Multimodal optical clearing to minimize light attenuation in biological tissues.
The biggest obstacle to optical imaging is light attenuation in biological tissues. Conventional clearing techniques, such as agent-based clearing, improve light penetration depth by reducing scattering, but they are hampered by drawbacks including toxicity, low efficiency, slowness, and superficial performance, which prevent them from resolving the attenuation problem on their own. Therefore, quick, safe, and effective procedures have been developed. One of them involves using standing ultrasonic waves to build light waveguides that function effectively in the tissue depth while minimizing scattering. Temporal optical clearing is another agent-free strategy that we introduced in our previous article. Whereas not deep, this technique minimizes both light absorption and scattering by pulse width variation in ultra-short pulse regime. Consequently, it can be a complementary method for ultrasonic optical clearing. In this work, we enhanced the light penetration depth in chicken breast tissue by 10 times (0.67-6.7 cm), setting a record in literature by integrating three clearing methods: agent-based, ultrasound-based, and temporal. Here, optical coherence tomography, Bear-Lambert, and fluorescence tests have been used to study the light penetration depth and optical clearing efficiency. Presented work is an essential step in development of diagnostic techniques for human body, from cells to organs.


Phase-unwrapping algorithm for images with high noise content based on a local histogram.
We present a robust algorithm of phase unwrapping that was designed for use on phase images with high noise content. We proceed with the algorithm by first identifying regions with continuous phase values placed between fringe boundaries in an image and then phase shifting the regions with respect to one another by multiples of 2pi to unwrap the phase. Image pixels are segmented between interfringe and fringe boundary areas by use of a local histogram of a wrapped phase. The algorithm has been used successfully to unwrap phase images generated in a three-dimensional shape measurement for noninvasive quantification of human skin structure in dermatology, cosmetology, and plastic surgery.


Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure.
Coronary blood flow (CBF) and myocardial oxygen consumption (MVO(2)) are reduced in dogs with pacing-induced congestive heart failure (CHF), which suggests that energy metabolism is downregulated. Because nitric oxide (NO) can inhibit mitochondrial respiration, we examined the effects of NO inhibition on CBF and MVO(2) in dogs with CHF. CBF and MVO(2) were measured at rest and during treadmill exercise in 10 dogs with CHF produced by rapid ventricular pacing before and after inhibition of NO production with N(G)-nitro-L-arginine (L-NNA, 10 mg/kg iv). The development of CHF was accompanied by decreases in aortic and left ventricular (LV) systolic pressure and an increase in LV end-diastolic pressure (25 +/- 2 mmHg). L-NNA increased MVO(2) at rest (from 3.07 +/- 0.61 to 4.15 +/- 0.80 ml/min) and during exercise; this was accompanied by an increase in CBF at rest (from 31 +/- 2 to 40 +/- 4 ml/min) and during exercise (both P < 0.05). Although L-NNA significantly increased LV systolic pressure, similar increases in pressure produced by phenylephrine did not increase MVO(2). The findings suggest that NO exerts tonic inhibition on respiration in the failing heart.


Fluids--good and bad actors: observations from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology.
Body cavity fluid examination presents a common and sometimes difficult diagnostic challenge in daily cytology practice. Separating benign from malignant cellular changes may require meticulous screening, careful scrutiny of cellular features, and an understanding of the range of reactive changes. We use the data from the College of American Pathologists (CAP) Interlaboratory Comparison Program in Nongynecologic Cytology (NGC) to identify characteristics of fluids that place them at opposite ends of the diagnostic spectrum. To assess the features of individual body cavity fluid slides that demonstrated good performance characteristics and compare them to slides that were poor performers. A databank of 10 396 laboratory responses, including a variety of malignant and benign cases obtained from 1997 through 2001, was used to select cases. A cumulative slide history was used to identify slides that performed well or poorly in each reference diagnosis. Cases were confirmed by consensus of 4 CAP Cytopathology Resource Committee members. Observations and characterizations of good and bad performers in each category were recorded and summarized. Percentage of concordance of poor performers ranged from 0% to 58%. Conversely, good performers were identified with high concordance of laboratory diagnosis in each reference category (>80%). Several patterns emerged. Poorly performing cases of adenocarcinoma consisted of slides with rare tumor cells, hypercellular malignant cases without 2 cell populations, and cases with single cells. Poor performance in confirmed squamous cell carcinoma cases related to rare cells without keratinization. Small cell carcinoma and melanoma cases performed poorly when there were few malignant cells. Lymphoma cases demonstrated poor performance when there were abundant pleomorphic lymphoid cells or when rare Reed- Sternberg-like cells were present. Reactive or negative slides performed best with a polymorphous population; poor performers were those with a predominant lymphocyte population mistaken for a hematopoietic neoplasm. Close attention to classic cytologic criteria and careful examination of slides may enhance the educational experience of participants and the performance characteristics of body cavity fluid specimens in the CAP NGC program. Lessons from bad actors in the CAP NGC program may increase awareness of potential diagnostic problems in daily practice or help identify areas for laboratory quality improvement.


Posterolateral portal tibial tunnel drilling for posterior cruciate ligament reconstruction: technique and evaluation of safety and tunnel position.
To evaluate the safety for neurovascular structures and accuracy for tunnel placement of the posterolateral portal tibial tunnel drilling technique in posterior cruciate ligament (PCL) reconstruction. Fifteen fresh-frozen human cadaveric knees were used. The tibial tunnel for the PCL was created using a flexible reamer from the posterolateral portal. Then, the flexible pin was left in place, and the distance from the posterolateral portal, the flexible pin, and the tibial tunnel to the peroneal nerve and popliteal artery was measured. Additionally, the distance between the tibial tunnel and several landmarks related to the PCL footprint was measured, along with the distance from the exit point of the flexible pin to the superficial medial collateral ligament and gracilis tendon. The peroneal nerve and the popliteal neurovascular bundle were not damaged in any of the specimens. The median (range) distance in mm from the peroneal nerve and popliteal artery to the posterolateral portal and flexible pin was: 52 (40-80) and 50 (40-61), and 35 (26-51) and 22 (16-32), respectively. The median (range) distance from the tibial tunnel to the popliteal artery was 21 mm (15-38). The tibial tunnel was located at a median (range) distance in mm of 3 (2-6), 6 (3-12), 5 (2-7), 4 (1-8), 9 (3-10), 10 (4-19), and 19 (6-24) to the champagne-glass drop-off, lateral cartilage point, shiny white fibre point, medial groove, medial meniscus posterior root, lateral meniscus posterior root, and posterior aspect of the anterior cruciate ligament, respectively. The posterolateral portal tibial tunnel technique is safe relative to neurovascular structures and creates an anatomically appropriate tibial tunnel location. The clinical relevance of study is that this technique may be safely and accurately used in PCL reconstruction to decrease the risk of neurovascular damage (avoid use of a posteriorly directed pin), avoid the use of intraoperative fluoroscopy, and avoid the sharp turn during graft passage.


An Impending Paradigm Shift in Motor Imagery Based Brain-Computer Interfaces.
The development of reliable assistive devices for patients that suffer from motor impairments following central nervous system lesions remains a major challenge in the field of non-invasive Brain-Computer Interfaces (BCIs). These approaches are predominated by electroencephalography and rely on advanced signal processing and machine learning methods to extract neural correlates of motor activity. However, despite tremendous and still ongoing efforts, their value as effective clinical tools remains limited. We advocate that a rather overlooked research avenue lies in efforts to question neurophysiological markers traditionally targeted in non-invasive motor BCIs. We propose an alternative approach grounded by recent fundamental advances in non-invasive neurophysiology, specifically subject-specific feature extraction of sensorimotor bursts of activity recorded via (possibly magnetoencephalography-optimized) electroencephalography. This path holds promise in overcoming a significant proportion of existing limitations, and could foster the wider adoption of online BCIs in rehabilitation protocols.


Safety and Biodistribution Evaluation in Cynomolgus Macaques of rAAV2tYF-PR1.7-hCNGB3, a Recombinant AAV Vector for Treatment of Achromatopsia.
Applied Genetic Technologies Corporation (AGTC) is developing rAAV2tYF-PR1.7-hCNGB3, a recombinant adeno-associated viral (rAAV) vector expressing the human CNGB3 gene, for treatment of achromatopsia, an inherited retinal disorder characterized by markedly reduced visual acuity, extreme light sensitivity, and absence of color discrimination. We report here results of a study evaluating the safety and biodistribution of rAAV2tYF-PR1.7-hCNGB3 in cynomolgus macaques. Three groups of animals (n = 2 males and 2 females per group) received a subretinal injection in one eye of 300 μl containing either vehicle or rAAV2tYF-PR1.7-hCNGB3 at one of two concentrations (4 × 10(11) or 4 × 10(12) vector genomes/ml) and were evaluated over a 3-month period before being euthanized. Administration of rAAV2tYF-PR1.7-hCNGB3 was associated with a dose-related anterior and posterior segment inflammatory response that was greater than that observed in eyes injected with the vehicle control. Most manifestations of inflammation improved over time except that vitreous cells persisted in vector-treated eyes until the end of the study. One animal in the lower vector dose group was euthanized on study day 5, based on a clinical diagnosis of endophthalmitis. There were no test article-related effects on intraocular pressure, visual evoked potential responses, hematology or clinical chemistry parameters, or gross necropsy observations. Histopathological examination demonstrated minimal mononuclear infiltrates in all vector-injected eyes. Serum anti-AAV antibodies developed in all vector-injected animals. No animals developed antibodies to CNGB3. Biodistribution studies demonstrated high levels of vector DNA in the injected eye but minimal or no vector DNA in any other tissue. These results support the use of rAAV2tYF-PR1.7-hCNGB3 in clinical studies in patients with achromatopsia caused by CNGB3 mutations.


Associations between stress and depression symptom profiles vary according to serotonin transporter polymorphism in rural Australians.
Depression remains difficult to treat in all cases, and further investigation of the role of genetic and environmental factors may be valuable. This study was designed to investigate the association between the short (s) versus non-short (non-s) 5HTTLPR variants, presence of childhood stressors and recent life stressors, and depression, and to do so at two levels that would expose the associations between total depression scores and also individual depression items. Two hundred and forty-nine volunteers from one of the Australian Electoral Office electorates covering a large rural land area completed a series of questionnaires about childhood and recent life stress and depression, and provided a buccal cell sample for genotyping the 5-HTTLPR polymorphism into s versus non-s carriers. Although there were no significant differences in the depression scores of the s-carriers versus the non-s carriers, each subtype of the 5-HTTLPR polymorphism showed different patterns of association between childhood stress and depression symptoms, and between recent life stress and depression symptoms. Individualization of therapy for depression may be achieved through consideration of the specific associations that patients exhibit between life stress, 5-HTTLPR polymorphism, and depression symptomatology.


