Non-invasive imaging of endothelial progenitor cells in tumor neovascularization using a novel dual-modality paramagnetic/near-infrared fluorescence probe.
Bone-marrow derived endothelial progenitor cells (EPCs) play an important role in tumor neovasculature. Due to their tumor homing property, EPCs are regarded as promising targeted vectors for delivering therapeutic agents in cancer treatment. Consequently, non-invasive confirmation of targeted delivery via imaging is urgently needed. This study shows the development and application of a novel dual-modality probe for in vivo non-invasively tracking of the migration, homing and differentiation of EPCs. The paramagnetic/near-infrared fluorescence probe Conjugate 1 labeled EPCs were systemically transplanted into mice bearing human breast MDA-MB-231 tumor xenografts. Magnetic resonance imaging (MRI) and near-infrared (NIR) fluorescence optical imaging were performed at different stages of tumor development. The homing of EPCs and the tumor neovascularization were further evaluated by immunofluorescence. Conjugate 1 labeled EPCs can be monitored in vivo by MRI and NIR fluorescence optical imaging without altering tumor growth for up to three weeks after the systemic transplantation. Histopathological examination confirmed that EPCs were recruited into the tumor bed and then incorporated into new vessels two weeks after the transplantation. Tumor size and microvessel density was not influenced by EPCs transplantation in the first three weeks. This preclinical study shows the feasibility of using a MRI and NIR fluorescence optical imaging detectable probe to non-invasively monitor transplanted EPCs and also provides strong evidence that EPCs are involved in the development of endothelial cells during the tumor neovascularization.


A role for SENSITIVE TO FREEZING2 in protecting chloroplasts against freeze-induced damage in Arabidopsis.
The sensitive to freezing2 (SFR2) gene has an important role in freezing tolerance in Arabidopsis thaliana. We show that homologous genes are present, and expressed, in a wide range of terrestrial plants, including species not able to tolerate freezing. Expression constructs derived from the cDNAs of a number of different plant species, including examples not tolerant to freezing, are able to complement the freezing sensitivity of the Arabidopsis sfr2 mutant. In Arabidopsis the SFR2 protein is localized to the chloroplast outer envelope membrane, as revealed by the analysis of transgenic plants expressing SFR2 fusions to GFP, by confocal microscopy, and by the immunological analysis of isolated chloroplasts treated with thermolysin protease. Moreover, the chloroplasts of the sfr2 mutant show clear evidence of rapid damage after a freezing episode, suggesting a role for SFR2 in the protection of the chloroplast.


Structure-activity relationship study of ProxyPhos chemosensors for the detection of proximal phosphorylation and other phosphate species.
Chemosensors for the detection of phosphate-containing biological species are in high need. Detection of proximally phosphorylated sites of PPi and those found in peptides and proteins has been demonstrated using chemosensors containing pyrene, as a fluorescent reporter, and a Zn2+-chelate, as a phosphate-binding group. Using these sensors, detection of proximal phosphate groups is afforded by binding of at least two of the sensor molecules to the adjacent phosphates, via the Zn2+ centres, leading to excimer formation between the pyrene groups and the corresponding shift in emission from 376 to 476 nm. Although several reports of this chemosensor class have been made, no detailed studies of selectivity of these sensors among major phosphate targets have been reported. In this study, a library of this class of chemosensors, termed ProxyPhos, which contained various linkers and Zn2+-chelating groups (i.e. DPA, cyclen and cyclam), was prepared and the effects of structural variation on the sensing efficiency and selectivity were evaluated among proximally phosphorylated peptides, proteins, nucleotides, Pi and PPi. As a result of this study, we have identified ProxyPhos library members that are most suitable for the detection of proximally phosphorylated peptides, PPi, UTP, and a DpYD peptide motif, and have generally provided a foundation for the selection of ProxyPhos chemosensors for further development of specific biologically relevant assays. The broad utility of ProxyPhos is further supported by the demonstrated lack of these sensors' cytotoxicity, ability to rapidly permeate into live and fixed cells and compatibility with gel staining methods.


Temporomandibular disorders in 19-year-old Korean men.
The purpose of this study was to determine the prevalence and the nature of the relationships between 3 temporomandibular joint disease (TMD) symptoms and symptoms of associated structures. This study was designed to rule out the effect from the uneven composition of the samples on TMD symptoms. The samples were collected from subjects who were of the same age, gender, district, and race. Nineteen-year old men (n = 27,978) were selected and investigated by means of questionnaires and clinical examinations. The prevalence of each symptom was studied and tried to determine the effects of the TMD-associated signs on the TMD signs. The indices allocated to reflect the TMD signs and symptoms and the others were dichotomized for bivariate analysis. The predictor variables were headache, neck pain, referred pain, stress, past trauma history in the TMJ, past TMJ dislocation, bruxism, and clenching. The outcome variables were mouth opening limitation, TMJ pain on rest, and TMJ pain during function. The incidence of masticatory muscle stiffness was 17.8%; TMJ sounds, 14.3%; headache, 7.2%; neck pain, 13.5%; bruxism, 8.4%; and clenching, 9.9%. Stress occurred in 12.8%, past trauma history in 11%, and previous joint dislocation in 2.5%. The experience of dislocation in the TMJ was found to be the most important risk factor in terms of mouth opening limitation (odds ratio, 4.08, P <.0001), joint pain during function (odds ratio, 5.50, P <.0001), and joint pain in the rest state (odds ratio, 4.63, P <.0001). Referred pain and the experience of trauma in TMJ were the secondary risk factors in terms of joint pain and referred pain and the stress in terms of mouth opening limitation. Considering referred pain can be induced by TMD, stress may be more related to mouth opening limitation (odds ratio, 2.18, P <.0001), and the experience of trauma in TMJ may be more related to pain in the rest state (odds ratio, 2.56, P <.0001) and during function (odds ratio, 2.47, P <.0001). The prevalence of TMD signs and symptoms as determined by this examination was in accord with the findings in women or mixed samples of other workers. Prior experience of a dislocated disc was found to be the most risky factor in TMD. Stress was related to limitations of mouth opening, and the experience of trauma in the TMJ was found to be related to pain in the joint region. Bruxism may not be a direct risk factor in TMD, and the clenching habit found to be more harmful than bruxism.


Mechanistic Multi-Tissue Modeling of Glucocorticoid-Induced Leucine Zipper Regulation: Integrating Circadian Gene Expression with Receptor-Mediated Corticosteroid Pharmacodynamics.
The glucocorticoid-induced leucine zipper (GILZ) is an important mediator of anti-inflammatory corticosteroid action. The pharmacokinetic/pharmacodynamic/pharmacogenomic effects of acute and chronic methylprednisolone (MPL) dosing on the tissue-specific dynamics of GILZ expression were examined in rats. A mechanism-based model was developed to investigate and integrate the role of MPL and circadian rhythms on the transcriptional enhancement of GILZ in multiple tissues. Animals received a single 50-mg/kg intramuscular bolus or a 7-day 0.3-mg/kg/h subcutaneous infusion of MPL and were euthanized at several time points. An additional group of rats were euthanized at several times and served as 24-hour light/dark (circadian) controls. Plasma MPL and corticosterone concentrations were measured by high-performance liquid chromatography. The expression of GILZ and glucocorticoid receptor (GR) mRNA was quantified in tissues using quantitative real-time reverse-transcription polymerase chain reaction. The pharmacokinetics of MPL were described using a two-compartment model. Mild-to-robust circadian oscillations in GR and GILZ mRNA expression were characterized in muscle, lung, and adipose tissues and modeled using Fourier harmonic functions. Acute MPL dosing caused significant down-regulation (40%-80%) in GR mRNA and enhancement of GILZ mRNA expression (500%-1080%) in the tissues examined. While GILZ returned to its rhythmic baseline following acute dosing, a new steady-state was observed upon enhancement by chronic dosing. The model captured the complex dynamics in all tissues for both dosing regimens. The model quantitatively integrates physiologic mechanisms, such as circadian processes and GR tolerance phenomena, which control the tissue-specific regulation of GILZ by corticosteroids. These studies characterize GILZ as a pharmacodynamic marker of corticosteroid actions in several tissues.


Laser-enhanced ionization detection of trace copper in high salt matrices.
Laser-enhanced ionization (LEI) is used to determine trace levels of metals in high salt matrices, an analysis that is difficult by conventional methods. Copper is presented in detail to demonstrate the capability of the method. Three-dimensional spectra of the stepwise excitation of copper are presented which illustrate the one photon, stepwise, and two-photon transitions. Seven copper transitions have been studied for analytical utility, and detection limits have been determined for each. Ionization interferences were accommodated by both matrix matching and separation of the interferences using ion exchange resin. Absolute determinations at the 0.05-ng level are possible with the use of a Teflon microsampling cup for low volume quantitative analysis. In addition to copper, silver, cobalt, iron, and nickel have been detected within the same dye tuning range. Twelve new LEI transitions have been identified for these elements along with detection limits.


