Protocol for a randomized controlled clinical trial investigating the effectiveness of Fast muscle Activation and Stepping Training (FAST) for improving balance and mobility in sub-acute stroke.
Following stroke, many people have difficulty activating their paretic muscles quickly and with sufficient power to regain their balance by taking quick and effective steps. Reduced dynamic balance and mobility following stroke, or 'walking balance', is associated with reduced self-efficacy and restrictions in daily living activities, community integration, and quality of life. Targeted training of movement speeds required to effectively regain balance has been largely overlooked in post-stroke rehabilitation. The Fast muscle Activation and Stepping Training (FAST) program incorporates fast functional movements known to produce bursts of muscle activation essential for stepping and regaining standing balance effectively. The purpose of this study is to: 1) compare the effectiveness of an outpatient FAST program to an active control outpatient physiotherapy intervention in improving walking balance following stroke, and 2) explore potential mechanisms associated with improvements in walking balance. This will be an assessor-blinded, parallel group randomized controlled trial design. Sixty participants (30 per group) who have sustained a stroke within the previous six months will be randomly assigned with stratification for lower limb motor recovery to receive twelve 45-minute 1:1 physiotherapy intervention sessions over 6 - 10 weeks in an outpatient setting of either: 1) FAST intervention - systematic and progressive practice of fast squatting and stepping exercises, or 2) active control - conventional physiotherapy directed at improving balance and mobility that includes no targeted fast movement training. The same blinded research physiotherapist will assess outcomes at three time points: 1) baseline (prior to intervention), 2) follow up (within one week post-intervention); and 3) retention (one month post-intervention). The primary outcome is dynamic balance assessed using the Community Balance and Mobility Scale. We will also assess fast and self-selected walking speed, balance self-efficacy, and the ability to respond to internal and external perturbations to balance and associated changes in postural muscle activation. The targeted training of fast functional movements in the FAST program is expected to improve walking balance following stroke compared to the active control intervention. Unique to this study is the investigation of potential mechanisms associated with improvements in walking balance. NCT01573585.


Spatial organization of repetitive DNA sequences in the bovine sperm nucleus.
During spermatogenesis, DNA in the sperm head becomes more tightly condensed as histones are replaced by protamine-like molecules. In this article, the question is asked whether, during the production of this highly differentiated cell, controls are imposed on the spatial organization of DNA within the nucleus. Heads from bull spermatozoa were isolated by a technique that removed the plasma membrane and acrosomal contents, and the DNA was induced to decondense by addition of 2-mercaptoethanol and trypsin. Under these conditions, decondensation was induced in all regions of the head. To determine whether there was any spatial restraint on packaging of the genome, three DNA probes were used (pl.709-512, containing an interspersed repetitive sequence; pCSIH, containing a copy of the major bovine centromeric statellite sequence; p18 s and p28 s, containing the 18 S and 28 S ribosomal genes) that might be expected to hybridize to different regions. Results showed that the interspersed repetitive probe hybridized to all regions of the head, whereas the ribosomal and centromeric probes hybridized to sequences that were largely confined to the equatorial region of the sperm. We conclude that organization of the genome in the bovine sperm nucleus is not random.


Targeted differential photostimulation alters reproductive activities of domestic birds.
Modern poultry production systems use environmentally controlled houses providing only artificial illumination. The role of light in reproduction of poultry depends on light quality (photoperiod, intensity/brightness, and spectrum), which enables us to provide custom-made illumination, targeted for the elevation of reproductive activities. Artificial targeted illumination significantly affects poultry reproduction. This phenomenon is based on the mechanism of light absorption in birds, which consists of two main components: the eye (retinal photoreceptors) and brain extraretinal photoreceptors. Several experiments on turkey hens and broiler breeder males and females have shown that photostimulation of brain extraretinal photoreceptors, while maintaining retinal photoreceptors under non-photostimulatory conditions, elevates reproductive activity by increasing egg production of hens and semen quality of roosters. In addition, we found acceleration in all gonadal axis parameters, leading to the acceleration in the production rate. Furthermore, we studied the role of retinal activation in gonadal axis suppuration and identified the role of serotonin in this phenomenon. As for today, several broiler breeder farms use targeted illumination based on our studies with excellent results.


