were of no statistical relevance to GPR. Malignant disease requiring anatomical lung resection is accompanied by delayed postoperative recovery when compared to lung resections for other reason. In contrast the width of opening of the retractor is of independent negative influence for reconvalescence. Once more the significance of a non-aggressive access procedure for lung resections is underlined.


Type II restriction endonuclease R.Eco29kI is a member of the GIY-YIG nuclease superfamily.
The majority of experimentally determined crystal structures of Type II restriction endonucleases (REases) exhibit a common PD-(D/E)XK fold. Crystal structures have been also determined for single representatives of two other folds: PLD (R.BfiI) and half-pipe (R.PabI), and bioinformatics analyses supported by mutagenesis suggested that some REases belong to the HNH fold. Our previous bioinformatic analysis suggested that REase R.Eco29kI shares sequence similarities with one more unrelated nuclease superfamily, GIY-YIG, however so far no experimental data were available to support this prediction. The determination of a crystal structure of the GIY-YIG domain of homing endonuclease I-TevI provided a template for modeling of R.Eco29kI and prompted us to validate the model experimentally. Using protein fold-recognition methods we generated a new alignment between R.Eco29kI and I-TevI, which suggested a reassignment of one of the putative catalytic residues. A theoretical model of R.Eco29kI was constructed to illustrate its predicted three-dimensional fold and organization of the active site, comprising amino acid residues Y49, Y76, R104, H108, E142, and N154. A series of mutants was constructed to generate amino acid substitutions of selected residues (Y49A, R104A, H108F, E142A and N154L) and the mutant proteins were examined for their ability to bind the DNA containing the Eco29kI site 5'-CCGCGG-3' and to catalyze the cleavage reaction. Experimental data reveal that residues Y49, R104, E142, H108, and N154 are important for the nuclease activity of R.Eco29kI, while H108 and N154 are also important for specific DNA binding by this enzyme. Substitutions of residues Y49, R104, H108, E142 and N154 predicted by the model to be a part of the active site lead to mutant proteins with strong defects in the REase activity. These results are in very good agreement with the structural model presented in this work and with our prediction that R.Eco29kI belongs to the GIY-YIG superfamily of nucleases. Our study provides the first experimental evidence for a Type IIP REase that does not belong to the PD-(D/E)XK or HNH superfamilies of nucleases, and is instead a member of the unrelated GIY-YIG superfamily.


The Ancient Immunoglobulin Domains of Peroxidasin Are Required to Form Sulfilimine Cross-links in Collagen IV.
The collagen IV sulfilimine cross-link and its catalyzing enzyme, peroxidasin, represent a dyad critical for tissue development, which is conserved throughout the animal kingdom. Peroxidasin forms novel sulfilimine bonds between opposing methionine and hydroxylysine residues to structurally reinforce the collagen IV scaffold, a function critical for basement membrane and tissue integrity. However, the molecular mechanism underlying cross-link formation remains unclear. In this work, we demonstrate that the catalytic domain of peroxidasin and its immunoglobulin (Ig) domains are required for efficient sulfilimine bond formation. Thus, these molecular features underlie the evolutionarily conserved function of peroxidasin in tissue development and integrity and distinguish peroxidasin from other peroxidases, such as myeloperoxidase (MPO) and eosinophil peroxidase (EPO).


Preformulation characterization and identification of excipients for nevirapine loaded niosomes.
Nevirapine (NVP) is used for the management of HIV/AIDS but must be dosed frequently, exhibits unpredictable bioavailability and a side effect profile that includes hepato- and dermo-toxicity. Niosomes are a colloidal drug delivery system that may be used to overcome the low bioavailability, side effect profile and frequent dosing needed when using conventional drug delivery systems. The compatibility of NVP with sorbitan esters, polysorbate, cholesterol and dihexadecyl phosphate (DCP) was investigated using Differential Scanning Calorimetry (DSC), Scanning Electron Microscopy (SEM), Fourier Transform Infra-red Spectroscopy (FTIR) and X-ray Powder Diffraction (XRPD). Screening studies were undertaken to identify potential excipients that would produce niosomes with target critical quality attributes (CQA) viz, a particle size (PS) < 1000 nm, a polydispersity index (PDI) < 0.500 and an entrapment efficiency >90%. The results revealed that sorbitan esters in combination with cholesterol and 5 μmol DCP produced niosomes with the best CQA and Zeta potential (ZP) < -30 mV which suggests good stability of the niosomes on storage. Sorbitan esters produced the smallest niosomes of < 400 nm diameter with a PDI < 0.400 and an entrapment efficiency > 78% without cholesterol. The addition of cholesterol and DCP was essential to form niosomes with target CQA.


Insights from a novel three-dimensional in vitro model of lyme arthritis: standardized analysis of cellular and molecular interactions between Borrelia burgdorferi and synovial explants and fibroblasts.
To develop a novel 3-dimensional (3-D) in vitro model of Lyme arthritis to use in the study of the interactions between Borrelia burgdorferi (Bb) and human synovial host cells with respect to phagocytosis and potential persistence of Bb as well as the induction of proinflammatory cytokines and chemokines. Two distinct culture systems, consisting of synovial membrane explants or interactive synovial cells embedded in 3-D fibrin matrices, were chosen. Both systems were artificially infected with Bb, and the interactions between Bb and synovial tissue/cells were studied by histology, immunohistochemistry, and electron microscopy. Functional analyses included the induction/secretion of cytokines by Bb in the model system. Both culture systems proved to be stable and reproducible. The host cells and spirochetes showed high levels of viability and maintained their physiologic shape for >3 weeks. Bb invaded the synovial tissue and the artifical matrix in a time-dependent manner. Host cells were activated by Bb, as indicated by the induction of interleukin-1beta and tumor necrosis factor alpha. Electron microscopic analysis revealed Bb intracellularly within macrophages as well as synovial fibroblasts, suggesting that not only professional phagocytes, but also resident synovial cells are capable of phagocytosing Bb. Most interestingly, the uptake of the spirochetes appeared to cause severe damage of the synovial fibroblasts, since the majority of these cells displayed ultrastructural features of disintegration. A novel 3-D in vitro model has been established that allows the study of distinct aspects of Lyme arthritis under conditions that resemble the pathologic condition in humans. This reproducible, standardized model supplements animal studies and conventional 2-D cultures. The disintegration of synovial fibroblasts containing Bb or Bb fragments challenges the concept of an intracellular persistence of Bb and may instead reflect a mechanism that contributes to the inflammatory processes characteristic of Lyme arthritis.