Fatty Acids and Phenolic Profiles of Extravirgin Olive Oils from Selected Italian Cultivars Introduced in Southwestern Province of Pakistan.
Mediterranean olive trees have been cultivated in Pakistan for decades to promote olive cultivation and use of olive oil. The qualitative characteristics of seven mono and one multi-varietal extra virgin olive oils (EVOOs) extracted from Italian cultivars grown in different areas of Balochistan a southwestern province of Pakistan were evaluated. Present study aims to assess the impact of bioclimatological change on biochemical profile of exotic cultivars. The dominating fatty acids found in analyzed EVOOs were oleic (65-72%), linoleic (10.61-18.33%) and palmitic acids (12-16%). The tocopherols α, (β+γ) and δ contents showed a great diversity which ranged from (60-408) mg/kg while, total phenol concentration ranged from (200-370) mg/kg. The analyses of phenolic compounds revealed the presence of phenolic acids, phenolic alcohols, secoiridoids, flavonoids, oleuropein and verbascosides. One-way ANOVA revealed significant differences (p < 0.05) regarding studied parameters. Principal component analysis (PCA) was applied to identify the main components and to classify samples into groups in terms of fatty acids and phenolic profiles. The first group (Frantoio, Moraiolo, Pendolino, Multi-varietal mixture) characterized by high amount of oleic acid and MUFAs/PUFAs ratio. The second group (Maurino and Leccino) correlates with SFAs and third (Ottobrattica, Coratina) with PUFAs. Based on the PCA of phenolic profile the studied cultivars were divided into two main groups. Morialo, Pendolino and Maurino correlated with (phenolic acids, hydroxytyrosol, flavonoids and secoiridoids). Frantoio, Ottobrattica, Coratina, multi-varietal and Leccino were correlated with oleuropein, tyrosol and ligstroside aglycon. The obtained data was compared with those obtained from same cultivars in their original and/or different growing area. Marked differences were observed in the composition of oleic, linoleic, palmitic acids, secoiridoids and total phenolic contents. These differences could be due to change in geographical location and climatical condition of Balochistan. The cultivar Moraiolo has shown best adaptation and preserved its biochemical composition among all studied cultivars.


Axin expression delays herpes simplex virus-induced autophagy and enhances viral replication in L929 cells.
Axin, a negative regulator of the Wnt signaling pathway, plays a critical role in various cellular events including cell proliferation and cell death. Axin-regulated cell death affects multiple processes, including viral replication. For example, axin expression suppresses herpes simplex virus (HSV)-induced necrotic cell death and enhances viral replication. Based on these observations, this study investigated the involvement of autophagy in regulation of HSV replication and found axin expression inhibits autophagy-mediated suppression of viral replication in L929 cells. HSV infection induced autophagy in a time- and viral dose-dependent manner in control L929 cells (L-EV), whereas virus-induced autophagy was delayed in axin-expressing L929 cells (L-axin). Subsequent analysis showed that induction of autophagy by rapamycin reduced HSV replication, and that inhibiting autophagy by 3-methyladenine (3MA) and beclin-1 knockdown facilitated viral replication in L-EV cells. In addition, preventing autophagy with 3MA suppressed virus-induced cytotoxicity in L-EV cells. In contrast, HSV replication in L-axin cells was resistant to changes in autophagy. These results suggest that axin expression may render L929 cells resistant to HSV-infection induced autophagy, leading to enhanced viral replication.


Synthesis of adenosine triphosphate during release of intravesicular and membrane-bound calcium ions from passively loaded sarcoplasmic reticulum.
Sarcoplasmic reticulum isolated from rabbit skeletal muscle and incubated in a medium containing Ca2+ in the absence of ATP retains intravesicular and/or membrane-bound Ca2+. The synthesis of ATP coupled with the release of intravesicular Ca2+ is totally inhibited by the ionophore X-537A. Release of the membrane-bound Ca2+, retained after short periods of incubation (10min) or after release of the intravesicular Ca2+ by ionophore X-537A, still supports some synthesis of ATP. The ratios of Ca2+ released to ATP synthesized are 2.5-3.2, when bound and intravesicular Ca2+ are released simultaneously, and 3.1-4.0, when only bound Ca2+ is released. The results show that the synthesis of ATP by sarcoplasmic reticulum during release of passively accumulated Ca2+ by EGTA [ethanedioxybis(ethylamine)tetra-acetic acid] is accompanied by a loss of membrane-bound Ca2+.


Sustainability of mHealth Effects on Cardiometabolic Risk Factors: Five-Year Results of a Randomized Clinical Trial.
The long-term effects of mobile health (mHealth) interventions have not been documented, especially in resource-constrained settings. This study aimed to assess the effects of a 1-year mHealth intervention on blood pressure levels and body weight in low-resource urban settings in Peru, 4 years after the completion of the original study. Four years after the original Grupo de Investigación en Salud Móvil en America Latina (GISMAL) study, we attempted to contact the 212 individuals originally enrolled in the study in Peru. The primary outcomes were systolic and diastolic blood pressure levels and hypertension incidence. Secondary outcome measures were body weight, BMI, and self-reported target behaviors. The study personnel collecting the data were masked to the group assignment. Linear mixed models were used to evaluate the effects of the intervention on primary and secondary outcomes in an intention-to-treat analysis. Data from 164 (77.4%) of the 212 originally enrolled participants were available and analyzed (80 in the intervention group and 84 in the control group). The intervention did not result in changes in systolic (-2.54 mm Hg, 95% CI -8.23 to 3.15) or diastolic (3.41 mm Hg, 95% CI -0.75 to 7.57) blood pressure compared with the control group. The intervention reduced the risk of developing hypertension, but the result was not significant (risk ratio (RR) 0.76, 95% CI 0.45-1.28). However, those who received the intervention had lower body weight (-5.42 kg, 95% CI -10.4 to -0.48) and BMI (-2.56 kg/m2, 95% CI -4.46 to -0.66). In addition, compared to the control participants, those who received ≥50% of the scheduled calls during the intervention had greater reductions in body weight (-6.23 kg, 95% CI -11.47 to -0.99) and BMI (-2.81 kg/m2, 95% CI -4.77 to -0.85). An mHealth intervention comprising motivational interview calls and SMS text messaging appears to have effects on health 4 years after intervention completion. Although there were no effects on blood pressure levels, important reductions in body weight and BMI were seen 5 years after randomization. Thus, mHealth appears to be a promising preventive strategy for noncommunicable diseases in resource-constrained settings. Clinicaltrials.gov NCT01295216; https://clinicaltrials.gov/ct2/show/NCT01295216.


Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development.
The importance of folate in reproduction can be appreciated by considering that the existence of the vitamin was first suspected from efforts to explain a potentially fatal megaloblastic anemia in young pregnant women in India. Today, low maternal folate status during pregnancy and lactation remains a significant cause of maternal morbidity in some communities. The folate status of the neonate tends to be protected at the expense of maternal stores; nevertheless, there is mounting evidence that inadequate maternal folate status during pregnancy may lead to low infant birthweight, thereby conferring risk of developmental and long-term adverse health outcomes. Moreover, folate-related anemia during childhood and adolescence might predispose children to further infections and disease. The role of folic acid in prevention of neural tube defects (NTD) is now established, and several studies suggest that this protection may extend to some other birth defects. In terms of maternal health, clinical vitamin B12 deficiency may be a cause of infertility or recurrent spontaneous abortion. Starting pregnancy with an inadequate vitamin B12 status may increase risk of birth defects such as NTD, and may contribute to preterm delivery, although this needs further evaluation. Furthermore, inadequate vitamin B12 status in the mother may lead to frank deficiency in the infant if sufficient fetal stores of vitamin B12 are not laid down during pregnancy or are not available in breastmilk. However, the implications of starting pregnancy and lactation with low vitamin B12 status have not been sufficiently researched.


Crowders perturb the entropy of RNA energy landscapes to favor folding.
Biological macromolecules have evolved to fold and operate in the crowded environment of the cell. We have shown previously that molecular crowding stabilizes folded RNA structures. Here we report SAXS measurements on a 64 kDa bacterial group I ribozyme in the presence of mono- and divalent ions and PEG crowders of different molecular weight. These experiments show that crowders always stabilize the folded RNA, but this stabilization is weaker in NaCl solutions than MgCl2 solutions. Additionally, we find that RNAs with the same global structure, parametrized by Rg, have different scattering functions depending upon the ratio of electrostatic and entropic stabilization by ions and crowders, respectively. We quantify this difference using the scattering length per scattering volume and find that this ratio is larger for RNAs that fold in lower ionic strength solutions due to the higher crowder content. We conclude that lower RNA flexibility, or reduced configurational entropy, widens the free energy gap between the unfolded and folded RNA in crowded MgCl2 solutions.


Comparative understanding of UTS2 and UTS2R genes for their involvement in type 2 diabetes mellitus.
Several reports have shown that urotensin 2 (UTS2) and its receptor (UTS2R) are involved in glucose metabolism and insulin resistance, which lead to development of type 2 diabetes mellitus (T2DM) in humans. In the present study, we annotated both bovine UTS2 and UTS2R genes and identified 5 single nucleotide polymorphisms (SNPs) for the former gene and 14 mutations for the latter gene. Four mutations were genotyped on a Wagyu x Limousin reference population, including 6 F(1 )bulls, 113 F(1 )dams and ~250 F(2 )progeny. Among 12 phenotypes related to fat deposition and fatty acid composition, we observed that the UTS2 gene was significantly associated with the amount of skeletal saturated fatty acids, while its receptor (UTS2R) gene had significant effects on amounts of saturated and monounsaturated fatty acids, Delta(9) desaturase activity for converting 16:0 into 16:1, muscle fat (marbling) score and Longissimus Dorsi muscle area. However, in this population, these markers were not associated with subcutaneous fat depth or percent kidney, pelvic and heart fat. We also found that mutations in the promoter regions altered the promoter activities in both genes and coding SNPs might affect the mRNA stability in the UTS2R gene. Overall, our present study provides the first evidence that both UTS2 and UTS2R genes regulate skeletal muscle fat accumulation and fatty acid metabolism, thus indicating their potential pathological functions related to obesity and T2DM in humans.


[Occupational extreme stress factors determining psychological disorders in drivers].
To reveal drivers attitude to danger in their work, the researchers polled 100 taxi drivers according to special questionnaires. According to the poll, 80% of the drivers are afraid mostly of being attacked and robbed by the passengers. The study also covered various psychogenic and psychic disorders in 28 automobile drivers who faced robbery. Those disorders were mainly acute posttraumatic, stress and others.