Temporal and spatial characteristics of post-silent period electromyographic bursting in low back muscles: comparison between persons with and without low back pain.
Purpose/aim: Recently, a novel measure of cortical disinhibition was identified using transcranial magnetic stimulation (TMS). This measure, described as post-silent period electromyographic (EMG) bursting, may inform on the corticomotor control of movement in health and disease; however, it has not been investigated for muscles outside the hand or in musculoskeletal conditions. Thus, the aim of this study was to investigate the temporal and spatial characteristics of "EMG bursting" in individuals with and without low back pain (LBP). TMS was used to map the motor cortical representation of paraspinal muscles in 11 individuals with LBP and 11 pain-free controls. The latency, duration and magnitude of bursting, number of active burst sites, map volume and coordinates of the burst "hotspot" were compared between the groups. In pain-free controls, the latency, duration and magnitude of bursts were similar to the hand; however, bursts occurred earlier and were of smaller magnitude in LBP. Bursting was widespread throughout the cortical representation in both groups; however, there was a trend towards smaller mean EMG burst and map volume in LBP. We confirm the presence of EMG bursting in back muscles and provide a description of the spatial profile of this mechanism. Our observations in LBP suggest that cortical disinhibition may be altered in this condition.


How does the oxidative burst of macrophages kill bacteria? Still an open question.
Reactive oxygen species (ROS) are critical components of the antimicrobial repertoire of macrophages, yet the mechanisms by which ROS damage bacteria in the phagosome are unclear. The NADH-dependent phagocytic oxidase produces superoxide, which dismutes to form H(2)O(2). The Barras and Méresse labs use a GFP fusion to an OxyR regulated gene to show that phagocyte-derived H(2)O(2) is gaining access to the Salmonella cytoplasm. However, they have also shown previously that Salmonella has redundant systems to detoxify this H(2)O(2). Although Salmonella propagate in a unique vacuole, their data suggest that ROS are not diminished in this modified phagosome. These recent results are put into the context of our overall understanding of potential oxidative bacterial damage occurring in macrophages.


Placebo Response in Rheumatoid Arthritis Clinical Trials.
Understanding the placebo response is critical to interpreting treatment efficacy, particularly for agents with a ceiling to their therapeutic effect, where an increasing placebo response makes it harder to detect potential benefit. The objective of this study is to assess the change in placebo responses over time in rheumatoid arthritis (RA) randomized placebo-controlled trials (RCT) for drug licensing authorization. The Cochrane Controlled Trials Register database was searched to identify RCT of biological or targeted synthetic disease-modifying antirheumatic drugs (DMARD) in RA. Studies were excluded if patients were conventional synthetic DMARD (csDMARD)-naive, not receiving background csDMARD therapy, or were biologic experienced. Metaregression model was used to evaluate changes in American College of Rheumatology (ACR) 20, ACR50, and ACR70 treatment response over time. There were 32 trials in total: anti-tumor necrosis factor therapy (n = 15), tocilizumab (n = 4), abatacept (n = 2), rituximab (n = 2), and Janus kinase inhibitors (n = 9). From 1999 to 2018, there was no significant trend in the age or sex of patients in the placebo arm. Disease duration, swollen joint count, and 28-joint count Disease Activity Score using erythrocyte sedimentation rate at baseline all significantly declined over time. There was a statistically significant increase in placebo ACR50 and ACR70 responses (ACR50 β = 0.41, 95% CI 0.09-0.74, p = 0.01; ACR70 β = 0.18, 95% CI 0.04-0.31, p = 0.01) that remained significant after controlling for potential confounders. There has been a rise in the placebo response in RA clinical trials over the last 2 decades. Shifting RA phenotype, changes in trial design, and expectation bias are possible explanations for this phenomenon. This observation has important implications when evaluating newer novel agents against established therapies.


Healthcare professionals' and consumers' knowledge, attitudes, perspectives, and education needs in oncology pharmacogenomics: A systematic review.
Clinical implementation of pharmacogenomic (PGx)-guided prescribing in oncology lags behind research evidence generation. We aimed to identify healthcare professionals' (HCPs) and consumers' knowledge, attitudes, perspectives, and education needs to inform strategies for implementation of scalable and sustainable oncology PGx programs. Systematic review of original articles indexed in EMBASE, EMCARE, MEDLINE, and PsycInfo from January 2012 until June 2022, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and using the Mixed Methods Appraisal Tool. PROSPERO registration number CRD42022352348. Of 1442 identified studies; 23 met inclusion criteria with 87% assessed high quality. Of these, 52% reported on HCPs, 35% on consumers, and 13% on both HCPs and consumers. Most were conducted in the United States (70%) and included multiple cancer types (74%). Across studies, HCPs and consumers mostly perceived value in PGx, however, both groups reported barriers to utilization, including cost, lack of consistent recommendations across guidelines, and limited knowledge among HCPs; test accuracy, clear testing benefits, and genomic information confidentiality among consumers. HCPs and consumers value and want to engage in PGx strategies in oncology care, however, are inhibited by unmet needs and practice and knowledge gaps. Implementation strategies aimed at addressing these issues may best support increased PGx uptake in oncology practice.


New biocompatible polymeric micelles designed for efficient intracellular uptake and delivery.
New amphiphilic block copolymers are easily synthesised by post-polymerisation modifications of poly(glycidyl methacrylate) chain derivatives. The obtained material, upon dispersion in water, is capable of self-assembling into robust micelles. These nanoparticles, which are also characterised by adaptable stability, were loaded with different thiophene based fluorophores. The photoluminescent micelles were administered to cultured cells revealing a high and rapid internalisation of structurally different fluorescent molecules by the same internalisation pathway. Appropriate pairs of chromophores were selected and loaded into the micelles to induce Förster resonance energy transfer (FRET). The disappearing of the FRET phenomenon, after cell uptaking, demonstrated the intracellular release of the nanoparticle contents. The studied nanomaterial and the loaded chromophores have also shown to be biocompatible and non toxic towards the tested cells.


Integration of protein tethering in a rapid and label-free SERS screening platform for drugs of abuse.
Surface enhanced Raman spectroscopy (SERS) has emerged as a promising technique for the rapid and ultrasensitive detection of molecular species such as drugs of abuse in biofluids. Yet, it remains a significant challenge to create a viable screening tool for multiple drug classes, owing to the lack of affinity of certain species for the SERS substrate and to the matrix interference in complex media. Here we report a protein tethering SERS approach, which blends plasmonic enhancement with facile drug binding, to engineer a rapid, label-free and versatile screening tool for narcotics. By exploiting the known binding attributes of human serum albumin, we determine the effective concentration of narcotics present in solution through differential enhancement of the spectral markers. In conjunction with chemometric methods, this approach not only enables unambiguous recognition of different drug classes, such as barbiturates, opiates, amphetamines and benzodiazepines, but also offers a lower limit of detection in comparison to direct SERS application. Through molecular docking simulations, we probe the mechanistic underpinnings of the protein tethering approach paving the way for narcotic detection in clinical samples in the near future.


Age, working memory, figurative language type, and reading ability: influencing factors in African American adults' comprehension of figurative language.
This study investigated the cognitive and linguistic factors presumed to be associated with adult comprehension of figurative language, including age, working memory (WM), figurative language type, and reading comprehension (RC). Forty younger (M = 22 years) and 40 older (M = 63 years) healthy African American adults completed WM and reading tasks, and the 60-item forced-choice multiple-category (20 idioms, 20 metaphors, and 20 metonyms) Figurative Language Comprehension Test. After controlling for WM and RC, the older adults outperformed the younger adults on idioms and metonyms. Metaphor comprehension was comparable between the groups. Findings demonstrate that WM and RC underlie adults' comprehension of figurative language and should be considered when interpreting performance on tests assessing figurative language competence in this population.


Regulation of firing response gain by calcium-dependent mechanisms in vestibular nucleus neurons.
Behavioral reflexes can be modified by experience via mechanisms that are largely unknown. Within the circuitry for the vestibuloocular reflex (VOR), neurons in the medial vestibular nucleus (MVN) show adaptive changes in firing rate responses that are correlated with VOR gain (the ratio of evoked eye velocity to input head velocity). Although changes in synaptic strength are typically assumed to underlie gain changes in the VOR, modulation of intrinsic ion channels that dictate firing could also play a role. Little is known, however, about how ion channel function or regulation contributes to firing responses in MVN neurons. This study examined contributions of calcium-dependent currents to firing responses in MVN neurons recorded with whole cell patch electrodes in rodent brain stem slices. Firing responses were remarkably linear over a wide range of firing rates and showed modest spike frequency adaptation. Firing response gain, the ratio of evoked firing rate to input current, was reduced by increasing extracellular calcium and increased either by lowering extracellular calcium or with antagonists to SK- and BK-type calcium-dependent potassium channels and N- and T-type calcium channels. Blockade of SK channels occluded gain increases via N-type calcium channels, while blocking BK channels occluded gain increases via presumed T-type calcium channels, indicating specific coupling of potassium channels and their calcium sources. Selective inhibition of Ca(2+)/calmodulin-dependent kinase II and broad-spectrum inhibition of phosphatases modulated gain via BK-dependent pathways, indicating that firing responses are tightly regulated. Modulation of firing response gain by phosphorylation provides an attractive mechanism for adaptive control of VOR gain.


[A method of isolating Vibrio parahaemolyticus from different substrates].
A method for isolation of parahemolytic vibrios is suggested, based on their high mobility in semiliquid agar gel. A special semiliquid medium was designed and tried, containing agar-agar, peptone, sodium chloride, mannose, gelatin, indicator, Progress agent. The material is inoculated into the center of a petri dish. After incubation at 37 degrees C parahemolytic vibrios form macrocolonies on the surface of the medium, colored black against the red background of the medium. This method permits ruling out preliminary enrichment of the inoculation material in liquid medium, is more effective and rapid.