Free hemoglobin concentration in severe sepsis: methods of measurement and prediction of outcome.
Hemolysis can be induced in sepsis via various mechanisms, its pathophysiological importance has been demonstrated in experimental sepsis. However, no data on free hemoglobin concentrations in human sepsis are available. In the present study we measured free hemoglobin in patients with severe sepsis as well as in postoperative patients using four methods. It was our aim to determine the potential value of free hemoglobin as a biomarker for diagnosis and outcome of severe sepsis in critical illness. Plasma concentration of free hemoglobin was determined in patients with severe sepsis (n = 161) and postoperative patients (n = 136) on day 1 of diagnosis and surgery. For the measurement of free hemoglobin, an enzyme linked immunosorbent assay and three spectrophotometric algorithms were used. Moreover, SAPS II- and SOFA scores as well as procalcitonin concentration and outcome were determined. Kaplan-Meier analysis was performed and odds ratios were determined after classification of free hemoglobin concentrations in a high and low concentration group according to the median. For statistical evaluation the Mann-Whitney test and logistic regression analysis were used. In non-survivors of severe sepsis, free hemoglobin concentration was twice the concentration compared to survivors. Thirty-day survival of patients, as evidenced by Kaplan-Meier analysis, was markedly lower in patients with high free hemoglobin concentration than in patients with low free hemoglobin concentration. Best discrimination of outcome was achieved with the spectrophotometric method of Harboe (51.3% vs. 86.4% survival, p < 0.001; odds ratio 6.1). Multivariate analysis including free hemoglobin, age, SAPS II- and SOFA-score and procalcitonin demonstrated that free hemoglobin, as determined by all 4 methods, was the best and an independent predictor for death in severe sepsis (p = 0.022 to p < 0.001). Free hemoglobin concentrations were not significantly different in postoperative and septic patients in three of four assays. Thus, free hemoglobin can not be used to diagnose severe sepsis in critical illness. Free hemoglobin is an important new predictor of survival in severe sepsis.


Adding Value to Bycatch Fish Species Captured in the Portuguese Coast-Development of New Food Products.
We live in a world of limited biological resources and ecosystems, which are essential to feed people. Consequently, diversifying target species and considering full exploitation are essential for fishery sustainability. The present study focuses on the valorization of three low commercial value fish species (blue jack mackerel, Trachurus picturatus; black seabream, Spondyliosoma cantharus; and piper gurnard, Trigla lyra) and of two unexploited species (comber, Serranus cabrilla and boarfish, Capros aper) through the development of marine-based food products with added value. A preliminary inquiry with 155 consumers from Região de Lisboa e Vale do Tejo (Center of Portugal) was conducted to assess fish consumption, the applicability of fish product innovation, and the importance of valorizing discarded fish. Five products (black seabream ceviche, smoked blue jack mackerel pâté, dehydrated piper gurnard, fried boarfish, and comber pastries) were developed and investigated for their sensory characteristics and consumer liking by hedonic tests to 90 consumers. The most important descriptors were identified for each product (texture, flavor, color, and appearance). Comber pastries had the highest purchase intention (88%), followed by black seabream ceviche (85%) and blue jack mackerel pâté (76%). Sensory evaluations showed a clear tendency of consumers to accept reformulated products, with the introduction of the low-value and unexploited species under study.


Role of lipopolysaccharide in opsonization and phagocytosis of Pseudomonas aeruginosa.
When the opsonization of various Pseudomonas aeruginosa strains--PAC 1, its O-chain-deficient mutant PAC 605, and an intermediate strain, P14--was measured either directly by determination of the amount of C3b attached to the bacterial surface or indirectly by assessing phagocytosis by human polymorphonuclear leukocytes and the responses of chemiluminescence, it was demonstrated that PAC 1 was opsonized and phagocytized to a lower extent than P14 and PAC 605. In contrast to PAC 605, PAC 1 showed an increased consumption of complement in the fluid phase and a rapid release of lipopolysaccharide antibodies bound to the bacterial surface due to the alternative pathway of the complement system. Furthermore, it was shown that with respect to PAC 1 and PAC 605, the lack of an O-chain resulted in increased sensitivity to serum and decreased virulence. From both in vivo and in vitro experiments, we concluded that the structure of the O-antigen polysaccharide chain of lipopolysaccharide is an important virulence factor of P. aeruginosa against the defense mechanisms of the host.


Diagnostic challenges and opportunities in older adults with infectious diseases.
Infections remain a major threat to the well-being of our growing aged population. The correct and timely diagnosis of infections in older adults is increasingly important in the current age of antimicrobial resistance. Urinary tract infection, pneumonia, and bacteremia present particular challenges. In older patients with bacteremia, blood cultures have comparable yield as compared with younger patients. However, the routine triggers for ordering blood cultures may not be appropriate in older adults. In addition, resistance patterns of isolated pathogens may change with age. The main difficulties in diagnosing urinary tract infections in older adults are caused by an increased prevalence of asymptomatic bacteriuria and frequent use of urinary catheters. However, a combined noninvasive approach that includes history, physical examination, urinary dipstick testing, urine cultures, and simple blood tests can provide direction. In addition, specific guidelines for specific populations are available. In older patients suspected of bacterial pneumonia, bedside pulse oximetry and urinary antigen testing for Streptococcus pneumoniae and Legionella pneumophila provide direction for the clinician. Although infected older adults pose specific and unique diagnostic challenges, a thorough history and physical examination combined with minimally invasive testing will lead to the correct diagnosis in most older adults with infectious diseases, limiting the need for empiric antibiotics in this age group.


Studies by e.p.r. spectroscopy of carbon monoxide oxidases from Pseudomonas carboxydovorans and Pseudomonas carboxydohydrogena.
E.p.r. spectra were obtained at 8-120 K for carbon monoxide oxidases isolated from the carboxydotrophic bacteria Pseudomonas carboxydovorans and Pseudomonas carboxydohydrogena. Spectra from the two enzymes are extremely similar to one another. Under appropriate conditions each enzyme shows signals from Mo(V) atoms in two different chemical environments, as well as showing signals from two distinct iron-sulphur centres, presumed to be [2Fe-2S] clusters, and weak FADH X free-radical signals. Parameters of most of the signals were measured, and they show considerable similarities to those of the corresponding signals from xanthine oxidase and related enzymes. Though the signals from carbon monoxide oxidases appear and disappear under reducing and oxidizing conditions, we have so far failed to demonstrate the kinetic competence of any of them. It seems likely that this was due to the presence in the enzyme preparation examined of high amounts of desulpho carbon monoxide oxidase together with another non-functional form of the enzyme giving a stable 'Resting' Mo(V) e.p.r. signal.