An intentional dynamics approach to comparing robots with their biological targets.
After identifying similarities in the paradigmatic problems of biorobotics and ecological psychology, we suggest a way to compare the performance of robots with that of their biological targets. The crucial comparison is between the intentional dynamics of the robot and those of the targeted animal, a measure that depends critically on recognizing and describing the underlying affordance-effectivity match of the target system.


Influencing Factors of Understanding COVID-19 Risks and Coping Behaviors among the Elderly Population.
It is known that the elderly population has weak immune functioning and is a susceptible and high-risk group with respect to the current coronavirus disease 2019 (COVID-19) epidemic. In this study, to understand the influencing factors of COVID-19-related risks and coping behaviors of elderly individuals with respect to COVID-19 and to provide a basis for taking corresponding protective measures, a questionnaire survey was applied to an elderly population. One-way analysis of variance (ANOVA) and linear regression analysis were used to explore the influencing factors of the level of understanding of COVID-19 risks among the elderly population. Additionally, the chi-square test and logistic regression analysis were used to explore the influencing factors of the elderly population's protective behaviors against COVID-19. This study found: (1) The sex, age, and self-care ability of elderly individuals were significantly correlated with their level of understanding of COVID-19, and that those who were female, were of a younger age, or had better self-care ability had higher levels of understanding; (2) The sex, place of residence, and level of understanding of COVID-19 among the elderly individuals were significantly correlated with their protective behaviors, e.g., those who were women, had high levels of understanding, and lived in cities were more likely to have good behaviors; (3) Elderly individuals' assessments of COVID-19 information provided by the government were significantly correlated with their protective behaviors-those who had a positive evaluation of relevant information provided by the government were more likely to develop protective behavior. The conclusions of this study show that it is crucial to implement COVID-19 prevention and control measures in the elderly population. Society, communities, and families need to increase their concerns about the health and risk awareness of the elderly individuals.


Patient reported outcomes of duodenum-preserving pancreatic head resection in chronic pancreatitis: high effectivity is impaired by prolonged non-surgical management.
Chronic pancreatitis (CP) causes suffering and socioeconomic burden. This study evaluated perioperative results and patient-reported outcomes (PRO) in CP patients treated with duodenum-preserving pancreatic head resection (DPPHR). Data were analyzed of CP patients undergoing DPPHR between 01/2001-10/2014. PROs were measured using a specifically designed questionnaire and the EORTC QLQ-C30/PAN26. Associations between treatment variables and PROs were examined. Of 332 patients who received DPPHR, most (n = 251, 75.6%) underwent the Berne modification. Surgical morbidity was 21.5% (n = 71) and 90-day mortality 1.5% (n = 5). Median follow-up was 79.9 months, 5-year survival 90.5%, and 1.8% of patients developed pancreatic cancer. Of 283 patients alive, 178 (62.9%) returned questionnaires. Referral for surgery was self-initiated (38.0% of cases), by gastroenterologists (27.5%) and by general practitioners (21.1%). QoL improved in 78.7% of patients, remained stable in 12.1%, and worsened in 9.1%. Median Izbicki scores decreased from 90 to 5 points after surgery (p < 0.0001). Time from diagnosis to DPPHR was an independent, proportional predictor of a higher postoperative Izbicki score (p = 0.04). DPPHR is an effective, safe treatment for CP. A delay in surgery decreases surgical effectivity, hence CP patients should be referred to surgery early to ensure satisfactory outcomes.