Naturally acquired simian retrovirus infections in central African hunters.
Hunting and butchering of wild non-human primates infected with simian immunodeficiency virus (SIV) is thought to have sparked the HIV pandemic. Although SIV and other primate retroviruses infect laboratory workers and zoo workers, zoonotic retrovirus transmission has not been documented in natural settings. We investigated zoonotic infection in individuals living in central Africa. We obtained behavioural data, plasma samples, and peripheral blood lymphocytes from individuals living in rural villages in Cameroon. We did serological testing, PCR, and sequence analysis to obtain evidence of retrovirus infection. Zoonotic infections with simian foamy virus (SFV), a retrovirus endemic in most Old World primates, were identified in people living in central African forests who reported direct contact with blood and body fluids of wild non-human primates. Ten (1%) of 1099 individuals had antibodies to SFV. Sequence analysis from these individuals revealed three geographically-independent human SFV infections, each of which was acquired from a distinct non-human primate lineage: De Brazza's guenon (Cercopithecus neglectus), mandrill (Mandrillus sphinx), and gorilla (Gorilla gorilla), two of which (De Brazza's guenon and mandrill) are naturally infected with SIV. Our findings show that retroviruses are actively crossing into human populations, and demonstrate that people in central Africa are currently infected with SFV. Contact with non-human primates, such as happens during hunting and butchering, can play a part in the emergence of human retroviruses and the reduction of primate bushmeat hunting has the potential to decrease the frequency of disease emergence.


Spirometry in laryngotracheal stenosis: a systematic review and meta-analysis.
This study aimed to assess the changes in spirometry parameters or indices after relieving laryngotracheal stenosis (LTS) in adult patients. A systematic review and meta-analysis of studies from PubMed, Scopus, Web of Science, Cochrane Library, and EBSCO databases was conducted for assessing changes in spirometry values after endoscopic balloon dilatation of LTS in adults. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Relevant data, such as changes in mean spirometry values between preoperative and postoperative interventions, and findings of receiver operating characteristic curve analyses for predicting the need for surgical intervention, were extracted. Ten studies including 330 patients overall met the inclusion criteria. Significant improvements were observed from preoperative to postoperative mean values of different spirometry parameters and indices. The overall mean differences in peak expiratory flow (ΔPEF), expiratory disproportion index (ΔEDI), and peak inspiratory flow (ΔPIF) were 2.26 L/s (95% CI 2.14-2.38), 27.94 s (95% CI 26.36-29.52), and 1.21 L/s (95% CI 0.95-1.47), respectively. ΔPEF and ΔPIF values increased, while ΔEDI decreased. In predicting the need for surgical intervention, EDI had the highest sensitivity (88%), and forced expiratory volume per second/forced vital capacity had the highest specificity (85%). Spirometry is a valuable tool for assessing patients with LTS. PEF, EDI, and PIF were the most commonly reported spirometry parameters that significantly improved after airway stenosis was relieved.


Outcomes of permanent inferior vena cava filters: experiences in Thai patients.
We aimed to study the outcomes of permanent inferior vena cava (IVC) filter implantation in Thai patients. This was a retrospective study of 28 patients with deep vein thrombosis (DVT) who underwent prophylactic implantation of IVC filters for fatal pulmonary embolism (PE) between January 2005 and June 2008. The patients' operative records, protocol and follow-up data were analysed. 11 (39%) patients had PE at the initial diagnosis. The mean age of the patients was 62.1 (range 33-83) years. Indications for IVC filter implantation included contraindications to and complications of anticoagulant therapy and floating thrombi in the iliofemoral veins. No significant technical complication was noted, except for malposition in one patient (3.5%) and failure of the permanent IVC filter to open fully in another. During the follow-up period (mean 17.5 ± 10.9 months), no patients had any episode of PE and nine (32%) died of unrelated causes. Two patients were lost to follow-up. Among the 17 survivors, six (35.2%) had non-recanalised thrombosis vein, four (23.5%) had clinical evidence of chronic venous insufficiency, two (11.7%) had recurrent DVT in the contralateral limb and one (5.8%) developed IVC thrombosis. There was no evidence of migration of the caval filters. No statistical significance was observed in the effects of post-filter anticoagulation drug on current DVT and in the relation between PE at initial diagnosis and death during follow-up. Permanent IVC filter implantation may be effective for preventing symptomatic PE in Thai patients, with no significant sequelae in the lower extremities.


Renal toxicity of radiolabeled peptides and antibody fragments: mechanisms, impact on radionuclide therapy, and strategies for prevention.
Peptide-receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs such as octreotide is an effective therapy against neuroendocrine tumors. Other radiolabeled peptides and antibody fragments are under investigation. Most of these compounds are cleared through the kidneys and reabsorbed and partially retained in the proximal tubules, causing dose-limiting nephrotoxicity. An overview of renal handling of radiolabeled peptides and resulting nephrotoxicity is presented, and strategies to reduce nephrotoxicity are discussed. Modification of size, charge, or structure of radiolabeled peptides can alter glomerular filtration and tubular reabsorption. Coinfusion of competitive inhibitors of reabsorption also interferes with the interaction of peptides with renal endocytic receptors; coinfusion of basic amino acids is currently used for kidney protection in clinical PRRT. Furthermore, nephrotoxicity may be reduced by dose fractionation, use of radioprotectors, or use of mitigating agents. Decreasing the risk of nephrotoxicity allows for administration of higher radiation doses, increasing the effectiveness of PRRT.


Mobilizing technology for developing countries.
A new problem in technology policy-a discipline hitherto largely concerned with the modern industrial sector-is posed by the need for technology suited to creating productive jobs and providing minimum public services at a cost and level of sophistication within the reach of poor people in developing countries. Careful consideration must be given to overall and sectoral development objectives, economic and manpower resources, and the local institutional and sociocultural context. This may indicate the need for both hardware innovation, such as low-cost alternatives to waterborne sewerage, and social ("software") innovation, such as training large numbers of supervisors to implement improved technologies for labor-intensive civil works.


The electronic structure, mechanical flexibility and carrier mobility of black arsenic-phosphorus monolayers: a first principles study.
New artificial layered semiconductors - black arsenic-phosphorus (b-AsP) - which have tunable band gaps owing to good tunability of the chemical compositions have been synthesized in a recent experiment. In the present work, first principles calculations are performed to systematically study the structure, and mechanical, electrical, and transport properties of b-AsP monolayers. The mechanical analysis demonstrates that the exfoliation of single-layer b-AsP systems from the bulk form is more difficult compared with that of pure black phosphorus (BP). In addition, the breaking strain of the b-AsP monolayer is comparable with other widely studied two dimensional materials, indicating their excellent mechanical flexibility and good potential for flexible device applications. Besides, the electronic structures of b-AsP system monolayers are not sensitive to their specific compositions, which however, can be flexibly modulated by the strain effect. The predicted carrier mobilities of b-AsP systems are directionally anisotropic, similar to pure BP. However, the degradation of their carrier mobilities may become a practical limitation in real electronic device applications.


Are we close to knowing the plant diversity of the Amazon?
Amazonia is often cited as having the most diverse flora on the planet. However, the total number of species of higher plants in the region has been largely a matter of guesswork. Some recent publications have estimated the total number of species present, which indicate a lower overall diversity than was estimated in the past. However, analysis of the sampling density across the region, and data from various sources suggest that there may be reason why the recent figures may be considerable underestimates. I believe that much more investment in extensive collecting of quality plant specimens is needed to encounter the very large number of rare and local species that might never have been collected. Unfortunately the tendencies of investment in botany, in terms of geography and types of project, suggest that we will probably not be able to accurately assess the real diversity of the region.


Friends With Benefits: Exploring the Phycosphere of the Marine Diatom Skeletonema marinoi.
Marine diatoms are the dominant phytoplankton in the temperate oceans and coastal regions, contributing to global photosynthesis, biogeochemical cycling of key nutrients and minerals and aquatic food chains. Integral to the success of marine diatoms is a diverse array of bacterial species that closely interact within the diffusive boundary layer, or phycosphere, surrounding the diatom partner. Recently, we isolated seven distinct bacterial species from cultures of Skeletonema marinoi, a chain-forming, centric diatom that dominates the coastal regions of the temperate oceans. Genomes of all seven bacteria were sequenced revealing many unusual characteristics such as the existence of numerous plasmids of widely varying sizes. Here we have investigated the characteristics of the bacterial interactions with S. marinoi, demonstrating that several strains (Arenibacter algicola strain SMS7, Marinobacter salarius strain SMR5, Sphingorhabdus flavimaris strain SMR4y, Sulfitobacter pseudonitzschiae strain SMR1, Yoonia vestfoldensis strain SMR4r and Roseovarius mucosus strain SMR3) stimulate growth of the diatom partner. Testing of many different environmental factors including low iron concentration, high and low temperatures, and chemical signals showed variable effects on this growth enhancement by each bacterial species, with the most significant being light quality in which green and blue but not red light enhanced the stimulatory effect on S. marinoi growth by all bacteria. Several of the bacteria also inhibited growth of one or more of the other bacterial strains to different extents when mixed together. This study highlights the complex interactions between diatoms and their associated bacteria within the phycosphere, and that further studies are needed to resolve the underlying mechanisms for these relationships and how they might influence the global success of marine diatoms.


Dynamic Single-Leg Postural Control Is Impaired Bilaterally Following Anterior Cruciate Ligament Reconstruction: Implications for Reinjury Risk.
Study Design Cross-sectional, controlled laboratory study. Background Postural control following anterior cruciate ligament reconstruction (ACLR) primarily has been investigated during static single-leg balance tasks. Little is known about dynamic postural control deficits post-ACLR. Objectives To compare dynamic postural control (bilaterally) in individuals who have undergone ACLR and in healthy controls, and to evaluate the relationship between dynamic postural control and self-reported and objective function. Methods Ninety-seven participants (66 male; median age, 28 years) 12 months post-ACLR and 48 healthy controls (20 male; median age, 30 years) underwent balance assessment using a Nintendo Wii Balance Board during a single-leg squat. Center-of-pressure (CoP) path velocity, as well as CoP amplitude and standard deviation, in both mediolateral (ML) and anteroposterior (AP) directions were recorded. Self-reported function was assessed with the International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC), while hop for distance was used to evaluate functional status. Results Compared to healthy controls, the ACLR group had greater mean CoP path velocity (16% higher, P = .004), ML range (23%, P<.001), ML SD (28%, P<.001), AP range (14%, P = .009), and AP SD (15%, P = .013), indicating worse dynamic balance post-ACLR. Dynamic balance performance was similar between the ACLR limb and the uninjured contralateral limb. The AP SD was weakly associated with hop performance (β = -.2, P = .046); no balance measures were associated with IKDC score. Conclusion Individuals who have undergone ACLR demonstrate impaired dynamic balance bilaterally when performing a single-leg squat, which may have implications for physical function and future injury risk. Routine dynamic balance assessment may help identify patients who could benefit from targeted neuromuscular training programs to improve objective function and potentially lower reinjury risk. J Orthop Sports Phys Ther 2016;46(5):357-364. Epub 21 Mar 2016. doi:10.2519/jospt.2016.6305.