Crystal structure of human IPS-1/MAVS/VISA/Cardif caspase activation recruitment domain.
IPS-1/MAVS/VISA/Cardif is an adaptor protein that plays a crucial role in the induction of interferons in response to viral infection. In the initial stage of the intracellular antiviral response two RNA helicases, retinoic acid inducible gene-I (RIG-I) and melanoma differentiation-association gene 5 (MDA5), are independently able to bind viral RNA in the cytoplasm. The 62 kDa protein IPS-1/MAVS/VISA/Cardif contains an N-terminal caspase activation and recruitment (CARD) domain that associates with the CARD regions of RIG-I and MDA5, ultimately leading to the induction of type I interferons. As a first step towards understanding the molecular basis of this important adaptor protein we have undertaken structural studies of the IPS-1 MAVS/VISA/Cardif CARD region. The crystal structure of human IPS-1/MAVS/VISA/Cardif CARD has been determined to 2.1A resolution. The protein was expressed and crystallized as a maltose-binding protein (MBP) fusion protein. The MBP and IPS-1 components each form a distinct domain within the structure. IPS-1/MAVS/VISA/Cardif CARD adopts a characteristic six-helix bundle with a Greek-key topology and, in common with a number of other known CARD structures, contains two major polar surfaces on opposite sides of the molecule. One face has a surface-exposed, disordered tryptophan residue that may explain the poor solubility of untagged expression constructs. The IPS-1/MAVS/VISA/Cardif CARD domain adopts the classic CARD fold with an asymmetric surface charge distribution that is typical of CARD domains involved in homotypic protein-protein interactions. The location of the two polar areas on IPS-1/MAVS/VISA/Cardif CARD suggest possible types of associations that this domain makes with the two CARD domains of MDA5 or RIG-I. The N-terminal CARD domains of RIG-I and MDA5 share greatest sequence similarity with IPS-1/MAVS/VISA/Cardif CARD and this has allowed modelling of their structures. These models show a very different charge profile for the equivalent surfaces compared to IPS-1/MAVS/VISA/Cardif CARD.


Reinforcement learning-based control of tumor growth under anti-angiogenic therapy.
In recent decades, cancer has become one of the most fatal and destructive diseases which is threatening humans life. Accordingly, different types of cancer treatment are studied with the main aim to have the best treatment with minimum side effects. Anti-angiogenic is a molecular targeted therapy which can be coupled with chemotherapy and radiotherapy. Although this method does not eliminate the whole tumor, but it can keep the tumor size in a given state by preventing the formation of new blood vessels. In this paper, a novel model-free method based on reinforcement learning (RL) framework is used to design a closed-loop control of anti-angiogenic drug dosing administration. A Q-learning algorithm is developed for the drug dosing closed-loop control. This controller is designed using two different values of the maximum drug dosage to reduce the tumor volume up to a desired value. The mathematical model of tumor growth under anti-angiogenic inhibitor is used to simulate a real patient. The effectiveness of the proposed method is shown through in silico simulation and its robustness to patient parameters variation is demonstrated. It is demonstrated that the tumor reaches its minimal volume in 84 days with maximum drug inlet of 30 mg/kg/day. Also, it is shown that the designed controller is robust with respect to ± 20% of tumor growth parameters changes. The proposed closed-loop reinforcement learning-based controller for cancer treatment using anti-angiogenic inhibitor provides an effective and novel result such that with a clinically valid and safe dosage of drug, the volume reduces up to 1mm3 in a reasonable short period compared to the literature.


Positive technology: a free mobile platform for the self-management of psychological stress.
We describe the main features and preliminary evaluation of Positive Technology, a free mobile platform for the self-management of psychological stress (http://positiveapp.info/). The mobile platform features three main components: (i) guided relaxation, which provides the user with the opportunity of browsing a gallery of relaxation music and video-narrative resources for reducing stress; (ii) 3D biofeedback, which helps the user learning to control his/her responses, by visualizing variations of heart rate in an engaging 3D environment; (iii) stress tracking, by the recording of heart rate and self-reports. We evaluated the Positive Technology app in an online trial involving 32 participants, out of which 7 used the application in combination with the wrist sensor. Overall, feedback from users was satisfactory and the analysis of data collected online indicated the capability of the app for reducing perceived stress levels. A future goal is to improve the usability of the application and include more advanced stress monitoring features, based on the analysis of heart rate variability indexes.


Polymorphism and divergence at three duplicate genes in Brassica nigra.
The CONSTANS-like gene family has been shown to evolve exceptionally fast in Brassicaceae. In the present study we analyzed sequence polymorphism and divergence of three genes from this family: COL1 (CONSTANS-LIKE 1) and two copies of CO (CONSTANS), COa and COb, in B. nigra. There was a significant fourfold difference in overall nucleotide diversity among the three genes, with BniCOb having twice as much variation as BniCOL1, which in turn was twice as variable as BniCOa. The ratio of nonsynonymous-to-synonymous substitutions (dN/dS) was high for all three genes, confirming previous studies. While we did not detect evidence of selection at BniCOa and BniCOb, there was a significant excess of polymorphic synonymous mutations in a McDonald-Kreitman test comparing COL1 in B. nigra and A. thaliana. This is apparently the result of an increase in selective constraint on COL1 in B. nigra combined with a decrease in A. thaliana. In conclusion, a complex scenario involving both demography and selection seems to have shaped the pattern of polymorphism at the three genes.


[Assessment of a leprosy control program in a hyperendemic county in the State of Maranhão, Brazil, 1991-1995].
This is a descriptive study to assess the leprosy control program in the municipality of Buriticupu in Maranhão State, Brazil. The records of 214 patients with different forms of leprosy were studied. Patients were treated at a health center of the Federal University in Maranhão located in the above-mentioned municipality. The study population was comprised of 110 cases with paucibacillary leprosy (PB) and 104 with multibacillary leprosy (MB). The patients were registered between January 1991 and December 1995. Data on the form of the disease, number of contacts registered, examined, and assessed, degree of disability at the beginning and end of treatment, and the register's status were collected on a form designed specifically for this purpose. Analysis of results was based on operational guidelines developed by the Ministry of Health. There was a slight predominance of the PB form. Observation of patients with physical disabilities at the beginning and end of treatment was low, as were levels of successful treatment and examined contacts. There was a high dropout level. The program was considered "low-level performance" for all indicators used in the study.