Synthesis, characterization, and testing of supported Au catalysts prepared from atomically-tailored Au38(SC12H25)24 clusters.
Nearly monodispersed Au(38)(SC(12)H(25))(24) clusters (1.7 ± 0.2 nm) were synthesized using a modified Brust process while utilizing a "thiol etching" approach for the ligand exchange. HRTEM, MALDI, FTIR, and XAS analysis confirmed the formation of the 38-atom clusters in solution. This solution was used to impregnate a microporous TiO(2) support to give 0.7% Au(38)/TiO(2) catalyst. Subsequent drying in air and treatment with H(2)/He at 400 °C removed most of the sulfur ligands, and also increased the Au cluster size to 3.9 ± 0.96 nm. XPS and EXAFS analysis of this supported catalyst showed trace levels of residual sulfides, apparently located at the Au-TiO(2) interface. CO oxidation tests on these supported clusters show an activation energy and range of TOFs comparable to those reported by others. These results suggest that supported Au clusters of controllable size can be prepared with this thiol-ligated solution-based method, providing a new approach to the synthesis of these catalysts.


Investigation of Methodologies for Extracting Individual Brain Oscillations: Comparisons & Insights.
There is increasing evidence that the effects of non-invasive brain stimulation can be maximized when the applied intervention matches internal brain oscillations. Extracting individual brain oscillations is thus a necessary step for implementing personalized brain stimulation. In this context, different methods have been proposed for obtaining subject-specific spectral peaks from electrophysiological recordings. However, comparing the results obtained using different approaches is still lacking. Therefore, in the present work, we examined the following methodologies in terms of obtaining individual motor-related EEG spectral peaks: fast Fourier Transform analysis, power spectrum density analysis, wavelet analysis, and a principal component based time-frequency analysis. We used EEG data obtained when performing two different motor tasks - a hand grip task and a hand opening- and-closing task. Our results showed that both the motor task type and the specific method for performing the analysis had considerable impact on the extraction of subject-specific oscillation spectral peaks.Clinical Relevance-This exploratory study provides insights into the potential effects of using different methods to extract individual brain oscillations, which is important for designing personalized brain-machine-interfaces.


Expression and Reception: An Analytic Method for Assessing Message Production and Consumption in CMC.
This article presents an innovative methodology to study computer-mediated communication (CMC), which allows analysis of the multi-layered effects of online expression and reception. The methodology is demonstrated by combining the following three data sets collected from a widely tested eHealth system, the Comprehensive Health Enhancement Support System (CHESS): 1) a flexible and precise computer-aided content analysis; 2) a record of individual message posting and reading; and 3) longitudinal survey data. Further, this article discusses how the resulting data can be applied to online social network analysis and demonstrates how to construct two distinct types of online social networks - open and targeted communication networks - for different types of content embedded in social networks.


The underuse of carotid interventions in veterans with symptomatic carotid stenosis.
To examine the receipt of carotid intervention among eligible patients post stroke in the Veterans Health Administration (VA). We examined whether veterans admitted to a VA medical center in 2007 with a diagnosis of stroke and who were eligible for intervention, received carotid intervention in a period up to 6 months after their index hospitalization. We also examined whether demographics, comorbid conditions, stroke severity and availability of vascular intervention services were independently associated with receipt of intervention. Among the 5721 patients admitted, 253 ischemic stroke patients had evidence of some carotid stenosis and had data on side of stroke available. Among the 200 patients who had at least 50% to 99% stenosis of the carotid artery, 34 (17%) received intervention (95% confidence interval [CI], 11.79%-22.21%). In a multivariable model, black race and past history of diabetes were significantly associated with carotid intervention: An eligible black patient was 6 times more likely to NOT receive intervention compared to patients of other races (adjusted odds ratio [OR] = 6.54; 95% CI, 1.34-31.9), and a patient with diabetes was 3 times more likely to NOT receive intervention (adjusted OR = 3.38; 95% CI, 1.24- 9.24) compared to non-diabetics. Stroke severity and availability of vascular surgery services was not associated with receipt of intervention. Few patients with symptomatic carotid stenosis who were admitted with stroke to the VA received carotid intervention. Future research should be directed at improving access to this procedure among eligible patients in the VA.


Galectin-1-based tumour-targeting for gold nanostructure-mediated photothermal therapy.
To demonstrate delivery of Au nanocages to cells using the galectin-1 binding peptide anginex (Ax) and to demonstrate the value of this targeting for selective in vitro photothermal cell killing. Au nanocages were synthesised, coated with polydopamine (PDA), and conjugated with Ax. Tumour and endothelial cell viability was measured with and without laser irradiation. Photoacoustic (PA) mapping and PA flow cytometry were used to confirm cell targeting in vitro and in tissue slices ex vivo. Cell viability was maintained at ≥50% at 100 pM suggesting low toxicity of the nanocage alone. Combining the targeted construct (25 pM) with low power 808 nm laser irradiation for 10-20 min (a duration previously shown to induce rapid and sustained heating of Au nanocages [AuNC] in solution), resulted in over 50% killing of endothelial and tumour cells. In contrast, the untargeted construct combined with laser irradiation resulted in negligible cell killing. We estimate approximately 6 × 104 peptides were conjugated to each nanocage, which also resulted in inhibition of cell migration. Binding of the targeted nanocage reached a plateau after three hours, and cell association was 20-fold higher than non-targeted nanocages both in vitro and ex vivo on tumour tissue slices. A threefold increase in tumour accumulation was observed in preliminary in vivo studies. These studies demonstrate Ax's potential as an effective targeting agent for Au-based theranostics to tumour and endothelial cells, enabling photothermal killing. This platform further suggests potential for multimodal in vivo therapy via next-generation drug-loaded nanocages.


OSA and cardiorespiratory fitness: a review.
The effects of untreated obstructive sleep apnea (OSA) on cardiopulmonary function remain unclear. Cardiorespiratory fitness (CRF), commonly reflected by VO2 max measured during cardiopulmonary exercise testing, has gained popularity in evaluating numerous cardiopulmonary conditions and may provide a novel means of identifying OSA patients with the most clinically significant disease. This emerging testing modality provides simultaneous assessment of respiratory and cardiovascular function with results helping uncover evidence of evolving pathology in either organ system. In this review, we highlight the current state of the literature in regard to OSA and CRF with a specific focus on changes in cardiovascular function that have been previously noted. While OSA does not appear to limit respiratory function during exercise, studies seem to suggest an abnormal cardiovascular exercise response in this population including decreased cardiac output, a blunted heart rate response (ie, chronotropic incompetence), and exaggerated blood pressure response. Surprisingly, despite these observed changes in the cardiovascular response to exercise, results involving VO2 max in OSA remain inconclusive. This is reflected by VO2 max studies involving middle-aged OSA patients showing both normal and reduced CRF. As prior studies have not extensively characterized oxygen desaturation burden, we propose that reductions in VO2 max may exist in OSA patients with only the most significant disease (as reflected by nocturnal hypoxia). Further characterizing this relationship remains important as some research suggests that positive airway pressure therapy or aerobic exercise may improve CRF in patients with OSA. In conclusion, while it likely that severe OSA, via an abnormal cardiovascular response to exercise, is associated with decreased CRF, further study is clearly warranted to include determining if OSA with decreased CRF is associated with increased morbidity or mortality. Powell TA, Mysliwiec V, Brock MS, Morris MJ. OSA and cardiorespiratory fitness: a review. J Clin Sleep Med. 2022;18(1):279-288.


Inhibitors of glutamate release from breast cancer cells; new targets for cancer-induced bone-pain.
Glutamate is an important signaling molecule in a wide variety of tissues. Aberrant glutamatergic signaling disrupts normal tissue homeostasis and induces several disruptive pathological conditions including pain. Breast cancer cells secrete high levels of glutamate and often metastasize to bone. Exogenous glutamate can disrupt normal bone turnover and may be responsible for cancer-induced bone pain (CIBP). CIBP is a significant co-morbidity that affects quality of life for many advanced-stage breast cancer patients. Current treatment options are commonly accompanied by serious side-effects that negatively impact patient care. Identifying small molecule inhibitors of glutamate release from aggressive breast cancer cells advances a novel, mechanistic approach to targeting CIBP that could advance treatment for several pathological conditions. Using high-throughput screening, we investigated the ability of approximately 30,000 compounds from the Canadian Compound Collection to reduce glutamate release from MDA-MB-231 breast cancer cells. This line is known to secrete high levels of glutamate and has been demonstrated to induce CIBP by this mechanism. Positive chemical hits were based on the potency of each molecule relative to a known pharmacological inhibitor of glutamate release, sulfasalazine. Efficacy was confirmed and drug-like molecules were identified as potent inhibitors of glutamate secretion from MDA-MB-231, MCF-7 and Mat-Ly-Lu cells.


[Vitamin D and pregnancy: current state of the problem in the central regions of the Russian Federation].
It has been proven that vitamin D plays an important role in pregnancy. Deficiency of this element may be associated with the risk of developing gestational diabetes mellitus, preeclampsia, placentar insufficiency, low birth weight and premature birth. To conduct an epidemiological analysis of vitamin D supply in women at different stages of pregnancy, living in Russia. We included 1198 pregnant women living in 3 regions of Russia in the observational, multicenter, cross-sectional, continuous study. All pregnant women were tested for serum 25(OH)D levels. We collected biomaterial from August 2018 to December 2019. The end point of the study was the indicator of vitamin D supply in pregnant women and its level depending on the trimester of pregnancy and region of Russia. Statistical analysis included counting and grouping according to vitamin D levels, and calculating the median vitamin D concentration in each region. We confirmed vitamin D deficiency in all regions. The optimum level of this element is present in less than 7% of women. Insufficiency of this element is present in 20,62% of all women. The largest percentage of them is in a deficit of this element - 46,66%. We found that the lowest rates are in Smolensk, where the median was 12,75 ng/ml. In addition, we found changes in vitamin D concentration: with an increase in gestational age revealed a decrease in its level. In our study, we confirmed the presence of a 25(OH)D deficiency in most of the examined pregnant women, which is consistent with international epidemiological data. We should remember about these both at the stage of pre-gravid preparation and at the stage of pregnancy itself in order to achieve the optimal level of vitamin D.