Short- to medium-term outcomes and future direction of reverse shoulder arthroplasty: Current concepts.
Reverse shoulder arthroplasty is typically indicated for patients with severe shoulder osteoarthritis, rotator cuff tear arthropathy, or proximal humerus fractures that have failed to heal properly. The primary goal of reverse shoulder arthroplasty is to improve shoulder function and reduce pain, while also restoring the ability to perform daily activities. There is a growing body of evidence supporting the effectiveness of reverse shoulder arthroplasty in improving shoulder function and reducing pain in patients with severe shoulder osteoarthritis or rotator cuff tear arthropathy. Reverse shoulder arthroplasty is associated with significant improvements in shoulder function and pain reduction compared to non-surgical treatments. This paper aims to summarize current knowledge, practices and present a summary of the long-term effects of reverse shoulder arthroplasty (RSA) on patient outcomes, including how these outcomes are defined and what measures are typically used to assess them. It will also cover newer definitions of outcomes for RSA that have been developed in recent years in order to better understand the long-term effects of the procedure on patient-reported outcomes and functional ability, as well as information on revision surgery and implant survivorship, and the future of RSA (3D-navigation, patient-specific instrumentation, robotics and artificial intelligence) and its effects on outcomes.


In Vitro and In Vivo Studies of Spironolactone as an Antischistosomal Drug Capable of Clinical Repurposing.
Schistosomiasis is a parasitic flatworm disease that infects over 200 million people worldwide, especially in poor communities. Treatment and control of the disease rely on just one drug, praziquantel. Since funding for drug development for poverty-associated diseases is very limited, drug repurposing is a promising strategy. In this study, from a screening of 13 marketed diuretics, we identified that spironolactone, a potassium-sparing diuretic, had potent antischistosomal effects on Schistosoma mansoniin vitro and in vivo in a murine model of schistosomiasis. In vitro, spironolactone at low concentrations (<10 µM) is able to alter worm motor activity and the morphology of adult schistosomes, leading to parasitic death. In vivo, oral treatment with spironolactone at a single dose (400 mg/kg) or daily for five consecutive days (100 mg/kg/day) in mice harboring either patent or prepatent infections significantly reduced worm burden, egg production, and hepato- and splenomegaly (P < 0.05 to P < 0.001). Taken together, with the safety profile of spironolactone, supported by its potential to affect schistosomes, these results indicate that spironolactone could be a potential treatment for schistosomiasis and make it promising for repurposing.


Nudging Urban Food Pantry Users in Utah Toward Healthier Choices.
Purpose. To evaluate the impact of a nudge program on food pantry clients' self-reported selection and use of healthy foods. Method. A convenience sample of clients of six urban food pantries in Utah were surveyed about their experience with the Thumbs Up for Healthy Choices nudge program. Chi-square tests were used to identify associations between demographic characteristics and self-reported program impact. Results. Ninety-four percent (n = 158) of respondents agreed that the program made it easier to make healthy choices. Sixty-five percent reported healthier diets since its implementation. Additionally, Hispanic respondents were more likely to report positive impacts than non-Hispanic respondents. Conclusions and Implications. Nudge programs are effective in increasing the selection of healthy foods among pantry clients in Utah. Impacts seemed to be particularly positive for Hispanic pantry users in Utah. Nutrition programs should consider implementing these low-cost strategies to improve dietary quality of pantry users.


Comparison of toluene-induced and styrene-induced hearing losses.
Toluene and styrene are industrial solvents that can severely damage the auditory function in adult rats. In the present study, toluene (1000 to 2000 ppm) and styrene doses (500 to 1500 ppm) were investigated according to the same schedule: 6 hours per day, 5 days per week, for 4 consecutive weeks. The auditory function of the animals was tested by recording evoked potentials from the inferior colliculus over a frequency range from 2 to 32 kHz, whereas pathological data were evaluated by conventional histologic techniques. The permanent threshold shifts (PTS) were obtained with a styrene dose 2.4 times lower than that of the toluene. The slope of the regression line (PTS/doses) was 2.1 steeper with styrene than that obtained with toluene in the same experimental conditions. The sequence of histopathological events along the organ of Corti, especially the orderliness and the location of the traumas, was similar for paired concentrations of styrene and toluene, which were respectively 650 ppm, 1500 ppm for the first match, and 850 ppm, 1750 ppm for the second one. Both electrophysiological and histological findings point out the higher ototoxic potency of the styrene compared to that of the toluene. Assumptions concerning the ototoxic mechanism are addressed in the present paper.


Peptide cargo tunes a network of correlated motions in human leucocyte antigens.
Most biomolecular interactions are typically thought to increase the (local) rigidity of a complex, for example, in drug-target binding. However, detailed analysis of specific biomolecular complexes can reveal a more subtle interplay between binding and rigidity. Here, we focussed on the human leucocyte antigen (HLA), which plays a crucial role in the adaptive immune system by presenting peptides for recognition by the αβ T-cell receptor (TCR). The role that the peptide plays in tuning HLA flexibility during TCR recognition is potentially crucial in determining the functional outcome of an immune response, with obvious relevance to the growing list of immunotherapies that target the T-cell compartment. We have applied high-pressure/temperature perturbation experiments, combined with molecular dynamics simulations, to explore the drivers that affect molecular flexibility for a series of different peptide-HLA complexes. We find that different peptide sequences affect peptide-HLA flexibility in different ways, with the peptide cargo tuning a network of correlated motions throughout the pHLA complex, including in areas remote from the peptide-binding interface, in a manner that could influence T-cell antigen discrimination.


Associations of household structure and presence of children in the household with mental distress during the early stages of the U.S. COVID-19 pandemic.
The objectives of the current study were to (1) assess associations between household structure (i.e., living with spouse compared to living alone, with children, or with a spouse and children), presence of children, and mental distress in April 2020 and change in mental distress (between April and August 2020); and (2) determine whether these associations are moderated by income or sex. A total of 2,214 adults aged 25-55 from the April and August 2020 waves of the Understanding America study were included in the analytic sample. Multivariable, survey-weighted linear regression models were used to examine associations between explanatory variables (i.e., household structure and number of children) and outcome variables (mental distress in April and change in mental distress), measured via the Patient Health Questionnaire (PHQ)-4. In adjusted models, each additional child under the age of 12 was associated with lower mental distress in April 2020 (β = -.30, p = .002). Having children aged 13 to 18 and household structure were not significantly associated with mental distress. In interaction models, living with children only was associated with decreased mental distress among individuals reporting low income (interaction β = -1.28, p = .016) but not high income. Similarly, living with children only was associated with decreased mental distress in females (interaction β = -1.09, p = .025) but not males. This study supports prior literature that demonstrates the positive association of child rearing with psychological well-being and suggests that these benefits may be present even under stay-at-home orders in the early stages of the U.S. COVID-19 pandemic. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Mesoscale simulation of semiflexible chains. I. Endpoint distribution and chain dynamics.
The endpoint distribution and dynamics of semiflexible fibers are studied by numerical simulation. A brief overview is given over the analytical theory of flexible and semiflexible polymers. In particular, a closed expression is given for the relaxation spectrum of wormlike chains, which determines polymer diffusion and rheology. Next a simulation model for wormlike chains with full hydrodynamic interaction is described, and relations for the bending and torsion modulus are given. Two methods are introduced to include torsion stiffness into the model. The model is validated by simulating single chains in a heat bath, and comparing the endpoint distribution of the chains with established Monte Carlo results. It is concluded that torsion stiffness leads to a slightly shorter effective persistence length for a given bending stiffness. To further validate the simulation model, polymer diffusion is studied for fixed persistence length and varying polymer length N. The diffusion constant shows crossover from Rouse (D [proportionality] N(-1)) to reptation behaviour (D [proportionality] N(-2)). The terminal relaxation time obtained from the monomer displacement is consistent with the theory of wormlike chains. The probability for chain crossing has also been studied. This probability is so low that it does not influence the present results.


[Analysis of a dacrolith ].
Dacryoliths are uncommon and there are only a few reports in the literature. In a patient with recurrent stenosis of the lacrimal drainage system a lacrimal stone (dacryolith) was removed from the lacrimal sac during dacryocystorhinostomy. A histological and immunohistochemical examination was performed and keratin antibodies could be detected. In a chemical analysis calcium, sulfur and some phosphorus were determined as major constituents.


Attitudes and practices of family paediatricians in Italy regarding infant feeding.
The aim of this study was to examine attitudes and practices of family paediatricians in Italy towards infant feeding. A questionnaire was sent to 850 paediatricians across Italy, asking about attitudes and practices towards infant feeding with focus on the World Health Organization's criteria. The response rate was 91.2%. Breastfeeding is recommended for 6-11 months (70.6%) or longer (29.4%). A 95% of paediatricians recommend introducing complementary foods throughout 4-5.9 months. Among paediatricians who give indications about the minimum acceptable diet (61.7%), recommendations agree with WHO in 71.3% and 83.3% of cases for infants aged 6-8 or 9-11 months, respectively. A 95.6% of paediatricians recommend consumption of meat for infants aged 6 months or more, and 98.4% use of formula milk for infants having breastfeeding stopped in the first year of life. Paediatricians reported own experience (73.4%) and reading (54.2%) as main sources of information. A 70% of paediatricians know the WHO/Infant and Young Child Feeding Practices criteria regarding breastfeeding but <5% the complementary feeding indicators. Family paediatricians in Italy have positive disposition towards infant feeding but their knowledge and practices are suboptimal with respect to the WHO criteria, especially regarding complementary feeding.


Inhibition and decay of motor and nonmotor priming.
Motor responses can be facilitated by congruent visual stimuli and prolonged by incongruent visual stimuli that are made invisible by masking (direct motor priming). Recent studies on direct motor priming showed a reversal of these priming effects when a three-stimulus paradigm was used in which a prime was followed by a mask and a target stimulus was presented after a delay. A similar three-stimulus paradigm on nonmotor priming, however, showed no reversal of priming effects when the mask was used as a cue for processing of the following target stimulus (cue priming). Experiment 1 showed that the time interval between mask and target is crucial for the reversal of priming. Therefore, the time interval between mask and target was varied in three experiments to see whether cue priming is also subject to inhibition at a certain time interval. Cues indicated (1) the stimulus modality of the target stimulus, (2) the task to be performed on a multidimensional auditory stimulus, or (3) part of the motor response. Whereas direct motor priming showed the reversal of priming about 100 msec after mask presentation, cue priming effects simply decayed during the 300 msec after mask presentation. These findings provide boundary conditions for accounts of inverse priming effects.