Artificial feedback for remotely supervised training of motor skills.
Electromyographic (EMG) biofeedback can be used to train motor functions at a distance, which makes therapy at home a possibility. To enable patients to train properly without the presence of a therapist, artificial feedback is considered essential. We studied the combined effect of age and timing of artificial feedback on training muscle relaxation in 32 healthy subjects (younger: 20-35 years; older: 55-70 years). All subjects improved their performance significantly (F = 6.1, P<0.001). The effect of different timing of feedback (feedback provided during or after performance) was similar in young and older adults. However, this conclusion should be interpreted with caution owing to the small sample size. It can be argued that the artificial feedback used was too complicated for older adults to interpret. When designing remotely supervised treatment programmes, one should consider carefully the way that artificial feedback is being applied as it may enable (elderly) subjects to train without the presence of a therapist.


[Early detection of mental disorders in infants or children].
Early detection of babies or children mental disorders enables specific diagnosis and care in the very early life of the distressed children. It is critical to make all physicians able to identify early signs. Autism, depression, anguage and learning disorders are pathologies whose early diagnosis enables early care thus limiting the negative impact on child and family lives. In the specific context of child abuse, it is our duty to detect alarming signs as soon as possible to fully protect the abused baby or child.


Factors Influencing Telehealth Implementation and Use in Frontier Critical Access Hospitals: Qualitative Study.
Telehealth has potential to help individuals in rural areas overcome geographical barriers and to improve access to care. The factors that influence the implementation and use of telehealth in critical access hospitals are in need of exploration. The aim of this study is to understand the factors that influenced telehealth uptake and use in a set of frontier critical access hospitals in the United States. This work was conducted as part of a larger evaluation of a Centers for Medicare & Medicaid Services-funded demonstration program to expand cost-based reimbursement for services for Medicare beneficiaries for frontier critical access hospitals. Our sample was 8 critical access hospitals in Montana, Nevada, and North Dakota that implemented the telehealth aspect of that demonstration. We reviewed applications and progress reports for the demonstration program and conducted in-person site visits. We used a semistructured discussion guide to facilitate conversations with clinical, administrative, and information technology staff. Using NVivo software (QSR International), we coded the notes from the interviews and then analyzed the themes. Several factors influenced the implementation and use of telehealth in critical access hospitals, including making changes to workflow and infrastructure as well as practitioner acceptance and availability. Participants also cited technical assistance and support for implementation as supportive factors. Frontier critical access hospitals may adopt telehealth to overcome challenges such as distance from specialty practitioners and workforce challenges. Telehealth can be used for provider-to-patient and provider-to-provider interactions to improve access to care, remove barriers, and improve quality. However, the ability of telehealth to improve outcomes is limited by factors such as workflow and infrastructure changes, practitioner acceptance and availability, and financing.


[Expression in Escherichia coli cells of mutant human interferon alpha2].
cDNA library was obtained from mRNA isolated from human leukocytes induced by Newcastle disease virus. Clones containing cDNA for alpha 2-interferons were identified by colony hybridization with two synthetic hexadecanucleotides. One of the positive clones contained a NH2-terminal part of cDNA of human interferon identical to cDNA for IFN-alpha 2. The only difference between these two clones was the Ser-8 leads to Asn-8 substitution in deduced sequenced of mature interferons. This mutant interferon, named alpha 2, was expressed in E. coli and its properties were compared with those of interferon alpha 2.


In vivo effects of propyl gallate, a novel Ca(2+) sensitizer, in a mouse model of dilated cardiomyopathy caused by cardiac troponin T mutation.
We have previously demonstrated that propyl gallate has a Ca(2+) sensitizing effect on the force generation in membrane-permeabilized (skinned) cardiac muscle fibers. However, in vivo beneficial effects of propyl gallate as a novel Ca(2+) sensitizer remain uncertain. In the present study, we aim to explore in vivo effects of propyl gallate. We compared effects of propyl gallate on ex vivo intact cardiac muscle fibers and in vivo hearts in healthy mice with those of pimobendan, a clinically used Ca(2+) sensitizer. The therapeutic effect of propyl gallate was investigated using a mouse model of dilated cardiomyopathy (DCM) with reduced myofilament Ca(2+) sensitivity due to a deletion mutation ΔK210 in cardiac troponin T. Propyl gallate, as well as pimobendan, showed a positive inotropic effect. Propyl gallate slightly increased the blood pressure without changing the heart rate in healthy mice, whereas pimobendan decreased the blood pressure probably through vasodilation via inhibition of phosphodiesterase and increased the heart rate. Propyl gallate prevented cardiac remodeling and systolic dysfunction and significantly improved the life-expectancy of knock-in mouse model of DCM with reduced myofilament Ca(2+) sensitivity due to a mutation in cardiac troponin T. On the other hand, gallate, a similarly strong antioxidant polyphenol lacking Ca(2+) sensitizing action, had no beneficial effects on the DCM mice. These results suggest that propyl gallate might be useful for the treatment of inherited DCM caused by a reduction in the myofilament Ca(2+) sensitivity.


Continuous renal replacement therapy after cardiac surgery in patients with acute renal failure.
Acute renal failure is an important adverse effect of cardiopulmonary bypass that can result in high mortality or morbidity rates. It can be treated with continuous renal replacement therapy after cardiac surgery. The purpose of this study was to determine the factors associated with the mortality and incidence of acute renal failure in patients of post cardiac surgery. Patients (1564) who underwent cardiac surgery between January 2007 and January 2012 and treated with continuous renal replacement therapy were included (N=40). Patients with previous renal disorders were excluded. A retrospective analysis was carried out. Overall, continuous renal replacement therapy was used in 40 (2.6%) patients. The mean age was 62.7 ± 11 years. Mean duration of cardiopulmonary bypass was 166 ± 80 min, and aorta cross-clamping time was 97 ± 35 min. The patients' mean pretherapy creatinine level and mean creatinine level before hospital discharge were 3.3 ± 1.1 mg/dL and 1.1 ± 0.4 mg/dl, respectively. Thirty-day mortality was 35%. Only 6 patients required long-term renal replacement therapy. Conclusion Acute renal failure requiring hemodialysis after cardiac surgery is associated with higher mortality and morbidity and prolonged hospital stay. Early renal recovery with continuous renal replacement therapy seems to offer an evident survival benefit. CONTINUOUS: renal replacement therapy may represent an important therapy and reduce mortality rates. We believe that these rates might decrease even more with detailed preoperative evaluation and meticulous postoperative care with collaborative management.