Tucatinib has Selective Activity in HER2-Positive Cancers and Significant Combined Activity with Approved and Novel Breast Cancer-Targeted Therapies.
Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the mAb, trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small-molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small-molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single-agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard-of-care trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER; HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies.


Sexual dimorphic metabolic and cognitive responses of C57BL/6 mice to Fisetin or Dasatinib and quercetin cocktail oral treatment.
Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4-13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma, tissue specific markers of senescence-associated secretory phenotype (SASP), and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D + Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Male and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4-13 months of age. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. Females treated with D + Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. No effects were observed in females treated with Fisetin or males treated with D + Q.


Prevalence and associated factors of sarcopenia and severe sarcopenia in older Taiwanese living in rural community: the Tianliao Old People study 04.
The aim of the present study was to show the prevalence and associated factors of sarcopenia and severe sarcopenia in rural community-dwelling older Taiwanese. Using the whole community sampling method, a total of 285 men and 264 women aged over 65 years were randomly sampled (response rate = 50%) from Tianliao District, southern Taiwan, in 2012. Participants were interviewed by trained investigators to complete a validated structural questionnaire. Body composition was measured by bioelectrical impedance analysis, and skeletal muscle mass was estimated by Janssen's equation. The Mini-Nutritional Assessment (MNA) score, Short Portable Mental Status Questionnaire, grip strength, gait speed and short physical performance battery (SPPB) were obtained by the standard procedures. Sarcopenia and severe sarcopenia were defined according to the 2010 consensus of the Report of the European Working Group on Sarcopenia in Older People. Of the 549 study participants, 39 (7.1%) were classified as having sarcopenia and 31 (5.6%) participants were classified as having severe sarcopenia. Using multiple logistic regression models, the age, sex, working status, waist circumference, body mass index, hypertensive history, MNA and SPPB score were independently associated with different stages of sarcopenia. Approximately one-fifth of community-dwelling older adults were facing the threat of sarcopenia in southern Taiwan. The older age, female sex, lower body mass index, higher waist circumference, a history of hypertension, lower MNA or SPPB score and not working regularly were associated factors for either sarcopenia or severe sarcopenia.


Nano-photonic light trapping near the Lambertian limit in organic solar cell architectures.
A critical step to achieving higher efficiency solar cells is the broad band harvesting of solar photons. Although considerable progress has recently been achieved in improving the power conversion efficiency of organic solar cells, these cells still do not absorb upto ~50% of the solar spectrum. We have designed and developed an organic solar cell architecture that can boost the absorption of photons by 40% and the photo-current by 50% for organic P3HT-PCBM absorber layers of typical device thicknesses. Our solar cell architecture is based on all layers of the solar cell being patterned in a conformal two-dimensionally periodic photonic crystal architecture. This results in very strong diffraction of photons- that increases the photon path length in the absorber layer, and plasmonic light concentration near the patterned organic-metal cathode interface. The absorption approaches the Lambertian limit. The simulations utilize a rigorous scattering matrix approach and provide bounds of the fundamental limits of nano-photonic light absorption in periodically textured organic solar cells. This solar cell architecture has the potential to increase the power conversion efficiency to 10% for single band gap organic solar cells utilizing long-wavelength absorbers.


Use of geocoding and surname analysis to estimate race and ethnicity.
To review two indirect methods, geocoding and surname analysis, for estimating race/ethnicity as a means for health plans to assess disparities in care. Review of published articles and unpublished data on the use of geocoding and surname analyses. Few published studies have evaluated use of geocoding to estimate racial and ethnic characteristics of a patient population or to assess disparities in health care. Three of four studies showed similar estimates of the proportion of blacks and one showed nearly identical estimates of racial disparities, regardless of whether indirect or more direct measures (e.g., death certificate or CMS data) were used. However, accuracy depended on racial segregation levels in the population and region assessed and geocoding was unreliable for identifying Hispanics and Asians/Pacific Islanders. Similarly, several studies suggest surname analyses produces reasonable estimates of whether an enrollee is Hispanic or Asian/Pacific Islander and can identify disparities in care. However, accuracy depends on the concentrations of Asians or Hispanics in areas assessed. It is less accurate for women and more acculturated and higher SES persons due intermarriage, name changes, and adoption. Surname analysis is not accurate for identifying African Americans. Recent unpublished analyses suggest plans can successfully use a combined geocoding/surname analyses approach to identify disparities in care in most regions. Refinements based on Bayesian methods may make geocoding/surname analyses appropriate for use in areas where the accuracy is currently poor, but validation of these preliminary results is needed. Geocoding and surname analysis show promise for estimating racial/ethnic health plan composition of enrollees when direct data on major racial and ethnic groups are lacking. These data can be used to assess disparities in care, pending availability of self-reported race/ethnicity data.


A Psychosocial Care Model for Families Affected by Congenital Heart Disease.
To develop a model of family-based psychosocial care for congenital heart disease (CHD). Qualitative study using crowdsourced data collected from parents of young children with CHD who received care across 42 hospitals. Yammer, a social networking platform used to facilitate online crowdsourcing and qualitative data collection. Geographically diverse sample of 100 parents (72 mothers and 28 fathers) of young children with CHD. None. Parents joined a private group on Yammer and responded to 37 open-ended study questions over a 6-month period. Qualitative data were coded and analyzed using an iterative process. Three broad themes corresponding to pillars of family-based psychosocial care were identified: pillar 1) parent partnership in family-integrated medical care, pillar 2) supportive interactions focused on parent and family wellbeing, and pillar 3) integrated psychosocial care and peer support for parents and families. Each pillar was supported by subthemes corresponding to specific intervention strategies. Most parents described the need for intervention strategies across multiple pillars, with almost half reporting needs across all three pillars of psychosocial care. Parents' preferences for psychosocial support changed over time with changes to their child's medical status and across care settings (e.g., hospital, outpatient clinic). Results support a model of family-based psychosocial care that is multidimensional and flexible to meet the needs of families affected by CHD. All members of the healthcare team play an important role in providing psychosocial support. Future research incorporating components of implementation science is needed to promote uptake of these findings, with the goal of optimizing family-based psychosocial support in the hospital setting and beyond.


[Effect ot thyroliberin on rat brain opiate receptors].
The ability of thyroliberin to interact with opiate receptors of the rat midbrain and hypothalamus has been studied. It was shown by competitive displacement analysis that thyroliberin did not replace labeled opioid peptides in opiate receptor binding sites when added in vitro at concentrations of up to 10(-5) M. The specific binding of opioid peptides was increased by 10-20% in the presence of 10(-7)-10(-6) M thyroliberin. This effect was, probably, due to the rise in the affinity of high-affinity opiate receptors. At the same time the affinity of low-affinity binding sites was decreased. It is suggested that the antagonistic properties of thyroliberin are mediated by the modulation of the binding characteristics of enkephalin-low-affinity opiate receptors.


Monte-Carlo modeling of the central carbon metabolism of Lactococcus lactis: insights into metabolic regulation.
Metabolic pathways are complex dynamic systems whose response to perturbations and environmental challenges are governed by multiple interdependencies between enzyme properties, reactions rates, and substrate levels. Understanding the dynamics arising from such a network can be greatly enhanced by the construction of a computational model that embodies the properties of the respective system. Such models aim to incorporate mechanistic details of cellular interactions to mimic the temporal behavior of the biochemical reaction system and usually require substantial knowledge of kinetic parameters to allow meaningful conclusions. Several approaches have been suggested to overcome the severe data requirements of kinetic modeling, including the use of approximative kinetics and Monte-Carlo sampling of reaction parameters. In this work, we employ a probabilistic approach to study the response of a complex metabolic system, the central metabolism of the lactic acid bacterium Lactococcus lactis, subject to perturbations and brief periods of starvation. Supplementing existing methodologies, we show that it is possible to acquire a detailed understanding of the control properties of a corresponding metabolic pathway model that is directly based on experimental observations. In particular, we delineate the role of enzymatic regulation to maintain metabolic stability and metabolic recovery after periods of starvation. It is shown that the feedforward activation of the pyruvate kinase by fructose-1,6-bisphosphate qualitatively alters the bifurcation structure of the corresponding pathway model, indicating a crucial role of enzymatic regulation to prevent metabolic collapse for low external concentrations of glucose. We argue that similar probabilistic methodologies will help our understanding of dynamic properties of small-, medium- and large-scale metabolic networks models.


Development and validation of a noninvasive method to determine arterial pressure and vascular compliance.
The ability not only to record automated systolic and diastolic pressure, but also to derive measurements of the rate of pressure change during the cardiac cycle, would have great potential clinical value. A new method has been developed to obtain pressure measurements at 20-ms intervals by oscillometric cuff signal pattern recognition. Derivation of noninvasive pressure measurements is based on a T tube aorta and straight tube brachial artery, and assumes that the systolic phase of the suprasystolic cuff signal and the diastolic phase of the subdiastolic cuff signal most closely approximate systolic and diastolic aortic pressures, respectively. Arterial pressures obtained by this method were compared with simultaneous invasive measurements from the thoracic aorta in 36 patients. Good agreement was observed between noninvasive and invasive methods for systolic (146 +/- 4 vs 145 +/- 5 mm Hg), diastolic (80 +/- 2 vs 77 +/- 2 mm Hg), and mean (100 +/- 3 vs 100 +/- 3 mm Hg) arterial pressures, and correlation coefficients were r = 0.94, 0.91, and 0.95, respectively. To assess the validity of measurements of the rate of pressure change, oscillometric cuff signals from a subgroup of 14 patients were analyzed in detail for the peak positive pressure derivative (dP/dt(Max)), peak negative pressure derivative (dP/dt(Min)), and time interval between peak positive and peak negative pressure derivatives [t(pp)]. Results (mean +/- SEM) were: [table in text]. The incorporation of measurements of the rate of pressure change into a physical model of the brachial artery was used to derive vascular compliance. A significant correlation was observed between vascular compliance derived from the oscillometric signal and determinations by either thermodilution or Fick methods and noninvasive pressures (n = 20, r = 0.83, p <0.001). Day-to-day variability for blood pressure and vascular compliance derived by the noninvasive method did not differ by >4%, representing a reproducible measure of vascular structure and function. We conclude that the measurement of absolute pressure and rate of pressure change show good correlation with catheter data and that vascular compliance can be reliably assessed by this new method. The technology should provide a valuable noninvasive tool for the assessment of both cardiac function and vascular properties.