Gloiocephala cerkezii, a new species from Croatia.
A new species, Gloiocephala cerkezii, is described from Croatia. It is characterized by a pale brown to rusty brown pileus, an elongated central to slightly eccentric stipe, vein-like lamellae, large and elongate spores, subcapitate to capitate cystidia, a gelatinized trama, and the absence of hairs on the pileus and stipe. The description is accompanied by black and white photograph of basidiocarps and line drawings of microscopic elements. G. cerkezii is compared to closely related species, and a dichotomous key to European species of the genus Gloiocephala is provided. A new combination Gloiocephala pseudocaricis is made.


Fauna of Noctuidae (Lepidoptera: Noctuoidea) in a pasture area in Altamira, Eastern Amazon, Pará, Brazil.
This study evaluated the nocturnal fauna of Noctuidae in a pasture area in Altamira, Pará. Samples were collected monthly for two nights at the new moon period, from August 2007 to July 2008. We collected a total of 345 specimens (N) of 66 species (S). The most abundant species were Ptichodes basilans (Guenée) (n = 87), Leucania jaliscana (Schaus), Spodoptera frugiperda (JE Smith) (n = 28) and Argidia palmipes Guenée (n = 21). For the entire period, the following indexes were found: Shannon diversity H'= 3.20 and Brillouin H = 2.94, evenness of Shannon E'= 0.76 and Brillouin E= 0.76, and Berger-Parker dominance BP= 0.252. The greatest diversity was found in the dry season. According to the estimates of species richness, it is possible that between 14 to 72 more species exist in the region.


Neurologic Evaluation in Children With Laryngeal Cleft.
Referral to a neurologist and imaging play important roles in the management of laryngeal cleft. Swallowing involves a complex series of neuromuscular interactions, and aspiration can result from anatomical causes (eg, laryngeal cleft), neuromuscular disorders, or some combination thereof. To date, no protocols or guidelines exist to identify which patients with laryngeal cleft should undergo neuroimaging studies and/or consultation with a neurologist. To establish guidelines for neurologic evaluation and imaging techniques to identify or rule out neuromuscular dysfunction in children with laryngeal cleft. Retrospective review of the medical records of 242 patients who were diagnosed with laryngeal cleft at a tertiary children's hospital between March 1, 1998, and July 6, 2015. Based on this review, an algorithm to guide management of laryngeal cleft is proposed. Data extracted from patient medical records included the type of laryngeal cleft, details of neurologic referral, results of neuroimaging studies, and objective swallow study outcomes. Of the 242 patients, 142 were male and 100 were female. Mean age at the time of data analysis was 8.7 years (range, 10 months to 25 years), and there were 164 type I clefts, 64 type II, 13 type III, and 1 type IV. In all, 86 patients (35.5%) were referred to a neurologist; among these, 33 (38.4%) had examination findings indicative of neuromuscular dysfunction or dyscoordination (eg, hypotonia, spasticity, or weakness). Abnormal findings were identified in 32 of 50 patients (64.0%) who underwent brain imaging. Neurosurgical intervention was necessary in 3 patients diagnosed with Chiari malformation and in 1 patient with an intraventricular tumor detected on neuroimaging. A substantial proportion of patients with laryngeal cleft have coexistent neuromuscular dysfunction as a likely contributing factor to dysphagia and aspiration. Collaboration with a neurologist and appropriate neuroimaging may provide diagnostic and prognostic information in this subset of patients. At times, imaging will identify critical congenital malformations that require surgical treatment.


Diffuse idiopathic skeletal hyperostosis masquerading as asthma: case report.
A 52-year-old man with a 10-year history of treatment-resistant asthma presented with repeated exacerbations over the course of 10 months. His symptoms were not responsive to salbutamol or inhaled corticosteroid agents, and he developed avascular necrosis of his left hip as a result of prolonged steroid therapy. Physical examination and radiography revealed signs consistent with diffuse idiopathic skeletal hyperostosis (DISH), including a C7-T1 osteophyte causing severe tracheal compression. The patient underwent C6-T1 anterior discectomy and fusion, and the compressive osteophyte was removed, which completely resolved his "asthma." Postoperative pulmonary function tests showed normalization of his FEV1/FVC ratio, and there was no airway reactivity on methacholine challenge. DISH is a systemic, noninflammatory condition characterized by ossification of spinal entheses, and it can present with respiratory disturbances due to airway compression by anterior cervical osteophytes. The authors present, to the best of their knowledge, the first documented case of asthma as a presentation of DISH.


Polyphenols produced during red wine ageing.
Over the past few years, it has been accepted that a moderate red wine consumption is a factor beneficial to human health. Indeed, people of France and Italy, the two major wine-producing European countries, eat a lot of fatty foods but suffer less from fatal heart strokes than people in North-America or in the northern regions of Europe, where wine is not consumed on a regular basis. For a time, ethanol was thought to be the "good" chemical species hiding behind what is known as the "French paradox". Researchers now have turned their investigations towards a family of natural substances called "polyphenols", which are only found in plants and are abundant in grapes. It is well known that these molecules behave as radical scavengers and antioxidants, and it has been demonstrated that they can protect cholesterol in the LDL species from oxidation, a process thought to be at the origin of many fatal heart attacks. However, taken one by one, it remains difficult to demonstrate which are the best polyphenols as far as their antioxidant activities are concerned. The main obstacle in that kind of research is not the design of the chemical and biological tests themselves, but surprisingly enough, the limited access to chemically pure and structurally elucidated polyphenolic compounds. In this article, particular attention will be paid to polyphenols of red wine made from Vitis vinifera cultivars. With respect to the "French paradox", we address the following question: are wine polyphenolic compounds identical to those found in grapes (skin, pulp and seed), or are there biochemical modifications specifically taking place on the native flavonoids when a wine ages? Indeed, structural changes occur during wine conservation, and one of the most studied of those changes concerns red wine colour evolution, called "wine ageing". As a wine ages, it has been demonstrated that the initially present grape pigments slowly turn into new more stable red pigments. That phenomenon goes on for weeks, months and years. Since grape and wine polyphenols are chemically distinct, their antioxidant activities cannot be the same. So, eating grapes might well lead to beneficial effects on human health, due to the variety and sometimes large amounts of their polyphenolic content. However, epidemiological surveys have focused on wines, not on grapes....


[Peculiarities of clinical features and surgical treatment policy in old patients with acute cholecystitis].
The results of treatment of 138 patients with acute cholecystitis aged from 75 to 89 years are analyzed. Calculous cholecystitis was revealed in 126 patients, acalculous cholecystitis--in 12 patients. Cholelythiasis was revealed in 63 (45.6%), stricture of the large duodenal papilla (LDP)--in 13 (9.4%), combination of choledocholithiasis and stricture of LDP--in 16 (11.6%). Mechanical jaundice was revealed in 54 (39.1%) patients, purulent cholangitis--in 18 (13%). From 138 patients 113 (81.8%) underwent surgery. Urgent operations were carried out in 35 (30.9%), early operations--in 54 (47.8%), delayed operation--in 24 (21.2%) patients. Cholecystectomy was performed in 99 patients, it was supplemented with choledocholithotomy and various types of external drainage of the duct (n = 28), choledochoduodenostomy (in 40), transduodenal papillosphincterotomy (n = 6) and endoscopic papillosphincterotomy (n = 7). Cholecystostomy was carried out in 14 patients (including laparoscopic cholecystostomy, n = 5). Repeated operations were performed in 29 patients. Postoperative complications appeared in 28 (24.7%) patients. 16 patients (14.1%) died after the operation. The causes of death were hepatic functional deficiency (6), peritonitis (2), pancreatic necrosis (1), acute cardio-vascular failure (4), pulmonary artery thrombo-embolism (2), acute cerebro-vascular failure (1).


Hippocampal volume and cortical sources of EEG alpha rhythms in mild cognitive impairment and Alzheimer disease.
Atrophy of hippocampus and alteration of resting eyes-closed electroencephalographic (EEG) rhythms represent important features of mild cognitive impairment (MCI) and Alzheimer's disease (AD). Here we evaluated linear and non-linear aspects of the relationship between these features in the continuum along MCI and AD conditions, as a reflection of neurodegenerative processes. Eyes-closed resting EEG data were recorded in 60 healthy elderly (Nold), 88 MCI, and 35 Alzheimer's disease (AD) patients. Hippocampal volume was measured in magnetic resonance imaging of the MCI and AD subjects. Based on the normalized hippocampal volume, selected MCI subjects could be divided into two demographically paired sub-groups: those with larger hippocampal volume (MCI +h; N=40; mini mental state evaluation - MMSE - score=27.5+/-0.26 SE) and those with smaller hippocampal volume (MCI -h; N=40; h; MMSE=26.5+/-0.34 SE); the normalized hippocampal volume was statistically greater in the MCI +h than in the MCI -h and AD subjects (p<0.0001). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha 1 (8-10.5 Hz), alpha 2 (10.5-13 Hz), beta 1 (13-20 Hz), and beta 2 (20-30 Hz). Cortical EEG generators were estimated by LORETA software. Results showed that the power of occipital, parietal, and temporal alpha 1 sources was maximum in MCI +h, intermediate in MCI -h, and low in AD patients. Furthermore, the power of these sources was linearly and non-linearly correlated with the normalized hippocampal volume. These 3 EEG sources were given as input for evaluating correlations (linear, exponential, logarithmic and power) with hippocampal volume. When subjects were considered as a unique group, there was a significant linear correlation of hippocampal volume with the magnitude of alpha 1 sources in the parietal, occipital and temporal areas. In general, the EEG sources showing significant linear correlation with hippocampal volume also supported a non-linear correlation with hippocampal volume strongly for the logarithmic one. The present results suggest that progressive atrophy of hippocampus correlates with decreased cortical alpha power, as estimated by using LORETA source modeling, in the continuum along MCI and AD conditions.