Extracorporeal support with a cadaver liver as a bridge to transplantation.
Extracorporeal liver perfusion (ECLP) has been used for detoxifying blood in patients in class IV hepatic encephalopathy. Palliation of the moribund patient utilizing extracorporeal devices with cross-circulation of a cadaver liver has been documented for over three decades. Common problems associated with this procedure which appear in the literature include cadaver liver distention, increased resistance to blood flow, and limited time of extracorporeal support due to cadaver liver failure. This report summarizes the experiences of the perfusion team in utilizing an extracorporeal circuit with an otherwise nontransplantable cadaveric liver, to support the decompensating hepatic patient as a bridge to transplantation. Between January and July 1992, three patients were supported for hepatic failure with ECLP. Two patients were placed on ECLP with a modified circuit containing two positive displacement pumps and one centrifugal pump. The third patient was placed on ECLP with a circuit that contained two centrifugal pumps and one positive displacement pump. Patient age ranged from 6 to 38 years and length of support ranged from 24 to 72 hours. In all three patients, a centrifugal pump was placed in the suprahepatic inferior vena cava line to facilitate cadaver liver drainage and decompression. Intensive monitoring of both patient and cadaver liver hemodynamics, hepatic function, and hematological status was performed. All three patients were successfully weaned from ECLP. Two patients received successful orthotopic liver transplantation. The third died of complications unrelated to ECLP after support was discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)


Growth of pika in laboratory confinement.
Captive-born pikas (Ochotoma princeps) from 13 litters were maintained for up to three months in a laboratory setting. Mean litter size was 2.69 +/- 0.75, with litters of three the most frequent, and representing 68% of all litters observed. Mean individual birthweight was 11.7 g with a range of 8.8 to 16.8 g. Weights were taken every other day from birth, which yielded a growth curve equation of y = 12.18 + 1.72x. There was a strong positive linear correlation between bodyweight and time (r = 0.98, P less than 0.001), and a significant difference was noted between sexes, with females the heaviest. Subjects reached adult weight within 3 months. These data represent the first reports of growth in this species, and indicate that pikas are among the fastest growing species within the order Lagomorpha.


Developmental tumors and adjacent cortical dysplasia: single or dual pathology?
Developmental tumors often lead to refractory partial seizures and constitute a well-defined, surgically remediable epilepsy syndrome. Dysplastic features are often associated with these tumors, and their significance carries both practical and conceptual relevance. If associated focal cortical dysplasia (FCD) relates to the extent of the epileptogenic tissue, then presurgical evaluation and surgical strategies should target both the tumor and the surrounding dyslaminated cortex. Furthermore, the association has been included in the recently revised classification of FCD and the epileptogenicity of this associated dysplastic tissue is crucial to validate such revision. In addition to the possibility of representing dual pathology, the association of developmental tumors and adjacent dysplasia may instead represent a single developmental lesion with distinct parts distributed along a histopathologic continuum. Moreover, the possibility that this adjacent dyslamination is of minor epileptogenic relevance should also be entertained. Surgical data show that complete resection of the solid tumors and immediately adjacent tissue harboring satellites may disrupt epileptogenic networks and lead to high rates of seizure freedom, challenging the epileptogenic relevance of more extensive adjacent dyslaminated cortex. Whether the latter is a primary or secondary abnormality and whether dyslaminated cortex in the context of a second lesion may produce seizures after complete resection of the main lesion is still to be proven.


Cretaceous choristoderan reptiles gave birth to live young.
Viviparity (giving birth to live young) in fossil reptiles has been known only in a few marine groups: ichthyosaurs, pachypleurosaurs, and mosasaurs. Here, we report a pregnant specimen of the Early Cretaceous Hyphalosaurus baitaigouensis, a species of Choristodera, a diapsid group known from unequivocal fossil remains from the Middle Jurassic to the early Miocene (about 165 to 20 million years ago). This specimen provides the first evidence of viviparity in choristoderan reptiles and is also the sole record of viviparity in fossil reptiles which lived in freshwater ecosystems. This exquisitely preserved specimen contains up to 18 embryos arranged in pairs. Size comparison with small free-living individuals and the straight posture of the posterior-most pair suggest that those embryos were at term and had probably reached parturition. The posterior-most embryo on the left side has the head positioned toward the rear, contrary to normal position, suggesting a complication that may have contributed to the mother's death. Viviparity would certainly have freed species of Hyphalosaurus from the need to return to land to deposit eggs; taking this advantage, they would have avoided intense competition with contemporaneous terrestrial carnivores such as dinosaurs.