Cardiac small conductance Ca2+-activated K+ channel subunits form heteromultimers via the coiled-coil domains in the C termini of the channels.
Ca(2+)-activated K(+) channels are present in a wide variety of cells. We have previously reported the presence of small conductance Ca(2+)-activated K(+) (SK or K(Ca)) channels in human and mouse cardiac myocytes that contribute functionally toward the shape and duration of cardiac action potentials. Three isoforms of SK channel subunits (SK1, SK2, and SK3) are found to be expressed. Moreover, there is differential expression with more abundant SK channels in the atria and pacemaking tissues compared with the ventricles. SK channels are proposed to be assembled as tetramers similar to other K(+) channels, but the molecular determinants driving their subunit interaction and assembly are not defined in cardiac tissues. To investigate the heteromultimeric formation and the domain necessary for the assembly of 3 SK channel subunits (SK1, SK2, and SK3) into complexes in human and mouse hearts. Here, we provide evidence to support the formation of heteromultimeric complexes among different SK channel subunits in native cardiac tissues. SK1, SK2, and SK3 subunits contain coiled-coil domains (CCDs) in the C termini. In vitro interaction assay supports the direct interaction between CCDs of the channel subunits. Moreover, specific inhibitory peptides derived from CCDs block the Ca(2+)-activated K(+) current in atrial myocytes, which is important for cardiac repolarization. The data provide evidence for the formation of heteromultimeric complexes among different SK channel subunits in atrial myocytes. Because SK channels are predominantly expressed in atrial myocytes, specific ligands of the different isoforms of SK channel subunits may offer a unique therapeutic opportunity to directly modify atrial cells without interfering with ventricular myocytes.


Mutations in valosin-containing protein (VCP) decrease ADP/ATP translocation across the mitochondrial membrane and impair energy metabolism in human neurons.
Mutations in the gene encoding valosin-containing protein (VCP) lead to multisystem proteinopathies including frontotemporal dementia. We have previously shown that patient-derived VCP mutant fibroblasts exhibit lower mitochondrial membrane potential, uncoupled respiration, and reduced ATP levels. This study addresses the underlying basis for mitochondrial uncoupling using VCP knockdown neuroblastoma cell lines, induced pluripotent stem cells (iPSCs), and iPSC-derived cortical neurons from patients with pathogenic mutations in VCP Using fluorescent live cell imaging and respiration analysis we demonstrate a VCP mutation/knockdown-induced dysregulation in the adenine nucleotide translocase, which results in a slower rate of ADP or ATP translocation across the mitochondrial membranes. This deregulation can explain the mitochondrial uncoupling and lower ATP levels in VCP mutation-bearing neurons via reduced ADP availability for ATP synthesis. This study provides evidence for a role of adenine nucleotide translocase in the mechanism underlying altered mitochondrial function in VCP-related degeneration, and this new insight may inform efforts to better understand and manage neurodegenerative disease and other proteinopathies.


The efficacy of SMART Arm training early after stroke for stroke survivors with severe upper limb disability: a protocol for a randomised controlled trial.
Recovery of upper limb function after stroke is poor. The acute to subacute phase after stroke is the optimal time window to promote the recovery of upper limb function. The dose and content of training provided conventionally during this phase is however, unlikely to be adequate to drive functional recovery, especially in the presence of severe motor disability. The current study concerns an approach to address this shortcoming, through evaluation of the SMART Arm, a non-robotic device that enables intensive and repetitive practice of reaching by stroke survivors with severe upper limb disability, with the aim of improving upper limb function. The outcomes of SMART Arm training with or without outcome-triggered electrical stimulation (OT-stim) to augment movement and usual therapy will be compared to usual therapy alone. A prospective, assessor-blinded parallel, three-group randomised controlled trial is being conducted. Seventy-five participants with a first-ever unilateral stroke less than 4 months previously, who present with severe arm disability (three or fewer out of a possible six points on the Motor Assessment Scale [MAS] Item 6), will be recruited from inpatient rehabilitation facilities. Participants will be randomly allocated to one of three dose-matched groups: SMART Arm training with OT-stim and usual therapy; SMART Arm training without OT-stim and usual therapy; or usual therapy alone. All participants will receive 20 hours of upper limb training over four weeks. Blinded assessors will conduct four assessments: pre intervention (0-weeks), post intervention (4-weeks), 26 weeks and 52 weeks follow-up. The primary outcome measure is MAS item 6. All analyses will be based on an intention-to-treat principle. By enabling intensive and repetitive practice of a functional upper limb task during inpatient rehabilitation, SMART Arm training with or without OT-stim in combination with usual therapy, has the potential to improve recovery of upper limb function in those with severe motor disability. The immediate and long-term effects of SMART Arm training on upper limb impairment, activity and participation will be explored, in addition to the benefit of training with or without OT-stim to augment movement when compared to usual therapy alone. ACTRN12608000457347.


Microfilaria in human subcutaneous dirofilariasis: a case report.
Human subcutaneous dirofilariasis, a rare zoonosis is being increasingly reported from various parts of the world. Most of the reported cases have lesions in and around the eye. The adult female dirofilariae release microfilaria into the definitive host's blood. Various mosquitoes that serve as intermediate hosts such as Culex, Aedes and Anopheles take up the microfilariae (mf-L1) while feeding on an infected host. Microfilariae develop in the mosquitoes. The transmission to dogs or other hosts including humans occurs through mosquito bite during subsequent blood meal. Humans may be infected as aberrant (accidental) hosts, mainly by D. repens and D. immitis. D. repens usually resides subcutaneously, while D. immitis frequently ends up in the human lung. In human infections usually just one larva develops, which does not reach sexual maturity. In India, almost all reported cases of dirofilariasis in humans have involvement of face in the form of ocular dirofilariasis with a few reports on subcutaneous dirofilariasis. We report a case of human subcutaneous dirofilariasis, from western India, involving leg and showing microfilaria in tissue indicating presence of gravid female dirofilaria (sexual maturity). To the best of our knowledge, it is among rare cases of subcutaneous dirofilariasis wherein microfilariae have developed in human host.


Challenging Knosp high-grade pituitary adenomas.
Parasellar growth is one of the most important prognostic variables of pituitary adenoma surgery, with adenomas regarded as not completely resectable if they invade the cavernous sinus (CS) but potentially curable if they displace CS structures. This study was conducted to correlate surgical treatment options and outcomes to the different biological behaviors (invasion vs displacement) of adenomas with parasellar extension into the superior or inferior CS compartments or completely encasing the carotid artery (Knosp high grades 3A, 3B, and 4). This was a retrospective cohort analysis of 106 consecutive patients with Knosp high-grade pituitary adenomas with parasellar extension who underwent surgery via a primary endoscopic transsphenoidal approach between 2003 and 2017. Biological tumor characteristics (surgical status of invasiveness and tumor texture, 2017 WHO classification, proliferation rate), extent of resection, and complication rate were correlated with parasellar extension grades 3A, 3B, and 4 on preoperative MRI studies. Invasiveness was significantly less common in grade 3A (44%) than in grade 3B (72%, p = 0.037) and grade 4 (100%, p < 0.001) adenomas. Fibrous tumor texture was significantly more common in grade 4 (52%) compared to grade 3A (20%, p = 0.002), but not compared to grade 3B (28%) adenomas. Functioning macroadenomas had a significantly higher rate of invasiveness than nonfunctioning adenomas (91% vs 55%, p = 0.002). Mean proliferation rate assessed by MIB-1 was > 3% in all groups but without significant difference between the groups (grade 3A, 3.2%; 3B, 3.9%; 4, 3.7%). Rates of endocrine remission/gross-total resection were significantly higher in grade 3A (64%) than in grade 3B (33%, p = 0.021) and grade 4 (0%, p < 0.001) adenomas. In terms of complication rates, no significant difference was observed between grades. According to the authors' data, the biological behavior of pituitary adenomas varies significantly between parasellar extension patterns. Adenomas with extension into the superior CS compartment have a lower rate of invasive growth than adenomas extending into the inferior CS compartment or encasing the carotid artery. Consequently, a significantly higher rate of remission can be achieved in grade 3A than in grade 3B and grade 4 adenomas. Therefore, the distinction into grades 3A, 3B, and 4 is of importance for prediction of adenoma invasion and surgical treatment considerations.


Liver bridging techniques in the treatment of acute liver failure.
The introduction of orthotopic liver transplantation in the management of acute liver failure has dramatically increased the survival rates of patients at the cost of removing the patient's native liver and life-long dependence on immunosuppression. However, it is well known that in many patients with acute liver failure the diseased liver has the potential to recover. Death in these patients is often due to increased intra-cranial pressure or infection. Liver bridging techniques are assigned to temporarily provide liver function and enable the native liver to recover in patients with acute liver failure. They represent an attractive alternative to conventional liver transplantation in the management of acute liver failure, since after recovery of the native liver the patient is freed from immuno-suppression with all associated side-effects and risks. Auxiliary liver transplantation, artificial liver support devices and hepatocyte transplantation represent different ways of bridging liver function in acute liver failure. The aim of this review is to present the ideas and principles of these three different liver bridging techniques. We will discuss the relative importance and the future potential of theses bridging techniques in the treatment of acute liver failure by comparing the experimental and clinical results.