Electrophysiological studies of primary cultures of rabbit distal tubule cells.
Primary monolayers grown from F1 band of a Percoll gradient centrifugation ("distal" monolayers) were studied, after confluency, 6-14 days after seeding. Transmission and scanning electron microscopy revealed that two cell types, resembling principal cells of the rabbit cortical collecting tubule (CCT) and intercalated cells of either CCT or connecting tubule, constitute approximately 96% of the monolayer. About two-thirds of the intercalated cells fluoresced when treated with fluorescent peanut lectin. Indirect specific immunocytofluorescent staining revealed fluorescence in 96% of the cells, confirming that the monolayers were derived from CCT or connecting tubule cells. Exposure of monolayers to vasopressin or isoproterenol increases adenosine 3',5'-cyclic monophosphate (cAMP) content in the cells and bathing medium, whereas parathyroid hormone was ineffective. Electrophysiological studies revealed a transepithelial voltage (VT) of -11 +/- 2 mV, and basolateral membrane voltage (Vb) of -77 +/- 5 mV (n = 20). The transepithelial electrical resistance (RT) was 1,870 +/- 250 omega X cm2 (n = 13). In three out of six monolayers, amiloride (10(-5) M) applied to the apical side produced an increase in apical membrane voltage (Va) from -71 +/- 1 to -89 +/- 9 mV) and a decrease in VT (from -10 +/- 1 to -2 +/- 1 mV). The RT did not change during amiloride exposure. Exposure of the apical membrane to 140 mM K+-depolarized Va from -67 +/- 7 to -39 +/- 11 mV (P less than 0.002) and hyperpolarized VT from -7 +/- 2 to -15 +/- 3 mV (P less than 0.005). Exposure to high K+ from the basolateral side depolarized Vb from -76 +/- 11 to -43 +/- 10 mV (P less than 0.001) and depolarized VT from -9 +/- to 8 +/- 5 mV (P less than 0.001). This preparation is suitable to study basic aspects of epithelial transport by electrophysiological methods and other techniques. The findings are consistent with several of the known properties of cortical collecting tubules from rabbits studied by the isolated perfused tubule technique.


Teriflunomide induces Foxp3 expression in murine CD8 + T cells while IL-27 and retinoic acid exert a synergistic effect on the induction of CD39 expression on these cells.
The purpose of this study was to verify the possibility of pharmacological induction of Foxp3 +CD25 +CD8 + and Foxp3 -CD103 +CD8 + T regulatory cells 'armed' with immunosuppressive molecules, i.e. CD39 and IL-10. To achieve this purpose, stimulated and unstimulated murine lymphocytes were exposed to IL-27, teriflunomide (TER) and all trans retinoic acid (ATRA). The study found that: (a) IL-27 induced CD39 expression on Foxp3 +CD25 +CD8 + T cells and the ability of CD103+Foxp3-CD8+ T cells to produce IL-10 as well as increasing the absolute number of IL-10 +CD103 +Foxp3 -CD8 + T cells; (b) TER induced Foxp3 expression in CD25+CD8+ T cells and CD103 expression on Foxp3 -CD8 + T cells as well as increasing the absolute number of Foxp3 +CD25 +CD8 + T cells; (c) ATRA induced the capacity of Foxp3 +CD25 +CD8 + T cells to produce IL-10. The following desired interactions were demonstrated between IL-27 and ATRA: (a) a strong synergistic effect with respect to increasing CD39 expression and the ability to produce IL-10 by Foxp3 +CD25 +CD8 + T cells; (b) a synergistic effect with respect to increasing the absolute count of CD39 +Foxp3 +CD25 +CD8 + T cells. The study revealed that TER abolished all these effects. Therefore, a combination of the tested agents did not induce the generation of Foxp3 +CD25 +CD8 + and Foxp3 -CD103+CD8+ T cells characterized by extensive CD39 expression and IL-10 production. Thus, in the context of the pharmacological induction of IL-10 +CD39 +Foxp3 +CD25 +CD8 + and IL-10 +CD103 +Foxp3 -CD8 + T cells, these findings strongly suggest that a combination of TER with IL-27 and/or ATRA does not provide any benefits over TER alone; moreover, such a combination may result in abolishing the desired effects exerted by IL-27 and/or ATRA.


Rare structural variation of synapse and neurotransmission genes in autism.
Autism spectrum disorders (ASDs) comprise a constellation of highly heritable neuropsychiatric disorders. Genome-wide studies of autistic individuals have implicated numerous minor risk alleles but few common variants, suggesting a complex genetic model with many contributing loci. To assess commonality of biological function among rare risk alleles, we compared functional knowledge of genes overlapping inherited structural variants in idiopathic ASD subjects relative to healthy controls. In this study we show that biological processes associated with synapse function and neurotransmission are significantly enriched, with replication, in ASD subjects versus controls. Analysis of phenotypes observed for mouse models of copy-variant genes established significant and replicated enrichment of observable phenotypes consistent with ASD behaviors. Most functional terms retained significance after excluding previously reported ASD loci. These results implicate several new variants that involve synaptic function and glutamatergic signaling processes as important contributors of ASD pathophysiology and suggest a sizable pool of additional potential ASD risk loci.


Comparative long-term prognostic value of quantitative HER-2/neu protein expression, DNA ploidy, and morphometric and clinical features in paraffin-embedded invasive breast cancer.
Data regarding the prognostic value of HER-2/neu protein expression in breast cancer are conflicting, perhaps because of short follow-up and technical difficulties in the determination (the admixture of benign elements with the biochemical method and the subjectivity of the immunohistochemical assessment). Therefore, using digital image processing, we compared the correlation between and the prognostic value of (a) quantitative immunohistochemical HER-2/neu protein expression and (b) clinical, morphometric, and flow-cytometric DNA ploidy features; histologic grade; and biochemically assessed estrogen receptor content. Paraffin-embedded invasive breast Pancers of 82 patients with long-term follow-up were used. None of the patients had received adjuvant systemic therapy. HER-2/neu protein expression was significantly correlated with DNA index, lymph node status, and tumor size and, in the diploid tumors, was weakly correlated with the percentage of S-phase cells. Strong HER-2/neu protein expression was associated with a worse prognosis (although not significantly, p = 0.07). No differences were detected between cancers with or without axillary lymph node metastases. In survival analysis, the Multivariate Prognostic Index and the morphometric features were much stronger prognosticators than HER-2/neu protein overexpression, which, however, had additional prognostic value to that of many of the features analyzed, especially when more than 35% HER-2/neu protein levels (relative to the high expression SKBR3 cell line) were present. Combined diploidy and HER-2/neu protein content greater than 35% occurred in a small group of patients (n = 3), all of whom died. Likewise, in tetraploid cancers a combination of S-phase cells greater than or equal to 7% and HER-2/neu protein content greater than 35% was an ominous sign. In multivariate analysis, strong HER-2/neu protein overexpression was prognostically over-shadowed by the morphometric features. Nevertheless, it is important to further analyze the intriguing possibility of identifying a subgroup of breast cancer patients with a very poor outcome merely using cytometric analysis of paraffin-embedded material of the primary tumor.


Prediction of chemotherapy benefit by EndoPredict in patients with breast cancer who received adjuvant endocrine therapy plus chemotherapy or endocrine therapy alone.
EndoPredict (EPclin) is a prognostic test validated to inform decisions on adjuvant chemotherapy to endocrine therapy alone for patients with oestrogen receptor-positive, HER2-negative breast cancer. Here, we determine the performance of EPclin for estimating 10-year distant recurrence-free interval (DRFI) rates for those who received adjuvant endocrine therapy (ET) alone compared to those with chemotherapy plus endocrine therapy (ET + C). A total of 3746 women were included in this joint analysis. 2630 patients received 5 years of ET alone (ABCSG-6/8, TransATAC) and 1116 patients received ET + C (GEICAM 2003-02/9906). The primary objective was to evaluate the ability of EPclin to provide an estimate of the 10-year DR rate as a continuous function of EPclin separately for ET alone and ET + C. Cox proportional hazard models were used for these analyses. EPclin was highly prognostic for DR in women who received ET alone (HR 2.79 (2.49-3.13), P < 0.0001) as well as in those who received ET + C (HR 2.27 (1.99-2.59), P < 0.0001). Women who received ET + C had significantly smaller increases in 10-year DR rates with the increasing EPclin score than those receiving ET alone (EPclin = 5; 12% ET + C vs. 20% ET alone). We observed a significant positive interaction between EPclin and treatment groups (P-interaction = 0.022). In this comparative non-randomised analysis, the rate of increase in DR with EPclin score was significantly reduced in women who received ET + C versus ET alone. Our indirect comparisons suggest that a high EPclin score can predict chemotherapy benefit in women with ER-positive, HER2-negative disease.


Aflibercept-Related Sterile Intraocular Inflammation Outcomes.
A recent increase in sterile intraocular inflammation after aflibercept (EYLEA; Regeneron Pharmaceuticals, Inc, Tarrytown, NY) injection was reported to the American Society of Retina Specialists' Research and Safety in Therapeutics Committee. This study describes their clinical characteristics and outcomes. Case series. Sixty-eight eyes of 66 patients (97% reported from May 2017 through February 2018). Exclusion criteria were intravitreal antibiotic injection and follow-up of less than 7 days. Diagnosis was at each physician's discretion. Presenting signs and symptoms, injection characteristics, management details, and visual outcomes. Mean time to presentation was 2.6 days (median, 2.0 days; range, 0-15 days). Symptoms included blurry vision (93%), floaters (60%), pain (44%), severe pain (6%), and photophobia (19%). Mean visual acuities before and after injection were 20/50 and 20/178, respectively. All patients showed intraocular inflammation: 24% with only vitritis, 16% with only anterior chamber reaction, and 60% with both. Less common findings included keratic precipitates (22%), corneal edema (13%), conjunctival injection (10%), chemosis (4%), hypopyon (4%), and fibrin (3%). Two patients were affected bilaterally. Treatment included topical steroids (93%), with 1% supplemented by oral steroids. Inflammation resolved in 79% at study completion (mean, 34 days; range, 7-105 days; 51% resolved by 1 month). This group's mean final visual acuity (VA) was 20/55, and 15% lost 2 lines or more. This vision loss was associated with shorter time to presentation (P < 0.0001), magnitude of decrease in presenting VA (P = 0.0004), presence of fibrin (P = 0.02), and trended toward receiving only observation (P = 0.10). There were no other presenting factors that significantly affected visual outcome. In patients with unresolved inflammation at the final visit, mean follow-up was 29 days, and mean final VA was 20/118. Overall, 26 aflibercept lots were involved. This is the largest study of aflibercept-related sterile intraocular inflammation, and is the only large report to exclude eyes injected with intraocular antibiotics. Most patients presented early with decreased VA and intraocular inflammation, but without injection, hypopyon, fibrin, or severe pain. Final VA remained decreased in a significant minority of patients.