Alcoholism and Alcoholics Anonymous in U.S. films, 1945-1962: the party ends for the "wet generations".
At least 34 Hollywood films were made between The Lost Weekend (1945) and Days of Wine and Roses (1962) with an alcoholic as a major character; six depicted an Alcoholics Anonymous-like self-help organization. Presentations of alcoholism's origin as mysterious competed with psychodynamic interpretations and situational explanations, often in the same film and sometimes concerning the same character. Will-power and mutual help were each frequently shown as paths to recovery, whereas neither professional treatment nor AA's spiritual side were often shown. For the women alcoholics (17 of 39 depicted), drinking went with sexuality, but for men it replaced it. "Creative" occupations were hugely overrepresented among screen alcoholics, in part reflecting the personal struggles with drinking of the movies' creators. These writers, actors and directors were drawn from the "wet generations" of middle-class youth, who had adopted heavy drinking in their college years as a generational revolt against "Victorian morality." Alcoholics Anonymous was founded and peopled by members of these same cohorts as a generational solution to their eventual life-problems. The flurry of alcoholism films represented a parallel and overlapping generational response.


Sharing innovation: the case for technology standards in health professions education.
Information technologies have provided fertile ground for innovation in healthcare education, but too often these innovations have been limited in scope and impact. One way of addressing these limitations is the development of common and open technology standards to scale innovation across organizational boundaries. Research on the diffusion of standards indicates that environmental forces, such as regulatory changes, top-down management support, and feasibility are key determinants of standards adoption. This paper describes the perspective and work of MedBiquitous, the only internationally recognized standards body in healthcare education. Many innovators are implementing MedBiquitous healthcare education standards to effect change within and across organizations. In a resource-constrained and knowledge intensive domain such as healthcare education, collaboration is an imperative. Technology standards are essential to raise the quality of healthcare education and assessment in a cost-effective manner.


Changes in antibiotic resistance in equine bacterial ulcerative keratitis (1991-2000): 65 horses.
To document changes in antibiotic resistance of organisms in cases of equine bacterial ulcerative keratitis over a 10-year time period. A retrospective study. Medical records of equine patients with bacterial ulcerative keratitis seen at the University of Florida's VMTH for the years 1991-2000 were reviewed. All cases of equine bacterial ulcerative keratitis for the above mentioned years were examined. Bacterial isolates were identified and subjected to Kirby-Bauer disc diffusion method sensitivity tests. Antibiotics used in the sensitivity tests included bacitracin, ampicillin, gentamicin, chloramphenicol, polymyxin B, trimethoprim-sulfa, neomycin, kanamycin, carbenicillin, tobramycin and enrofloxacin. A total of 65 bacterial isolates were subjected to sensitivity testing. Of these isolates, Pseudomonas aeruginosa accounted for 14 of the bacterial isolates (22%), Streptococcus equi subspecies zooepidemicus accounted for 13 of the bacterial isolates (20%), and Staphylococcus aureus accounted for four of the isolates (6%). A statistically significant increase in resistance of Pseudomonas aeruginosa isolates to the antibiotics gentamicin and tobramycin was found between the isolates from 1992 to 1998 and those from 1999 to 2000. An increase in resistance of Streptococcus equi subspecies zooepidemicus to gentamicin was found between the isolates from 1993 to 1997 and those from 1998 to 2000. Streptococcus equi subspecies zooepidemicus and Pseudomonas aeruginosa were the most common organisms isolated from cases of equine bacterial keratitis referred to the University of Florida's VMTH for the years 1991-2000. There appears to be an increase in resistance of Streptococcus equi subspecies zooepidemicus to gentamicin over the past 10 years. In addition, there is a significant increase in resistance of Pseudomonas aeruginosa to both gentamicin and tobramycin over the same time period.


Incremental adoption of information security in health-care organizations: implications for document management.
The incremental adoption of electronic media in U.S. health care has created increased risk of security and privacy violations in provider organizations. Protective regulatory efforts have been proposed to address ineffective security of patient information, with severe noncompliance penalties. Using data from a nationwide survey of health information managers, this study examines how industry-wide knowledge management trends may influence the degree of security program adoption in health-care organizations. Results suggest that significant nonadoption of mandated security measures continues to occur across the health-care industry. Paper-based systems still prevail, and computerized settings tend to have less security measures. Implications for document management and knowledge policy are discussed.


Metabolic brain imaging with glucosamine CEST MRI: in vivo characterization and first insights.
The utility of chemical exchange saturation transfer (CEST) MRI for monitoring the uptake of glucosamine (GlcN), a safe dietary supplement, has been previously demonstrated in detecting breast cancer in both murine and human subjects. Here, we studied and characterized the detectability of GlcN uptake and metabolism in the brain. Following intravenous GlcN administration in mice, CEST brain signals calculated by magnetization transfer ratio asymmetry (MTRasym) analysis, were significantly elevated, mainly in the cortex, hippocampus, and thalamus. The in vivo contrast remained stable during 40 min of examination, which can be attributed to GlcN uptake and its metabolic products accumulation as confirmed using 13C NMR spectroscopic studies of brain extracts. A Lorentzian multi-pool fitting analysis revealed an increase in the hydroxyl, amide, and relayed nuclear Overhauser effect (rNOE) signal components after GlcN treatment. With its ability to cross the blood-brain barrier (BBB), the GlcN CEST technique has the potential to serve as a metabolic biomarker for the diagnosis and monitoring various brain disorders.