Interferons and collagen production.
The immunoregulatory, antiviral, and antiproliferative agents known as the interferons have profound effects on collagen synthesis. Interferons alpha, beta, and gamma suppress collagen synthesis by dermal fibroblasts. In addition, interferon gamma (IFN-gamma) inhibits the constitutively increased collagen synthesis characteristic of fibroblasts derived from lesions of patients with scleroderma. IFN-gamma also inhibits collagen synthesis by myofibroblasts and synovial fibroblast-like cells. Inhibition of collagen synthesis by IFN-gamma is associated with a coordinate inhibition of transcription for types I and III collagen. In addition, IFN-gamma suppresses levels of procollagen mRNA and type II collagen synthesis in human articular chondrocytes. In vivo studies in mice have demonstrated that IFN-gamma inhibits the collagen synthesis associated with the fibrotic response to an implanted foreign body, bleomycin-induced pulmonary fibrosis, and the healing response to cutaneous thermal burns. In the latter case, while collagen content of the wound scar was decreased, hyaluronic acid was increased in mice receiving IFN-gamma compared to controls. This is in accord with in vitro studies showing that, while interferons alpha and beta decrease production of glycosaminoglycans, IFN-gamma increases production of glycosaminoglycans. Of interest, acute inflammation at sites of thermal injury, or when elicited by proinflammatory agents in separate experiments, also was suppressed in mice treated with IFN-gamma. The means by which IFN-gamma inhibits collagen synthesis involves transcriptional regulation. There is a single report that interferon alpha can decrease the size of a keloid of recent onset in a human patient. Because the interferons can inhibit collagen synthesis in vivo, further studies may be warranted to evaluate the usefulness of these agents in the treatment of disease states characterized by abnormal fibrotic responses as well as their potential for altering the healing response associated with particular therapeutic interventions.


Antibodies that protect humans against Plasmodium falciparum blood stages do not on their own inhibit parasite growth and invasion in vitro, but act in cooperation with monocytes.
IgG extracted from the sera of African adults immune to malaria were injected intravenously into eight Plasmodium falciparum-infected nonimmune Thai patients. Clinical and parasitological improvement was reproducibly obtained in each case. After the disappearance of the transferred Ig, recrudescent parasites were equally susceptible to the same Ig preparation. High levels of antibodies to most parasite proteins were detected by Western blots in the receivers' sera (taken before transfer) as in the donors' Ig, thus indicating that the difference was qualitative rather than quantitative between donors and receivers. In vitro, the clinically effective Ig had no detectable inhibitory effect on either penetration or intra-erythrocytic development of the parasite. On the contrary, they sometimes increased parasite growth. In contrast, these IgG, as the receivers' Ig collected 4 d after transfer, but not those collected before transfer, proved able to exert an antibody-dependent cellular inhibitory (ADCI) effect in cooperation with normal blood monocytes. Results were consistent among the seven isolates studied in vitro, as with the recrudescent parasites. Thus, the results obtained in the ADCI assay correlate closely with clinical and parasitological observations.


A Polyvalent Adhesin-Toxoid Multiepitope-Fusion-Antigen-Induced Functional Antibodies against Five Enterotoxigenic Escherichia coli Adhesins (CS7, CS12, CS14, CS17, and CS21) but Not Enterotoxins (LT and STa).
The increasing prevalence and association with moderate-to-severe diarrhea make enterotoxigenic Escherichia coli (ETEC) adhesins CS7, CS12, CS14, CS17, and CS21 potential targets of ETEC vaccines. Currently, there are no vaccines licensed to protect against ETEC, a top cause of children's diarrhea and travelers' diarrhea. Recently, a polyvalent adhesin protein (adhesin MEFA-II) was demonstrated to induce antibodies that inhibited adherence from these five ETEC adhesins and reduced the enterotoxicity of ETEC heat-stable toxin (STa), which plays a key role in causing ETEC-associated diarrhea. To improve adhesin MEFA-II for functional antibodies against STa toxin and the other ETEC toxin, heat-labile toxin (LT), we modified adhesin MEFA-II by adding another STa toxoid and an LT epitope; we examined the new antigen immunogenicity (to five adhesins and two toxins) and more importantly antibody functions against ETEC adherence and STa and LT enterotoxicity. Data show that mice intramuscularly immunized with the new antigen (adhesin MEFA-IIb) developed robust IgG responses to the targeted adhesins (CS7, CS12, CS14, CS17, and CS21) and toxins (STa and LT). Mouse antibodies inhibited the adherence of ETEC strains expressing any of these five adhesins but failed to neutralize STa or LT enterotoxicity. In further studies, rabbits intramuscularly immunized with adhesin MEFA-IIb developed robust antigen-specific antibodies; when challenged with an ETEC isolate expressing CS21 adhesin (JF2101, CS21, and STa), the immunized rabbits showed a significant reduction in intestinal colonization by ETEC bacteria. These data indicate that adhesin MEFA-IIb is broadly immunogenic and induces functional antibodies against the targeted ETEC adhesins but not the toxins.


Association Between Vitamin D Status and Schizophrenia: A First Psychotic Episode Study.
Vitamin D deficiency has been linked with schizophrenia. We aimed to determine whether patients with a first episode of psychosis (FEP) had lower vitamin D levels compared with controls considering their final diagnosis. We conducted a cross-sectional study determining 25-hydroxyvitamin D blood levels. 25-Hydroxyvitamin D levels were considered optimum at 20 ng/mL or greater. A group of 45 adult patients with FEP and a group of 22 healthy controls matched for age were recruited. The patient group was subdivided in two final diagnosis groups (schizophrenia versus other psychoses) after a 6-month follow-up. Average vitamin D values were deficient for FEP patients, especially those 22 with a final diagnosis of schizophrenia. These results relating vitamin D and schizophrenia generate interest to further examine this association.


The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation.
To inform the debate over whether human sleep can be chronically reduced without consequences, we conducted a dose-response chronic sleep restriction experiment in which waking neurobehavioral and sleep physiological functions were monitored and compared to those for total sleep deprivation. The chronic sleep restriction experiment involved randomization to one of three sleep doses (4 h, 6 h, or 8 h time in bed per night), which were maintained for 14 consecutive days. The total sleep deprivation experiment involved 3 nights without sleep (0 h time in bed). Each study also involved 3 baseline (pre-deprivation) days and 3 recovery days. Both experiments were conducted under standardized laboratory conditions with continuous behavioral, physiological and medical monitoring. A total of n = 48 healthy adults (ages 21-38) participated in the experiments. Noctumal sleep periods were restricted to 8 h, 6 h or 4 h per day for 14 days, or to 0 h for 3 days. All other sleep was prohibited. Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days resulted in significant cumulative, dose-dependent deficits in cognitive performance on all tasks. Subjective sleepiness ratings showed an acute response to sleep restriction but only small further increases on subsequent days, and did not significantly differentiate the 6 h and 4 h conditions. Polysomnographic variables and delta power in the non-REM sleep EEG-a putative marker of sleep homeostasis--displayed an acute response to sleep restriction with negligible further changes across the 14 restricted nights. Comparison of chronic sleep restriction to total sleep deprivation showed that the latter resulted in disproportionately large waking neurobehavioral and sleep delta power responses relative to how much sleep was lost. A statistical model revealed that, regardless of the mode of sleep deprivation, lapses in behavioral alertness were near-linearly related to the cumulative duration of wakefulness in excess of 15.84 h (s.e. 0.73 h). Since chronic restriction of sleep to 6 h or less per night produced cognitive performance deficits equivalent to up to 2 nights of total sleep deprivation, it appears that even relatively moderate sleep restriction can seriously impair waking neurobehavioral functions in healthy adults. Sleepiness ratings suggest that subjects were largely unaware of these increasing cognitive deficits, which may explain why the impact of chronic sleep restriction on waking cognitive functions is often assumed to be benign. Physiological sleep responses to chronic restriction did not mirror waking neurobehavioral responses, but cumulative wakefulness in excess of a 15.84 h predicted performance lapses across all four experimental conditions. This suggests that sleep debt is perhaps best understood as resulting in additional wakefulness that has a neurobiological "cost" which accumulates over time.


A literature review of medical record keeping by foreign medical teams in sudden onset disasters.
Medical records are a tenet of good medical practice and provide one method of communicating individual follow-up arrangements, informing research data, and documenting medical intervention. The objective of this review was to look at one source (the published literature) of medical records used by foreign medical teams (FMTs) in sudden onset disasters (SODs). The published literature was searched systematically for evidence of what medical records have been used by FMTs in SODs. Findings The style and content of medical records kept by FMTs in SODs varied widely according to the published literature. Similarly, there was great variability in practice as to what happens to the record and/or the data from the record following its use during a patient encounter. However, there was a paucity of published work comprehensively detailing the exact content of records used. Interpretation Without standardization of the content of medical records kept by FMTs in SODs, it is difficult to ensure robust follow-up arrangements are documented. This may hinder communication between different FMTs and local medical teams (LMTs)/other FMTs who may then need to provide follow-up care for an individual. Furthermore, without a standard method of reporting data, there is an inaccurate picture of the work carried out. Therefore, there is not a solid evidence base for improving the quality of future response to SODs. Further research targeting FMTs and LMTs directly is essential to inform any development of an internationally agreed minimum data set (MDS), for both recording and reporting, in order that FMTs can reach the World Health Organization (WHO) standards for FMT practice.


Stacked fibula flap for unilateral total maxillectomy reconstruction with orbital preservation.
Unilateral total maxillectomy is indicated for locally advanced maxillary tumors that require complete removal of the midface bony structure and inferior orbital rim. Reconstruction of this defect is challenging due to aesthetic and functional concerns. A retrospective review of patients at two tertiary-care institutions undergoing unilateral total maxillectomy reconstruction with a stacked fibula flap from 2018 to 2022 was performed. Each patient's clinical course was reviewed, and attention was focused on the demonstration of surgical steps with photos. Twenty patients underwent stacked fibula flap reconstruction for unilateral total maxillectomy orbital preservation defects. Surgical extirpation was performed for malignancy (80%, 16/20) and for osteoradionecrosis or benign tumor in 20% (4/20). The complication rate was 30% (6/20). Most flaps survived (95%, 19/20). We present a modified, reproducible method of fibula flap reconstruction for unilateral total maxillectomy with orbital preservation that only requires two segments and maintains positive aesthetic and functional results.