[Role of proton-motive force in the conjugative DNA transport in Staphylococci].
Sensitivity of the conjugative process in staphylococci to the action of uncouplers of oxidative phosphorylation and inhibitors of electron transport systems have been proved, that testifies to the energy-dependent character of conjugative transport of DNA. Proceeding of the conjugation process depends upon the generation of delta microH+ on the membrane of both the donor and recipient cells. contribution of protonmotive forces to providing for the transfer of plasmids during conjugation to staphylococci has been defined.


[A comparative study of arthroscopic anterior cruciate ligament reconstruction via transtibial and transportal techniques].
To investigate the effectiveness of arthroscopic anterior cruciate ligament (ACL) reconstruction via transtibial (TT) and transportal (TP) techniques after 10 years follow-up. A clinical data of 103 patients who underwent arthroscopic ACL reconstruction with a single bundle of autologous hamstring tendon between March 2006 and March 2009 was retrospectively analyzed, among which 57 patients were reconstructed with TT technique (TT group) and 46 patients were reconstructed with TP technique (TP group). There was no significant difference in gender, age, cause of injury, interval between injury and operation, preoperative pivot shift test, preoperative International Knee Documentation Committee (IKDC) score, Lysholm score, and KT-2000 side-to-side difference (SSD) between the two groups ( P>0.05). At 10 years after operation, Lachman test was used to evaluate the forward joint stability and pivot shift test to evaluate the rotational stability of the knee; KT-2000 SSD was used to measure tibial anterior displacement; IKDC score and Lysholm score were used to evaluate knee function; MRI examination was performed to observe graft healing and measure coronal inclination angles of the tibia and femoral tunnels. The rate of return to sports was also calculated. The incisions healed by first intention in the two groups, and no early complication occurred after operation. All patients were followed up 10-13 years, with an average of 11.5 years. During the follow-up period, there was no limitation of knee extension and flexion, no discomfort of donor site or graft failure in either group. MRI examination showed that the graft healed well. The IKDC score, Lysholm score, and KT-2000 SSD in the two groups were significantly improved after 10 years ( P<0.05), and there was no significant difference between the two groups at 10 years after operation ( P>0.05). There were significant differences in coronal inclination angles of femoral tunnel and tibial tunnel between the two groups ( P<0.05). There was no significant difference in Lachman test and pivot shift test between the two groups ( P>0.05). The rate of return to sports of patients was 61.40% (35/57) in TT group and 63.04% (29/46) in TP group, showing no significant difference between the two groups ( χ 2=0.29, P=0.87). TT and TP techniques can both achieve good effectiveness in ACL reconstruction.


History of Lyme Disease as a Predictor of Atrial Fibrillation.
In many cases, atrial fibrillation (AF) is associated with a history of cardiac inflammation. One of the potential pathogens responsible for atrial inflammation might be Borrelia burgdorferi - a pathogen involved in Lyme carditis. This study aimed to assess whether the serological history of Borrelia infection was associated with the risk of AF. The study included 113 AF patients and 109 patients in sinus rhythm. All patients underwent a clinical evaluation, echocardiography and had their blood taken for the assessment of anti-Borrelia IgG antibodies. Patients with AF compared with the non-AF group had more often serological signs of Borrelia infection (34.5% vs 6.4%; p <0.0001). The multivariate analysis showed that positive results for anti-Borrelia IgG antibodies were a strong independent predictor of AF (odds ratio 8.21; 95% confidence interval 3.08 to 21.88; p < 0.0001). In conclusion, presented data show that exposure to Borrelia spp. infection is associated with an increased risk of AF. Whether the early treatment of Lyme disease lowers the risk of AF development remains to be explored.


Novel gene delivery systems.
Gene therapy is an emerging field in medical and pharmaceutical sciences because of its potential in treating chronic diseases like cancer, viral infections, myocardial infarctions, and genetic disorders. Application of gene therapy is limited because of lack of suitable methods for proper introduction of genes into cells and therefore, this is an area of interest for most of the researchers. To achieve successful gene therapy, development of proper gene delivery systems could be one of the most important factors. Several nonviral and viral gene transfer methods have been developed. Even though the viral agents have a high transferring efficiency, they are difficult to handle due to their toxicity. To overcome the safety problems of the viral counterpart, several nonviral in vitro and in vivo gene delivery systems are developed. Out of these, the most promising and latest systems include polymer-based nonviral gene carriers, dendrimers, and physical means like electroporation, microinjection, etc., Shunning of possible immunogenicity and toxicity, and the feasibility of repeated administration are some of the merits of nonviral gene delivery systems over viral gene delivery. An ideal nonviral gene carrying system should possess all these merits without any compromise to its gene transferring efficiency. The viral gene delivery systems include lytic and nonlytic vectors for drug delivery. Inspite of its toxicity they are still preferred because of their long term expression, stability, and integrity. This review explores the recent developments and relevancy of the novel gene delivery systems in gene therapy.


Potential genetic anticipation in hereditary leiomyomatosis-renal cell cancer (HLRCC).
Hereditary leiomyomatosis-renal cell cancer (HLRCC) is an autosomal dominant disorder characterised by cutaneous leiomyomas, symptomatic uterine leiomyomas and aggressive type II papillary renal cell carcinoma. It is caused by heterozygous mutations in the fumarate hydratase (FH) gene on chromosome 1q43. We present evidence of genetic anticipation in HLRCC syndrome. A comprehensive literature review was performed to determine the potential for genetic anticipation in HLRCC syndrome. The normal random effects model was used to evaluate for genetic anticipation to ensure reduction in bias. A total of 11 FH kindreds with available multi-generational data were identified for analysis. The mean difference in age at diagnosis of RCC between the first and second generation was -18.6 years (95 % CI -26.6 to -10.6, p < 0.001). The mean difference in age at diagnosis of RCC between the first and third generation was -36.2 years (95 % CI -47.0 to -25.4, p < 0.001). No evidence of anticipation for uterine leiomyomas was observed (p = 0.349). We report preliminary evidence of genetic anticipation of RCC in HLRCC syndrome. Additional clinical validation is important to confirm this observation, which may have practical implications on counseling and timing of surveillance initiation. Exploration of the underlying mechanisms of anticipation in HLRCC would be of considerable biological interest.


Implementation of an experimental isolated lung perfusion model on surgically resected human lobes.
Isolated lung perfusion (ILP) is an ideal model to study treatment effects on a variety of pathologies. As published research mostly relies on rejected donor lungs or animal organs, this study investigates the use of surgically resected human lobes as an alternative and novel model for personalized experimental research. Ten surgically resected lobes were perfused in acellular and normothermic condition. The indication for surgery was lung cancer. Perfusion and ventilation were adapted to the size of the lobes and both functional and metabolic parameters were assessed during ILP. Patients (age 67.5 y (59-81)|♀n = 3|♂n = 7) underwent anatomic pulmonary lobectomy. Ischemic time between arterial ligation and ILP was 226 minutes (161-525). Median duration of ILP was 135 (87-366) minutes. Gas exchange and mechanical respiratory parameters remained steady during ILP (pulmonary venous pO2 196(151-219) mmHg | peak AWP: 14.5(11-22) cmH2O). Metabolism stayed constant during ILP (Glucose consumption: 1.86 mg/min/LTLC (95%CI: -2.09 to -1.63) | lactate production: 0.005 mmol/min/ LTLC (95%CI: 0.004 to 0.007)). ILP of surgically resected human lobes is a feasible and promising method. By maintaining a near physiological setting, this model may pave the way for future experimental lung research including cancer research, transplantation, physiology, pharmacology and mechanical ventilation.


Strategy for profiling and structure elucidation of mucin-type oligosaccharides by mass spectrometry.
A strategy combining accurate mass determination, tandem mass spectrometry, structure homology, and exoglycosidases is described that allows the structural characterization of mucin-type O-linked oligosaccharides. The method is used to profile with quantitation the O-linked oligosaccharide (both neutral and anionic) components of the only diploid Xenopus frog, Xenopus tropicalis. Collision-induced dissociation was used to determine connectivity, to identify previously characterized oligosaccharides, and to determine the presence of structural motifs in unknown oligosaccharides. Exoglycosidase digestion was used to identify the individual residues along with the linkages. The enzymes were also used to cleave larger oligosaccharides to smaller units that are similar to previously elucidated components. By using CID, isomeric structures were compared to determine whether they were identical. In this way, the exoglycosidases were more effectively used, and their use was minimized. A total of 35 oligosaccharides including neutral, sialylated, and sulfated were characterized in this way. The relative abundances of all components were also determined based on HPLC.


Social Communication across Reproductive Boundaries: Hormones and the Auditory Periphery of Songbirds and Frogs.
Most animals experience reproductive transitions in their lives; for example, reaching reproductive maturity or cycling in and out of breeding condition. Some reproductive transitions are abrupt, while others are more gradual. In most cases, changes in communication between the sexes follow the time course of these reproductive transitions and are typically thought to be coordinated by steroid hormones. We know a great deal about hormonal control of communication behaviors in birds and frogs, as well as the central neural control of these behaviors. There has also been significant interest in the effects of steroid hormones on central nervous system structures that control both the production and reception of communication signals associated with reproductive behaviors. However, peripheral sensory structures have typically received less attention, although there has been growing interest in recent years. It is becoming clear that peripheral sensory systems play an important role in reproductive communication, are plastic across reproductive conditions, and, in some cases, this plasticity may be mediated by steroid hormones. In this article, we discuss recent evidence for the role of peripheral auditory structures in reproductive communication in birds and frogs, the plasticity of the peripheral auditory system, and the role of steroid hormones in mediating the effects of the peripheral auditory system on reproductive communication. We focus on both seasonal and acute reproductive transitions, introduce new data on the role of hormones in modulating seasonal patterns, and make recommendations for future work.


Anticentromere Antibody-positive Scleroderma Renal Crisis Requiring Dialysis.
A 70-year-old man with prior Raynaud's phenomena developed hypertension and renal insufficiency. Raynaud's phenomena, finger skin thickening, interstitial lung disease, and positive anticentromere antibody findings indicated systemic sclerosis (SSc). Based on the presence of SSc, severe hypertension with rapidly progressive renal failure, and proliferative and obliterative arteriolar vasculopathy, scleroderma renal crisis (SRC) was diagnosed. Despite good blood pressure control with antihypertensive drugs, hemodialysis was initiated and could not be withdrawn owing to unimproved renal dysfunction. Although SRC in anticentromere antibody-positive limited cutaneous SSc is extremely rare, some patients may develop SRC, and their renal prognosis may be poor.