Functional and Structural Abnormalities in Deferoxamine Retinopathy: A Review of the Literature.
Deferoxamine mesylate (DFO) is the most commonly used iron-chelating agent to treat transfusion-related hemosiderosis. Despite the clear advantages for the use of DFO, numerous DFO-related systemic toxicities have been reported in the literature, as well as sight-threatening ocular toxicity involving the retinal pigment epithelium (RPE). The damage to the RPE can lead to visual field defects, color-vision defects, abnormal electrophysiological tests, and permanent visual deterioration. The purpose of this review is to provide an updated summary of the ocular findings, including both functional and structural abnormalities, in DFO-treated patients. In particular, we pay particular attention to analyzing results of multimodal technologies for retinal imaging, which help ophthalmologists in the early diagnosis and correct management of DFO retinopathy. Fundus autofluorescence, for example, is not only useful for screening patients at high-risk of DFO retinopathy, but is also a prerequisite for identify specific high-risk patterns of RPE changes that are relevant for the prognosis of the disease. In addition, optical coherence tomography may have a clinical usefulness in detecting extent and location of different retinal changes in DFO retinopathy. Finally, this review wants to underline the need for universally approved guidelines for screening and followup of this particular disease.


Expression pattern of zcchc24 during early Xenopus development.
We report the expression pattern of a novel Xenopus laevis gene, zcchc24, which encodes a protein containing two zinc finger domains from the zf-CCHC and zf-3CxxC superfamilies. This protein shares >84% amino acid identity with its vertebrate homologues. During X. laevis embryonic development, zcchc24 is expressed at gastrula stages in the dorsal mesoderm, including the cardiac precursors region. During neurula stages, zcchc24 is expressed as two stripes in the dorsal region, more precisely, in the somitogenic mesoderm until the cardiac mesoderm. At early tailbud stages, zcchc24 continues to be expressed in these regions, but starts to be expressed in the migrating neural crest. Later, this gene is expressed in the head, branchial arches, heart and somites. The zinc finger domains present in Zcchc24 protein and its dynamic gene expression pattern suggest that Zcchc24 might be involved in the regulation of heart, somites and of branchial arch formation/patterning, namely in the regulation of apoptosis.


Mouse models of Down syndrome: how useful can they be? Comparison of the gene content of human chromosome 21 with orthologous mouse genomic regions.
With an incidence of approximately 1 in 700 live births, Down syndrome (DS) remains the most common genetic cause of mental retardation. The phenotype is assumed to be due to overexpression of some number of the >300 genes encoded by human chromosome 21. Mouse models, in particular the chromosome 16 segmental trisomies, Ts65Dn and Ts1Cje, are indispensable for DS-related studies of gene-phenotype correlations. Here we compare the updated gene content of the finished sequence of human chromosome 21 (364 genes and putative genes) with the gene content of the homologous mouse genomic regions (291 genes and putative genes) obtained from annotation of the public sector C57Bl/6 draft sequence. Annotated genes fall into one of three classes. First, there are 170 highly conserved, human/mouse orthologues. Second, there are 83 minimally conserved, possible orthologues. Included among the conserved and minimally conserved genes are 31 antisense transcripts. Third, there are species-specific genes: 111 spliced human transcripts show no orthologues in the syntenic mouse regions although 13 have homologous sequences elsewhere in the mouse genomic sequence, and 38 spliced mouse transcripts show no identifiable human orthologues. While these species-specific genes are largely based solely on spliced EST data, a majority can be verified in RNA expression experiments. In addition, preliminary data suggest that many human-specific transcripts may represent a novel class of primate-specific genes. Lastly, updated functional annotation of orthologous genes indicates genes encoding components of several cellular pathways are dispersed throughout the orthologous mouse chromosomal regions and are not completely represented in the Down syndrome segmental mouse models. Together, these data point out the potential for existing mouse models to produce extraneous phenotypes and to fail to produce DS-relevant phenotypes.