Vestibular rehabilitation strategies in Meniere's disease.
Once the episodic spells of vertigo associated with Meniere's disease have abated, vestibular rehabilitation exercises play an important role in promoting adaptation to the decreased vestibular input. Outlines of different treatment approaches for three types of patients with Meniere's disease are presented. The exercise approaches advocated here consist of exercises to foster adaptation of the vestibular system in cases of unilateral loss or hypofunction and exercises to promote the substitution of alternative strategies and to enhance remaining function in cases of bilateral vestibular hypofunction. The selection of the appropriate exercises is based on the nature of the vestibular loss, the patient's symptoms, and the functional capabilities of the patient. Based on an understanding of the vestibular system, the balance system, and normal functional capabilities, appropriate rehabilitative exercises can be designed for this group of patients.


Home Exercise Programs for Adults With Neurological Injuries: A Survey.
The purpose of this study was to describe current occupational therapy practices in the usage and prescription of and clinical reasoning process supporting home exercise programs (HEPs) for clients with neurological injuries (CWNIs). A survey was distributed via mail to 2,000 members of the American Occupational Therapy Association. The survey questions concerned basic demographics, current HEP practices, and attitudes toward using HEPs with CWNIs. In the 360 returned surveys, occupational therapists reported numerous benefits of using HEPs and were able to clearly articulate their clinical reasoning. Commonly reported HEP activities were preparatory in nature, and the most frequently prescribed dosage was 16-30 min daily. Most therapists relied on the same clinical reasoning process but varied in implementation methods. This study's results highlight the gaps between evidence and practice. The active ingredients in HEPs for CWNIs need to be more clearly defined and described.


[Season fluctuations of carbamazepine and valproate concentration in patients with epilepsy].
We studied 107 patients with epilepsy who received monotherapy with valproic acid drugs (58) and carbamazepine (49). The seasonal distribution of number and severity of seizures assessed with the NHS3 scale in dependence of Cmin and Cmax content of antiepileptic drugs carbamazepine and valproates in the serum of patients was estimated. There was a significant increase in the number of seizures and their severity in the cycle spring>autumn>summer>winter. The serum content of carbamazepine and valproates was significantly lower in spring compared to autumn.


Methionine recycling pathways and antimalarial drug design.
5'-Deoxy-5'-(methylthio)adenosine (MTA) is an S-adenosylmethionine metabolite that is generated as a by-product of polyamine biosynthesis. In mammalian cells, MTA undergoes a phosphorolytic cleavage catalyzed by MTA phosphorylase to produce adenine and 5-deoxy-5-(methylthio)ribose-1-phosphate (MTRP). Adenine is utilized in purine salvage pathways, and MTRP is subsequently recycled to methionine. Whereas some microorganisms metabolize MTA to MTRP via MTA phosphorylase, others metabolize MTA to MTRP in two steps via initial cleavage by MTA nucleosidase to adenine and 5-deoxy-5-(methylthio)ribose (MTR) followed by conversion of MTR to MTRP by MTR kinase. In order to assess the extent to which these pathways may be operative in Plasmodium falciparum, we have examined a series of 5'-alkyl-substituted analogs of MTA and the related MTR analogs and compared their abilities to inhibit in vitro growth of this malarial parasite. The MTR analogs 5-deoxy-5-(ethylthio)ribose and 5-deoxy-5-(hydroxyethylthio)ribose were inactive at concentrations up to 1 mM, and 5-deoxy-5-(monofluoroethylthio)ribose was weakly active (50% inhibitory concentration = 700 microM). In comparison, the MTA analogs, 5'-deoxy-5'-(ethylthio)adenosine,5'-deoxy-5'-(hydroxyethylthio)ade nosine (HETA), and 5'-deoxy-5'-(monofluoroethylthio)adenosine, had 50% inhibitory concentrations of 80, 46, and 61 microM, respectively. Extracts of P. falciparum were found to have substantial MTA phosphorylase activity. Coadministration of MTA with HETA partially protected the parasites against the growth-inhibitory effects of HETA. Results of this study indicate that P. falciparum has an active MTA phosphorylase that can be targeted by analogs of MTA.


Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study.
Chronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance. In this study, 1,741 people with CKD stage 3 were individually recruited from 32 primary care practices in Derbyshire, United Kingdom. Study visits were undertaken at baseline, year 1, and year 5. Binomial logistic regression and Cox proportional hazards models were used to model progression, CKD remission, and all-cause mortality. We used Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define CKD progression and defined CKD remission as the absence of diagnostic criteria (estimated glomerular filtration rate [eGFR] >60 ml/min/1.73 m2 and urine albumin-to-creatinine ratio [uACR] <3 mg/mmol) at any study visit. Participants were predominantly elderly (mean ± standard deviation (SD) age 72.9 ± 9.0 y), with relatively mild reduction in GFR (mean ± SD eGFR 53.5 ± 11.8 mL/min/1,73 m2) and a low prevalence of albuminuria (16.9%). After 5 y, 247 participants (14.2%) had died, most of cardiovascular causes. Only 4 (0.2%) developed ESKD, but 308 (17.7%) evidenced CKD progression by KDIGO criteria. Stable CKD was observed in 593 participants (34.1%), and 336 (19.3%) met the criteria for remission. Remission at baseline and year 1 was associated with a high likelihood of remission at year 5 (odds ratio [OR] = 23.6, 95% CI 16.5-33.9 relative to participants with no remission at baseline and year 1 study visits). Multivariable analyses confirmed eGFR and albuminuria as key risk factors for predicting adverse as well as positive outcomes. Limitations of this study include reliance on GFR estimated using the Modification of Diet in Renal Disease study (MDRD) equation for recruitment (but not subsequent analysis) and a study population that was predominantly elderly and white, implying that the results may not be directly applicable to younger populations of more diverse ethnicity. Management of CKD in primary care should focus principally on identifying the minority of people at high risk of adverse outcomes, to allow intervention to slow CKD progression and reduce cardiovascular events. Efforts should also be made to identify and reassure the majority who are at low risk of progression to ESKD. Consideration should be given to adopting an age-calibrated definition of CKD to avoid labelling a large group of people with age-related decline in GFR and low associated risk as having CKD.


The effectiveness of housing interventions and housing and service interventions on ending family homelessness: a systematic review.
Family homelessness has become a growing public health problem over the last 3 decades. Despite this trend, few studies have explored the effectiveness of housing interventions and housing and service interventions. The purpose of this systematic review is to appraise and synthesize evidence on effective interventions addressing family homelessness. We searched 10 major electronic databases from 2007 to 2013. Empirical studies investigating effectiveness of housing interventions and housing and service interventions for American homeless families regardless of publication status were eligible for inclusion. Outcomes included housing status, employment, parental trauma and mental health and substance use, children's behavioral and academic status, and family reunification. Study quality was appraised using the Effective Public Health Practice Project tool. Six studies were included in this review. Overall, there was some postintervention improvement in housing and employment, but ongoing residential and work stability were not achieved. Methodological limitations, poor reporting quality, and inconsistent definitions across outcomes hindered between-study comparisons. Substantial limitations in research underscore the insufficiency of our current knowledge base for ending homelessness. Although many families were no longer literally homeless, long-term residential stability and employment at a livable wage were not ensured. Developing and implementing evidence-based approaches for addressing homelessness are long overdue.


Pacing the human stomach.
The aim of this study was to document the pattern of human gastric pacesetter potentials after abdominal operation and to determine whether the potentials could be paced by electrical stimuli. Ten patients undergoing cholecystectomy had temporary serosal electrodes positioned along the greater curvature of the stomach. Bipolar myoelectric recordings and attempts at electrical pacing were made after operation. On postoperative day 1, the pacesetter potentials had a regular frequency (3.2 +/- 0.1 cycles/min), and no gastric dysrhythmias were evident. The distal stomach of nine of ten patients could be entrained by pacing the proximal electrodes (forward pacing) to a maximal rate of 4.3 +/- 0.3 cycles/min (p less than 0.05 versus nonpacing) without a change in propagation velocity or direction. Backward pacing (maximum rate, 3.9 +/- 0.2 cycles/min) was possible in six patients. Forward pacing was successful by day 3 in only four of ten patients, and backward pacing was successful in none of ten patients. A meal given a median of 3.5 days after operation did not change the pacesetter potential frequency, rhythm, or direction of propagation, and three of ten patients had successful forward pacing after a meal. In conclusion, a regular pattern of gastric pacesetter potentials is present after cholecystectomy. The gastric pacesetter potentials can be paced with electrical stimuli, although refinements of the pacing electrodes or stimuli will be needed to achieve long-term pacing. Pacing holds promise as a potential treatment for gastric myoelectrical disorders.


Automated feature detection and imaging for high-resolution screening of zebrafish embryos.
The development of automated microscopy platforms has enabled large-scale observation of biological processes, thereby complementing genome scale biochemical techniques. However, commercially available systems are restricted either by fixed-field-of-views, leading to potential omission of features of interest, or by low-resolution data of whole objects lacking cellular detail. This limits the efficiency of high-content screening assays, especially when large complex objects are used as in whole-organism screening. Here we demonstrate a toolset for automated intelligent high-content screening of whole zebrafish embryos at cellular resolution on a standard wide-field screening microscope. Using custom-developed algorithms, predefined regions of interest-such as the brain-are automatically detected. The regions of interest are subsequently imaged automatically at high magnification, enabling rapid capture of cellular resolution data. We utilize this approach for acquiring 3-D datasets of embryonic brains of transgenic zebrafish. Moreover, we report the development of a mold design for accurate orientation of zebrafish embryos for dorsal imaging, thereby facilitating standardized imaging of internal organs and cellular structures. The toolset is flexible and can be readily applied for the imaging of different specimens in various applications.