A tool to identify patients with embolic stroke of undetermined source at high recurrence risk.
A tool to stratify the risk of stroke recurrence in patients with embolic stroke of undetermined source (ESUS) could be useful in research and clinical practice. We aimed to determine whether a score can be developed and externally validated for the identification of patients with ESUS at high risk for stroke recurrence. We pooled the data of all consecutive patients with ESUS from 11 prospective stroke registries. We performed multivariable Cox regression analysis to identify predictors of stroke recurrence. Based on the coefficient of each covariate of the fitted multivariable model, we generated an integer-based point scoring system. We validated the score externally assessing its discrimination and calibration. In 3 registries (884 patients) that were used as the derivation cohort, age, leukoaraiosis, and multiterritorial infarct were identified as independent predictors of stroke recurrence and were included in the final score, which assigns 1 point per every decade after 35 years of age, 2 points for leukoaraiosis, and 3 points for multiterritorial infarcts (acute or old nonlacunar). The rate of stroke recurrence was 2.1 per 100 patient-years (95% confidence interval [CI] 1.44-3.06) in patients with a score of 0-4 (low risk), 3.74 (95% CI 2.77-5.04) in patients with a score of 5-6 (intermediate risk), and 8.23 (95% CI 5.99-11.3) in patients with a score of 7-12 (high risk). Compared to low-risk patients, the risk of stroke recurrence was significantly higher in intermediate-risk (hazard ratio [HR] 1.78, 95% CI 1.1-2.88) and high-risk patients (HR 4.67, 95% CI 2.83-7.7). The score was well-calibrated in both derivation and external validation cohorts (8 registries, 820 patients) (Hosmer-Lemeshow test χ2: 12.1 [p = 0.357] and χ2: 21.7 [p = 0.753], respectively). The area under the curve of the score was 0.63 (95% CI 0.58-0.68) and 0.60 (95% CI 0.54-0.66), respectively. The proposed score can assist in the identification of patients with ESUS at high risk for stroke recurrence.


Insulin analogues with modifications at position B26. Divergence of binding affinity and biological activity.
In this study, we prepared several shortened and full-length insulin analogues with substitutions at position B26. We compared the binding affinities of the analogues for rat adipose membranes with their ability to lower the plasma glucose level in nondiabetic Wistar rats in vivo after subcutaneous administration, and also with their ability to stimulate lipogenesis in vitro. We found that [NMeHisB26]-DTI-NH 2 and [NMeAlaB26]-DTI-NH 2 were very potent insulin analogues with respect to their binding affinities (214 and 465%, respectively, compared to that of human insulin), but they were significantly less potent than human insulin in vivo. Their full-length counterparts, [NMeHisB26]-insulin and [NMeAlaB26]-insulin, were less effective than human insulin with respect to binding affinity (10 and 21%, respectively) and in vivo activity, while [HisB26]-insulin exhibited properties similar to those of human insulin in all of the tests we carried out. The ability of selected analogues to stimulate lipogenesis in adipocytes was correlated with their biological potency in vivo. Taken together, our data suggest that the B26 residue and residues B26-B30 have ambiguous roles in binding affinity and in vivo activity. We hypothesize that our shortened analogues, [NMeHisB26]-DTI-NH 2 and [NMeAlaB26]-DTI-NH 2, have different modes of interaction with the insulin receptor compared with natural insulin and that these different modes of interaction result in a less effective metabolic response of the insulin receptor, despite the high binding potency of these analogues.


Locomotion Behavior Is Affected by the GαS Pathway and the Two-Pore-Domain K+ Channel TWK-7 Interacting in GABAergic Motor Neurons in Caenorhabditis elegans.
Adjusting the efficiency of movement in response to environmental cues is an essential integrative characteristic of adaptive locomotion behavior across species. However, the modulatory molecules and the pathways involved are largely unknown. Recently, we demonstrated that in Caenorhabditis elegans, a loss-of-function of the two-pore-domain potassium (K2P) channel TWK-7 causes a fast, coordinated, and persistent forward crawling behavior in which five central aspects of stimulated locomotion-velocity, direction, wave parameters, duration, and straightness-are affected. Here, we isolated the reduction-of-function allele cau1 of the C. elegans gene kin-2 in a forward genetic screen and showed that it phenocopies the locomotor activity and locomotion behavior of twk-7(null) animals. Kin-2 encodes the negative regulatory subunit of protein kinase A (KIN-1/PKA). Consistently, we found that other gain-of-function mutants of the GαS-KIN-1/PKA pathway resemble kin-2(cau1) and twk-7(null) in locomotion phenotype. Using the powerful genetics of the C. elegans system in combination with cell type-specific approaches and detailed locomotion analyses, we identified TWK-7 as a putative downstream target of the GαS-KIN-1/PKA pathway at the level of the γ-aminobutyric acid (GABA)ergic D-type motor neurons. Due to this epistatic interaction, we suggest that KIN-1/PKA and TWK-7 may share a common pathway that is probably involved in the modulation of both locomotor activity and locomotion behavior during forward crawling.


Dissecting the non-canonical functions of telomerase.
It is now well established that the canonical function of telomerase protects the telomere repeats from erosion and the consequent induction of replicative senescence or apoptosis. In the absence of key cell cycle checkpoint proteins, the canonical function of telomerase also prevents chromosome fusions and immortalizes human cells. The canonical function of telomerase requires both the telomerase reverse transcriptase enzyme (TERT) which adds telomere (TTAGGG) repeats to the chromosome ends and the telomerase RNA component (TERC), which provides the template for TERT. However, there is growing evidence that telomerase has other (non-canonical) functions. These functions can be divided further into those that require telomerase activity but not telomere lengthening (non-canonical I or NC I) and those that require neither telomerase activity nor telomere lengthening (non-canonical II or NC II). NC I functions are associated with the induction of neoplasia in both epidermis and mammary gland, the correct response to DNA damage, and insensitivity to transforming growth factor beta. In contrast, NC II functions are not sufficient for the induction of neoplasia and are associated with the activation of the WNT and MYC signaling pathways in keratinocytes and a more general resistance to the induction of apoptosis by a variety of stimuli. The overexpression of either TERT or TERC appears to be capable of providing NC I functions but NC II functions require neither TERC nor the integrity of the TERT catalytic site. The molecular mechanisms underpinning both NC I and NC II are largely obscure but transcriptional profile changes have been reported by some groups. In this article, we will discuss the proposed mechanisms of NC I and NC II and their relevance to normal and neoplastic cell functions.


[Storytelling: discursive practices and gender violence].
This paper analyzes a storytelling workshop, an intervention based on the referential elements of oral narratives, held at an NGO in São Leopoldo, Rio Grande do Sul State, Brazil. The workshop was divided into three different stages: narration of a story with a focus on gender violence, a discussion based on the narrative, and an activity with body painting. The theoretical framework was based on discursive practices, and when workshop participants' discourse was assessed, at least two interpretive repertories were identified: one based on the gender category and the other on everyday life and recollections from participants' life stories. There was also considerable variety in the arguments, manifested in the contradictions and incongruence permeating the discourse. Narratives used as tools to work with abused women (especially for public health interventions) have received little attention thus far. In the current study, stories were analyzed as possible strategies to deal with gender inequalities, a powerful analytical tool for evaluating public health actions.


Bronchodilator effect of delta1-tetrahydrocannabinol administered by aerosol of asthmatic patients.
Ten volunteer inpatient asthmatics in a steady state were given a single inhalation of an aerosol (63 mul) delivered in random order, on each of three consecutive days, in the laboratory of a respiratory unit. Before, and for one hour after treatment the pulse, blood pressure (lying and standing), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), peak flow rate (PFR), and self-rating mood scales (SRMS) were recorded. Treatments were placebo-ethanol only; delta1-tetrahydrocannabinol (THC) 200 mug in ethanol; or salbutamol 100 mug (Ventolin inhaler), administered double blind. Salbutamol and THC significantly improved ventilatory function. Maximal bronchodilatation was achieved more rapidly with salbutamol, but at 1 hour both drugs were equally effective. No cardiovascular or mood disturbance was detected, and plasma total cannabinoids at 15 minutes were undectable by radioimmunoassay. The mode of action of THC differs from that of sympathomimetic drugs, and it or a derivative may make a suitable adjuvant in the treatment of selected asthmatics.


Knockout of M-LP/Mpv17L, a newly identified atypical PDE, induces physiological afferent cardiac hypertrophy in mice.
M-LP/Mpv17L (Mpv17-like protein) is an atypical cyclic nucleotide phosphodiesterase (PDE) without the molecular structure characteristic of the PDE family. Deficiency of M-LP/Mpv17L in mice has been found to result in development of β-cell hyperplasia and improved glucose tolerance. Here, we report another phenotype observed in M-LP/Mpv17L-knockout (KO) mice: afferent cardiac hypertrophy. Although the hearts of M-LP/Mpv17L-KO mice did not differ in size from those of wild-type mice, there was marked narrowing of the left ventricular lumen and thickening of the ventricular wall. The diameter and cross-sectional area of cardiomyocytes in 8-month-old M-LP/Mpv17L-KO mice were increased 1.16-fold and 1.35-fold, respectively, relative to control mice, but showed no obvious abnormalities of cell structure, fibrosis or impaired cardiac function. In 80-day-old KO mice, the expression of hypertrophic marker genes, brain natriuretic peptide (BNF), actin alpha cardiac muscle 1 (ACTC1) and actin alpha 1 skeletal muscle (ACTA1), as well as the Wnt/β-catenin pathway target genes, lymphoid enhancer-binding factor-1 (LEF1), axis inhibition protein 2 (AXIN2) and transcription factor 7 (TCF7), was significantly up-regulated relative to control mice, whereas fibrosis-related genes such as fibronectin 1 (FN1) and connective tissue growth factor (CTGF) were down-regulated. Western blot analysis revealed increased phosphorylation of molecules downstream of the cAMP/PKA signaling pathway, such as β-catenin, ryanodine receptor 2 (RyR2), phospholamban (PLN) and troponin I (cTnI), as well as members of the MEK1-ERK1/2 signaling pathway, which is strongly involved in afferent cardiac hypertrophy. Taken together, these findings indicate that M-LP/Mpv17L is one of the PDEs actively functioning in the heart and that deficiency of M-LP/Mpv17L in mice promotes physiological cardiac hypertrophy.