An investigation of the psychometric properties of the Chinese (Cantonese) version of Subjective Index of Physical and Social Outcome (SIPSO).
The objectives of this study were 1) to translate and make cultural adaptations to the English version of the SIPSO questionnaire to create a Chinese (Cantonese) version, 2) evaluate the internal consistency, test-retest reliability the C-SIPSO questionnaire, and 3) compare the SIPSO-C scores of stroke survivors with different demographic characteristics to establish the discriminant validity of the questionnaire Design: Translation of questionnaire, cross sectional study. University-based clinical research laboratory. Subjects Community-dwelling chronic stroke survivors. Not applicable. Subjective Index of Physical and Social Outcome, Geriatric Depression Scale, 10-metre Walk test. Two bilingual professional translators translated the SIPSO questionnaire independently. An expert panel comprising five registered physiotherapists verified the content validity of the final version (C-SIPSO). C-SIPSO demonstrated good internal consistency (Cronbach's α = 0.83) and excellent test-retest reliability (ICC3,1 = 0.866) in ninety-two community dwelling chronic stroke survivors. Stroke survivors scored higher than 10 in the Geriatric Depression Scale ( U = 555.0, P < 0.001) and with the comfortable walking speed lower than 0.8ms-1 ( U = 726.5; P = 0.012) scored significantly lower on SIPSO-C. SIPSO-C is a reliable instrument that can be used to measure the level of community integration in community-dwelling stroke survivors in Hong Kong and southern China. Stroke survivors who were at high risk of minor depression and with limited community ambulation ability demonstrated a lower level of community integration as measured with SIPSO-C.


Prevalence and determinants of pre-term deliveries in the University of Ilorin Teaching Hospital, Ilorin, Nigeria.
In Nigeria, over 900,000 children under the age of five years die every year. Early neonatal death is responsible for a little over 20% of these deaths. Prematurity remains a significant cause of these early neonatal deaths. In some series, it is reported to be responsible for 60-70% of these deaths. This study aimed to determine the prevalence and determinants of pre-term deliveries at the University of Ilorin Teaching Hospital, Ilorin. This was a prospective cohort study conducted over a 9-month period at the University of Ilorin Teaching Hospital. Records of deliveries and data on maternal socio-biological and antenatal variables were collected during this period in order to determine the prevalence and determinants of pre-term deliveries. Out of the 2,489 deliveries that took place over a 9-month period, there were 293 pre-terms, giving a pre-term delivery rate of 120 per 1,000 deliveries. Of the total deliveries, 1,522 singleton deliveries that satisfied inclusion criteria were recruited; 185 of them were pre-term deliveries giving a case:control ratio of 1:7. Significant determinants of pre-term delivery identified were previous pre-term delivery (P=0.001; OR=3.55; 95% CI=1.71-7.30), antepartum hemorrhage (P=0.000; OR=8.95; 95%CI=4.06-19.78), premature rupture of the membranes (P=0.000; OR=6.48; 95%CI=4.33-9.67), maternal urinary tract infection (P=0.006; OR=5.89; 95%CI=1.16-27.57), pregnancy induced hypertension (P=0.007; OR=3.23; 95%CI=2.09-4.99), type of labor (P=0.000; OR=6.44; 95%CI=4.42-9.38) and booking status (P=0.000; OR=4.67; 95%CI=3.33-6.56). The prevalence of pre-term delivery was 120 per 1,000 live births. Factors significantly associated with pre-term delivery were low socio-economic class, previous pre-term delivery, antepartum hemorrhage, premature rupture of fetal membranes, urinary tract infection, pregnancy induced hypertension, induced labor, and booking elsewhere outside the teaching hospital.


IL-21 is produced by NKT cells and modulates NKT cell activation and cytokine production.
The common gamma-chain cytokine, IL-21, is produced by CD4(+) T cells and mediates potent effects on a variety of immune cells including NK, T, and B cells. NKT cells express the receptor for IL-21; however, the effect of this cytokine on NKT cell function has not been studied. We show that IL-21 on its own enhances survival of NKT cells in vitro, and IL-21 increases the proliferation of NKT cells in combination with IL-2 or IL-15, and particularly with the CD1d-restricted glycosphingolipid Ag alpha-galactosylceramide. Similar to its effects on NK cells, IL-21 enhances NKT cell granular morphology, including granzyme B expression, and some inhibitory NK receptors, including Ly49C/I and CD94. IL-21 also enhanced NKT cell cytokine production in response to anti-CD3/CD28 in vitro. Furthermore, NKT cells may be subject to autocrine IL-21-mediated stimulation because they are potent producers of this cytokine following in vitro stimulation via CD3 and CD28, particularly in conjunction with IL-12 or following in vivo stimulation with alpha-galactosylceramide. Indeed, NKT cells produced much higher levels of IL-21 than conventional CD4 T cells in this assay. This study demonstrates that NKT cells are potentially a major source of IL-21, and that IL-21 may be an important factor in NKT cell-mediated immune regulation, both in its effects on NK, T, and B cells, as well as direct effects on NKT cells themselves. The influence of IL-21 in NKT cell-dependent models of tumor rejection, microbial clearance, autoimmunity, and allergy should be the subject of future investigations.


Kaiso represses the cell cycle gene cyclin D1 via sequence-specific and methyl-CpG-dependent mechanisms.
Kaiso is the first member of the POZ family of zinc finger transcription factors reported to bind DNA with dual-specificity in both a sequence- and methyl-CpG-specific manner. Here, we report that Kaiso associates with and regulates the cyclin D1 promoter via the consensus Kaiso binding site (KBS), and also via methylated CpG-dinucleotides. The methyl-CpG sites appear critical for Kaiso binding to the cyclin D1 promoter, while a core KBS in close proximity to the methyl-CpGs appears to stabilize Kaiso DNA binding. Kaiso's binding to both sites was demonstrated in vitro using electrophoretic mobility shift assays (EMSA) and in vivo using Chromatin immunoprecipitation (ChIP). To elucidate the functional relevance of Kaiso's binding to the cyclin D1 promoter, we assessed Kaiso overexpression effects on a minimal cyclin D1 promoter-reporter that contains both KBS and CpG sites. Kaiso repressed this minimal cyclin D1 promoter-reporter in a dose-dependent manner and transcriptional repression occurred in a KBS-specific and methyl-CpG-dependent manner. Collectively our data validates cyclin D1 as a Kaiso target gene and demonstrates a mechanism for Kaiso binding and regulation of the cyclin D1 promoter. Our data also provides a mechanistic basis for how Kaiso may regulate other target genes whose promoters possess both KBS and methyl-CpG sites.