Subcostal nerve injury after laparoscopic lipoma surgery: an unusual culprit for an unusual complication.
Endoscopic surgery has revolutionized the field of minimally invasive surgery. Nerve injury after laparoscopic surgery is presumably rare, with only scarce reports in the literature; however, the use of these techniques for new purposes presents the opportunity for novel complications. The authors report a case of subcostal nerve injury after an anterior laparoscopic approach to a posterior abdominal wall lipoma.A 62-year-old woman presented with a left abdominal flank bulge (pseudohernia) that developed after laparoscopic posterior flank wall lipoma resection. Imaging demonstrated frank ballooning of the oblique muscles; denervation atrophy and thinning of the external oblique, internal oblique, and transverse abdominis muscles; and thinning of the rectus abdominis muscle. The patient underwent subcostal nerve repair and removal of a foreign plastic material from the laparoscopic procedure. At 8 months, she has regained substantial improvement in abdominal wall strength.Although endoscopic procedures have resulted in significant reduction in morbidity, "minimally invasive" approaches should not be confused with "low risk" when approaching novel pathology. The subcostal nerve is at risk of injury in posterior abdominal wall surgery, whether laparoscopic or not. With the pseudohernia and abdominal bulge after this surgery, the cosmetic appeal of laparoscopic incisions was definitively undone. Selecting an approach based on the anatomy of adjacent structures may lead to a better functional result.


Predictive timing disturbance is a precise marker of schizophrenia.
Timing disturbances have being proposed as a key component of schizophrenia pathogenesis. However, the contribution of cognitive impairment to such disorders has not been clarified. Here, we investigated duration estimation and predictive timing in 30 patients with DSM-5 diagnosis of schizophrenia (SZ) compared to 30 healthy controls (HC). Duration estimation was examined in a temporal and colour discrimination task, fully controlled for working memory (WM) and attention requirements, and by more traditional temporal production and temporal bisection tasks. Predictive timing was measured in a temporal and spatial orienting of attention task. Expectations about stimulus onset (temporal condition) or location (spatial condition) were induced by valid and invalid symbolic cues. Results showed that discrimination of temporal and colour stimulus attributes was equally impaired in SZ. This, taken with the positive correlation between temporal bisection performance and neuropsychological measures of WM, indicates that duration estimation impairments in SZ are underpinned by WM dysfunction. Conversely, we found dissociation in temporal and spatial predictive ability in SZ. Unlike controls, patients were selectively unperturbed by events appearing at an unexpected moment in time, though were perturbed by targets appearing at an unexpected location. Moreover, patients were able to generate temporal expectations more implicitly, as their performance was influenced by the predictive nature of the flow of time itself. Our findings shed new light on the debate over the specificity of timing distortions in SZ, providing evidence that predictive timing is a precise marker of SZ, more sensitive than duration estimation, serving as a valid heuristic for studying the pathophysiology of the disorder.


Comparison of clinical probability-adjusted D-dimer and age-adjusted D-dimer interpretation to exclude venous thromboembolism.
Two new strategies for interpreting D-dimer results have been proposed: i) using a progressively higher D-dimer threshold with increasing age (age-adjusted strategy) and ii) using a D-dimer threshold in patients with low clinical probability that is twice the threshold used in patients with moderate clinical probability (clinical probability-adjusted strategy). Our objective was to compare the diagnostic accuracy of age-adjusted and clinical probability-adjusted D-dimer interpretation in patients with a low or moderate clinical probability of venous thromboembolism (VTE). We performed a retrospective analysis of clinical data and blood samples from two prospective studies. We compared the negative predictive value (NPV) for VTE, and the proportion of patients with a negative D-dimer result, using two D-dimer interpretation strategies: the age-adjusted strategy, which uses a progressively higher D-dimer threshold with increasing age over 50 years (age in years × 10 µg/L FEU); and the clinical probability-adjusted strategy which uses a D-dimer threshold of 1000 µg/L FEU in patients with low clinical probability and 500 µg/L FEU in patients with moderate clinical probability. A total of 1649 outpatients with low or moderate clinical probability for a first suspected deep vein thrombosis or pulmonary embolism were included. The NPV of both the clinical probability-adjusted strategy (99.7 %) and the age-adjusted strategy (99.6 %) were similar. However, the proportion of patients with a negative result was greater with the clinical probability-adjusted strategy (56.1 % vs, 50.9 %; difference 5.2 %; 95 % CI 3.5 % to 6.8 %). These findings suggest that clinical probability-adjusted D-dimer interpretation is a better way of interpreting D-dimer results compared to age-adjusted interpretation.


A Brief Review of Diagnosis of Small Ruminants Brucellosis.
Brucellosis caused by bacteria of the genus of Brucella remains a major zoonosis in the wide world, which is an infectious disease with a severe economic impact on animal husbandry and public health. The genus of Brucella includes ten species and the most prevalent is Brucella melitensis. The diagnosis of Brucella melitensis ruminant brucellosis is based on bacteriological and immunological tests. The use of vaccines and the false-positive serological reactions (FPSR) caused by other cross-reacting bacteria represent the immunological contexts. This complex context results in the development of the large number of diagnosis of Brucella melitensis brucellosis. The aim of this article is to briefly review the detection methods and compare the superiorities of different tests.


MRI and FDG PET/CT findings in a case of probable Heidenhain variant Creutzfeldt-Jakob disease.
Creutzfeldt-Jakob disease (CJD) is a neurodegenerative disease caused by the accumulation of a pathogenic isoform of a prion protein in neurons that is responsible for subacute dementia. The Heidenhain variant is an atypical form of CJD in which visual signs are predominant. This is a report of the case of a 65-year-old man with probable CJD of the Heidenhain variant, with topographical concordance between findings on magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose (FDG) photopenic areas on positron emission tomography (PET)/computed tomography (CT) for cortical parietooccipital lesions.


A neuro-cardiac self-regulation therapy to improve autonomic and neural function after SCI: a randomized controlled trial protocol.
Spinal cord injury (SCI) is associated with autonomic imbalance and significant secondary conditions, including cardiac and brain dysfunction that adversely impact health and wellbeing. This study will investigate the effectiveness (intention-to-treat) of a neuro-cardiac self-regulation therapy to improve autonomic and neural/brain activity in adults with SCI living in the community. A two-arm parallel, randomised controlled trial in which adults with SCI living in the community post-rehabilitation will be randomly assigned to a treatment or control group. The treatment group (N = 60) aged 18-70 years with a chronic traumatic or non-traumatic SCI, will receive intervention sessions once per week for 10 weeks, designed to regulate autonomic activity using computer-based feedback of heart rate variability and controlled breathing (called HRV-F). Comprehensive neurophysiological and psychological assessment will occur at baseline, immediate post-treatment, and 6 and 12-months post-treatment. Primary outcome measures include electrocardiography/heart rate variability (to assess autonomic nervous system function) and transcranial doppler sonography (to assess cerebral blood circulation in basal cerebral arteries). Secondary outcomes measures include continuous blood pressure, electroencephalography, functional near-infrared spectroscopy, respiration/breath rate, electrooculography, cognitive capacity, psychological status, pain, fatigue, sleep and quality of life. Controls (N = 60) will receive usual community care, reading material and a brief telephone call once per week for 10 weeks and be similarly assessed over the same time period as the HRV-F group. Linear mixed model analysis with repeated measures will determine effectiveness of HRV-F and latent class mixture modelling used to determine trajectories for primary and selected secondary outcomes of interest. Treatments for improving autonomic function after SCI are limited. It is therefore important to establish whether a neuro-cardiac self-regulation therapy can result in improved autonomic functioning post-SCI, as well as whether HRV-F is associated with better outcomes for secondary conditions such as cardiovascular health, cognitive capacity and mental health. The study has been prospectively registered with the Australian and New Zealand Clinical Trial Registry ( ACTRN12621000870853 .aspx). Date of Registration: 6th July 2021. Trial Sponsor: The University of Sydney, NSW 2006. Protocol version: 22/07/2021.


Detecting shape deformation of moving patterns.
This study measured thresholds for the discrimination of rigidly and nonridgidly rotating patterns in two dimensions. The stimuli employed were closed contours created by the sum of two 'radial frequency' components and sensitivity to their deformation was measured as a function of the difference in the angular velocities of the components. Results show that thresholds do not depend on the specific shape of the pattern. To quantify the influence of local computations versus global pooling, thresholds were measured with parts of the pattern covered by (invisible) pie-shaped apertures. One finds thresholds are not simply a function of the total amount of pattern visible but exhibit a dependence on the number of apertures. Moreover, sensitivity to deformation could neither be fully explained on the basis of local computations nor by linear global summation. A simultaneous masking paradigm was employed to elucidate potential mechanisms involved in the computation of deformation. While 1D masks (horizontal gratings and translating random dots) only marginally elevate thresholds, rotating and expanding motion significantly impairs sensitivity. This indicates that detectors tuned to radial and circular motion are involved in the computation of shape deformation.


Biomolecular AND logic gate based on immobilized enzymes with precise spatial separation controlled by scanning electrochemical microscopy.
A surface-localized enzymatic AND gate based on scanning electrochemical microscopy was designed and studied. The gate is composed of an insulating glass surface modified with the enzyme glucose oxidase (GOx) and another surface opposing it made of a microelectrode. The latter was modified with a second enzyme, invertase (INV). The distance separating the modified microelectrode and surface controlled the output of the AND gate produced upon the biocatalytic reaction of the confined enzymes. Specifically, as the GOx-modified glass substrate entered the diffusion layer of the microelectrode, it catalyzed the regeneration of an electron-transfer mediator, ferroceniummethanol, generated electrochemically at the tip by oxidizing glucose, also generated at the tip, by catalytic cleaving of sucrose by INV. To enhance the activity of the GOx, mutarotase was added to convert α- to β-glucose to be further consumed by GOx. Hence, an increase of the current at the microelectrode was obtained by approaching the glass surface only in the presence of all the components. This is the first micrometer-sized biomolecular logic gate, of which we are aware, that is surface-confined and shows the promise held by the localization of biomolecular information-processing species.