Colorectal cancer cells display chaperone dependency for the unconventional prefoldin URI1.
Chaperone dependency of cancer cells is an emerging trait that relates to the need of transformed cells to cope with the various stresses associated with the malignant state. URI1 (unconventional prefoldin RPB5 interactor 1) encodes a member of the prefoldin (PFD) family of molecular chaperones that acts as part of a heterohexameric PFD complex, the URI1 complex (URI1C), to promote assembly of multiprotein complexes involved in cell signaling and transcription processes. Here, we report that human colorectal cancer (CRCs) cell lines demonstrate differential dependency on URI1 and on the URI1 partner PFD STAP1 for survival, suggesting that this differential vulnerability of CRC cells is directly linked to URI1C chaperone function. Interestingly, in URI1-dependent CRC cells, URI1 deficiency is associated with non-genotoxic p53 activation and p53-dependent apoptosis. URI1-independent CRC cells do not exhibit such effects even in the context of wildtype p53. Lastly, in tumor xenografts, the conditional depletion of URI1 in URI1-dependent CRC cells was, after tumor establishment, associated with severe inhibition of subsequent tumor growth and activation of p53 target genes. Thus, a subset of CRC cells has acquired a dependency on the URI1 chaperone system for survival, providing an example of 'non-oncogene addiction' and vulnerability for therapeutic targeting.


Arteriovenous fistulas constructed using side-to-side anastomosis with ligation and division of distal venous arm; a tertiary care hospital experience.
The rising prevalence of end-stage renal disease has added to the demands of renal replacement therapy in the form of hemodialysis (HD) in lieu of unmitigated needs of renal transplants. The best available angioaccess for HD is the autogenous arteriovenous fistula. Many techniques for arteriovenous anastomosis have been reported, but there is dearth of data which study the side-to-side arteriovenous anastomosis with concomitant ligation and division of the distal venous arm. This study aimed to describe the clinical outcome of the fistulae constructed with this particular technique. It is a descriptive and retrospective review in which all patients who underwent the operation with this particular technique in a certain time period were included. The data entry and analysis was done using SPSS 15. Only descriptive statistics are used. Demographic details, primary patency, end point patency and fistula survival were calculated. There were 77 patients, 61 males and 16 females. Radiocephalic arteriovenous anastomosis was constructed in 65 patients, brachiocephalic in 11 patients and brachiobasilic in one patient. Primary patency was 96.1% and end point patency was 90.9% with a median survival of 44 weeks at the end point. This particular technique of fistula construction has excellent patency rates, fistula survival and lesser complications when compared to what has been reported for other methods. It is therefore recommended that the technique of angioaccess reported in this study may be considered as a first option.


Life threatening 'epilepsy'.
A 5 year old girl presenting with episodes of sudden loss of consciousness was found to have intermittent ventricular tachycardia and, on one occasion, self limiting fibrillation. Corrected QT interval was normal. After several therapeutic measures clinical and electrocardiographic improvement was achieved by administration of sotalol.