Absorption of phytol from dietary chlorophyll in the rat.
The fate of ingested chlorophyll-particularly of the phytol portion of the molecule-was studied. Uniformly (14)C-labeled pheophytin a (the Mg-free derivative of chlorophyll a) was prepared from an extract of tobacco leaves grown in (14)CO(2), and was administered by stomach tube to rats in which the thoracic duct had been cannulated. Only about 2% of the administered radioactivity was absorbed in 24 hr, largely into the thoracic duct lymph. Moreover, only a fraction of this lymph radioactivity was derived from phytol (i.e., was found in phytol, phytenic acid, or phytanic acid). The results indicated that not more than 1-2% of chlorophyll phytol is available for absorption by the rat. Similarly, after the administration of whole spinach or spinach extract (not labeled) to rats, only about 1% of the total phytol content was absorbed into the intestinal lymph. Nearly all of the administered phytol was found in the feces and the contents of the colon, and was still largely in the form of pheophytin. The study also indicated that little of the nonphytol portion of the chlorophyll molecule is absorbed.


The histologic response of soft tissue sarcoma to radiation therapy.
Twenty-seven patients with soft tissue sarcoma had preoperative radiotherapy, limb-sparing marginal surgical resection and whole-mount tumor histologic analysis. Incisional biopsy specimens before radiotherapy were reviewed for tumor type, grade, and extent of necrosis. Preoperative radiotherapy was given in either of two regimens: 13 patients received a mean total dose of 5250 cGy in one daily 180 to 200 cGy fractions and 14 patients a mean total dose of 4770 cGy in two daily fractions of 180 to 200 cGy separated by 4 hours. Twenty-one specimens had at least 80% necrosis or severely altered cells, a 3+ to 4+ response. Grade and size of the tumor appeared to be indicators of response to treatment rather than histologic type. Three of five patients (60%) with Grade 1, eight of 11 patients (73%) with Grade 2 lesions, and ten of 11 patients (91%) with Grade 3 tumors had 80% or greater necrosis or severely altered cells. For tumors 10 cm or less in greatest diameter, the 3+ to 4+ histologic response was seen in 12 of 14 patients (86%) whereas for lesions greater than 10 cm, this response was observed in nine of 13 patients (69%). For patients with Grade 2 or 3 soft tissue sarcoma, 13 of 14 patients (93%) treated with two fractions per day and two of four patients (50%) receiving one fraction per day exhibited significant response. All six patients treated twice daily for lesions greater than 10 cm had 3+ to 4+ histologic response compared to three of seven (43%) patients treated once per day. Therefore, grade and size of soft tissue sarcoma are important predictors of response to radiotherapy and preoperative twice daily radiotherapy may more likely permit the conservative surgical excision of sarcomas of borderline resectability.


Association between Cigarette Smoking Status and Composition of Gut Microbiota: Population-Based Cross-Sectional Study.
There have been few large-scale studies on the relationship between smoking and gut microbiota. We investigated the relationship between smoking status and the composition of gut microbiota. This was a population-based cross-sectional study using Healthcare Screening Center cohort data. A total of 758 men were selected and divided into three groups: never (n = 288), former (n = 267), and current smokers (n = 203). Among the three groups, there was no difference in alpha diversity, however, Jaccard-based beta diversity showed significant difference (p = 0.015). Pairwise permutational multivariate analysis of variance (PERMANOVA) tests between never and former smokers did not show a difference; however, there was significant difference between never and current smokers (p = 0.017) and between former and current smokers (p = 0.011). Weighted UniFrac-based beta diversity also showed significant difference among the three groups (p = 0.038), and pairwise PERMANOVA analysis of never and current smokers showed significant difference (p = 0.01). In the analysis of bacterial composition, current smokers had an increased proportion of the phylum Bacteroidetes with decreased Firmicutes and Proteobacteria compared with never smokers, whereas there were no differences between former and never smokers. In conclusion, gut microbiota composition of current smokers was significantly different from that of never smokers. Additionally, there was no difference in gut microbiota composition between never and former smokers.


[3-Hydroxyanthranilic acid in the blood of patients with kidney tumors].
Antigen containing the tryptophan metabolite -- 3-oxyanthranilic acid-(3-OAA-antigen) was determined by agarose precipitation method, using specific immune rabbit sera in 85 patients, admitted with the primary diagnosis of renal tumor. Among 85 patients 3-OAA-antigen was found in blood sera in 62 patients. Among 23 patients in whom 3-OAA-antigen was not revealed in 20 -- the diagnosis of renal tumor failed to be supported. The authors conclude, that it is possible to use the reaction of 3-OAA-antigen detection for establishing the diagnosis of tumors of the kidneys.


Artificial cornea transplantation and visual rehabilitation: an integrative review.
Due to the development of complications and the biocompatibility and scarcity of transplant donor tissues, artificial corneas, which can be used for the rehabilitation of optical functions, have been developed. The current study aimed to analyze the visual rehabilitation effects of the Boston type I keratoprosthesis, Boston type II keratoprosthesis, Aurolab keratoprosthesis, osteo-odonto-keratoprosthesis, and tibial bone keratoprosthesis. Results showed that the Boston type I keratoprosthesis was the most effective for visual rehabilitation in patients with moist ocular surfaces. The Aurolab keratoprosthesis had a lower efficacy for visual rehabilitation. Nevertheless, it is still a viable option for individuals in economically restricted countries. In patients with dry eyes, the Boston type II keratoprosthesis was associated with the best visual rehabilitation. However, the final visual acuity of patients who received osteo-odonto-keratoprosthesis and tibial bone keratoprosthesis implantation was not evaluated as the necessary information was not available.


Which Density Functional Should Be Used to Describe Protonated Water Clusters?
Protonated water cluster is one of the most important hydrogen-bond network systems. Finding an appropriate DFT method to study the properties of protonated water clusters can substantially improve the economy in computational resources without sacrificing the accuracy compared to high-level methods. Using high-level MP2 and CCSD(T) methods as well as experimental results as benchmark, we systematically examined the effect of seven exchange-correlation GGA functionals (with BLYP, B3LYP, X3LYP, PBE0, PBE1W, M05-2X, and B97-D parametrizations) in describing the geometric parameters, interaction energies, dipole moments, and vibrational properties of protonated water clusters H+(H2O)2-9,12. The overall performance of all these functionals is acceptable, and each of them has its advantage in certain aspects. X3LYP is the best to describe the interaction energies, and PBE0 and M05-2X are also recommended to investigate interaction energies. PBE0 gives the best anharmonic frequencies, followed by PBE1W, B97-D and BLYP methods. PBE1W, B3LYP, B97-D, and X3LYP can yield better geometries. The capability of B97-D to distinguish the relative energies between isomers is the best among all the seven methods, followed by M05-2X and PBE0.


Improving Digital Hospital Transformation: Development of an Outcomes-Based Infrastructure Maturity Assessment Framework.
Digital transformation in health care is being driven by the need to improve quality, reduce costs, and enhance the patient experience of health care delivery. It does this through both the direct intervention of technology to create new diagnostic and treatment opportunities and also through the improved use of information to create more engaging and efficient care processes. In a modern digital hospital, improved clinical and business processes are often driven through enhancing the information flows that support them. To understand an organization's ability to transform their information flows requires a clear understanding of the capabilities of an organization's information technology infrastructure. To date, hospital facilities have been challenged by the absence of uniform ways of describing this infrastructure that would enable them to benchmark where they are and create a vision of where they would like to be. While there is an industry assessment measure for electronic medical record (EMR) adoption using the Healthcare Information and Management Systems Society Analytics EMR Adoption Model, there is no equivalent for assessing the infrastructure and associated technology capabilities for digital hospitals. Our aim is to fill this gap, as hospital administrators and clinicians need to know how and why to invest in information infrastructure to support health information technology that benefits patient safety and care. Based on an operational framework for the Capability Maturity Model, devised specifically for health care, we applied information use characteristics to define eight information systems maturity levels and associated technology infrastructure capabilities. These levels are mapped to user experiences to create a linkage between technology infrastructure and experience outcomes. Subsequently, specific technology capabilities are deconstructed to identify the technology features required to meet each maturity level. The resulting assessment framework clearly defines 164 individual capabilities across the five technology domains and eight maturity levels for hospital infrastructure. These level-dependent capabilities characterize the ability of the hospital's information infrastructure to support the business of digital hospitals including clinical and administrative requirements. Further, it allows the addition of a scoring calculation for each capability, domain, and the overall infrastructure, and it identifies critical requirements to meet each of the maturity levels. This new Infrastructure Maturity Assessment framework will allow digital hospitals to assess the maturity of their infrastructure in terms of their digital transformation aligning to business outcomes and supporting the desired level of clinical and operational competency. It provides the ability to establish an international benchmark of hospital infrastructure performance, while identifying weaknesses in current infrastructure capability. Further, it provides a business case justification through increased functionality and a roadmap for subsequent digital transformation while moving from one maturity level to the next. As such, this framework will encourage and guide information-driven, digital transformation in health care.


Recent advances in social skills training for schizophrenia.
Social skills training consists of learning activities utilizing behavioral techniques that enable persons with schizophrenia and other disabling mental disorders to acquire interpersonal disease management and independent living skills for improved functioning in their communities. A large and growing body of research supports the efficacy and effectiveness of social skills training for schizophrenia. When the type and frequency of training is linked to the phase of the disorder, patients can learn and retain a wide variety of social and independent living skills. Generalization of the skills for use in everyday life occurs when patients are provided with opportunities, encouragement, and reinforcement for practicing the skills in relevant situations. Recent advances in skills training include special adaptations and applications for improved generalization of training into the community, short-term stays in psychiatric inpatient units, dually diagnosed substance abusing mentally ill, minority groups, amplifying supported employment, treatment refractory schizophrenia, older adults, overcoming cognitive deficits, and negative symptoms as well as the inclusion of social skills training as part of multidimensional treatment and rehabilitation programs.


Decision aid on radioactive iodine treatment for early stage papillary thyroid cancer: update to study protocol with follow-up extension.
Patient decision aids (P-DAs) are used to inform patients about healthcare choices, but there is limited knowledge about their longer term effects, beyond the time period of decision-making. We developed a computerized P-DA that explains the choice of radioactive iodine (RAI) adjuvant treatment or no RAI, for patients with low risk papillary thyroid cancer after total thyroidectomy. The original protocol for a randomized controlled trial, comparing the use of the P-DA (with usual care) to usual care alone, has been published in Trials http://www.trialsjournal.com/content/11/1/81. We found that P-DA (with usual care) significantly improved patients' medical knowledge at the time of decision-making (primary outcome) compared to usual care alone (control). In this update, we present the protocol for an extended follow-up study (15 to 23 months post-randomization), including qualitative and quantitative methods. The patient outcomes evaluated using quantitative questionnaires include: the degree to which patients feel well-informed about their RAI treatment choice, decision satisfaction, decision regret, cancer-related worry, mood, and trust in the treating physician. The qualitative component explores the experiences of RAI treatment decision-making, treatment satisfaction, and trial participation in a representative subgroup of patients. Extended follow-up study results will be described for the entire study population, and data will be compared between the P-DA and control groups. This mixed methods extended follow-up study will provide data on long term outcomes, relating to the use of a computerized P-DA in decision-making about adjuvant RAI treatment in early stage papillary thyroid cancer. Our results are intended to inform future research in this area, particularly relating to long term effects of the use of P-DAs in making healthcare choices. Clinicaltrials.gov identifier NCT01083550, registered 24 February 2010 and last updated 5 January 2015.


Regenerative Effect of Bone Marrow-derived Mesenchymal Stem Cells in Thioacetamide-induced Liver Fibrosis of Rats.
The present study determined the regenerative effect of bone marrow-derived stem cells (BMSCs) on thioacetamide (TA)-induced liver fibrosis in rats. A total of 30 male Wistar rats were randomly divided into sham control and treatment groups. The rats of the sham control group were subdivided into three groups and sampled on the 14th, 18th, and 20th weeks after fibrosis induction. The rats of the treatment group were subdivided into two groups and sampled on the 4th and 6th weeks after BMSCs treatment. Fibrosis was induced by the intraperitoneal administration of 200 mg/kg of TA twice a week for a period of 14 weeks. All the animals underwent liver function tests and histopathologic evaluation 4 and 6 weeks after BMSCs transplantation. The BMSCs were characterized using osteogenic induction and reverse transcription-polymerase chain reaction. The BMSCs were plastic adherent, spindle-shaped, and positive for osteogenic differentiation. They expressed CD73 and were negative for CD45. The infiltration of inflammatory cells and deposition of collagen fibers were noticed after TA administration. A significant decline in inflammatory cells and a healing process were detected 4 weeks after cell transplantation. The amelioration in hepatic tissue was significant 6 weeks after cell therapy. Following the injection of BMSCs, a nonsignificant decrease was visible in aspartate transaminase level; however, this decline was significant for alanine aminotransferase level. The alkaline phosphatase and albumin levels showed an increasing trend after cell administration. The transplantation of BMSCs resulted in a significant regenerative effect after hepatic injuries. Therefore, it was shown that BMSCs transplantation can open a new window and be a therapy of choice in the amelioration of liver fibrosis.