Plastic recycling plant as a point source of microplastics to sediment and macroinvertebrates in a remote stream.
Microplastic is now ubiquitous in freshwater, sediment and biota, globally. This is as a consequence of inputs from, for example, waste mismanagement, effluents from wastewater treatment plants and surface runoff from agricultural areas. In this study, we investigated point source pollution of plastic to an upland stream, originating from a recycling plant that recycles polyethylene film in a remote area of Norway. Sediment (~2 kg) and macroinvertebrates (549 individuals in total) were sampled at one site upstream and two sites downstream of the recycling plant to study microplastic deposition and food web uptake. In total, 340 microplastic films were identified through a combination of visual and µFTIR analysis in the sediment samples. This corresponded to a concentration of 0.23 (± 0.057) items per g sediment upstream of the plastic recycling plant and 0.45 (± 0.017) and 0.58 (± 0.34) items per g downstream. The dominant plastic polymer was polyethylene, which increased significantly downstream of the plastic recycling plant. This indicates the role of the plastic recycling plant as a point source for microplastic in this catchment. Among the three sites investigated, a fairly constant concentration of polypropylene was found, indicating a diffuse source of polypropylene films across the catchment possibly relating to low-intensity agricultural land-use. Low levels of polyethylene were also observed upstream, which may be linked to either local or longer-distance atmospheric transport. Despite the considerable presence of microplastic in sediments, concentrations in macroinvertebrates were extremely low with only a single microplastic particle identified in the total of 549 macroinvertebrates-belonging to three different feeding groups-investigated. Our study suggests that: 1) microplastic pollution can be transferred to remote areas as unintended losses from recycling facilities, 2) remote areas with limited land-use pressure still have detectable levels of microplastic and 3) microplastic is only taken up by stream macroinvertebrates to a limited degree despite relatively high sediment concentrations, and thus there are no strong indications for ecological risks posed by microplastic to this ecological group at this location. The online version contains supplementary material available at 10.1186/s43591-022-00045-z.


National evaluation of the association between stay-at-home orders on mechanism of injury and trauma admission volume.
The COVID-19 pandemic had numerous negative effects on the US healthcare system. Many states implemented stay-at-home (SAH) orders to slow COVID-19 virus transmission. We measured the association between SAH orders on the injury mechanism type and volume of trauma center admissions during the first wave of the COVID-19 pandemic. All trauma patients aged 16 years and older who were treated at the American College of Surgeons Trauma Quality Improvement Program participating centers from January 2018-September 2020. Weekly trauma patient volume, patient demographics, and injury characteristics were compared across the corresponding SAH time periods from each year. Patient volume was modeled using harmonic regression with a random hospital effect. There were 166,773 patients admitted in 2020 after a SAH order and an average of 160,962 patients were treated over the corresponding periods in 2018-2019 in 474 centers. Patients presenting with a pre-existing condition of alcohol misuse increased (13,611 (8.3%) vs. 10,440 (6.6%), p <0.001). Assault injuries increased (19,056 (11.4%) vs. 15,605 (9.8%)) and firearm-related injuries (14,246 (8.5%) vs. 10,316 (6.4%)), p<0.001. Firearm-specific assault injuries increased (10,748 (75.5%) vs. 7,600 (74.0%)) as did firearm-specific unintentional injuries (1,318 (9.3%) vs. 830 (8.1%), p<0.001. In the month preceding the SAH orders, trauma center admissions decreased. Within a week of SAH implementation, hospital admissions increased (p<0.001) until a plateau occurred 10 weeks later above predicted levels. On regional sub-analysis, admission volume remained significantly elevated for the Midwest during weeks 11-25 after SAH order implementation, (p<0.001).


Risk factors for nosocomial infection and mortality in burn patients: 10 years of experience at a university hospital.
To evaluate the risk factors for nosocomial infection (NI) and mortality in a university hospital, 10-year data of burn patients were assessed retrospectively. The study was conducted at Erciyes University's Burn Center during 2000 and 2009. The records of 1190 patients were obtained. Overall, 131 (11%) patients had 206 NIs with an incidence density of 14.7 infections/1000 patient days. Burn wound infection (n = 109, 53%) was the most common NI. High (%TBSA burned) and late excision were found to be the most significant risk factors for the development of NI. Pseudomonas aeruginosa was the most frequent causative microorganism. However, the prevalence of multidrug-resistant Acinetobacter baumannii has increased in recent years with a prevalence of 47% in 2009. The carbapenem resistance of P. aeruginosa has decreased in recent years, whereas that of A. baumannii increased and it had a prevalence of 94% in the last year. Conversely, the most important risk factors for mortality were advanced age, high %TBSA and having an underlying disease. Prevention of NI is an important issue in burn units to reduce mortality rates. Early excision and wound closure are important therapeutic approaches for the prevention of burn wound infection.


Promotion of insulin-induced glucose uptake in C2C12 myotubes by osteocalcin.
A close relationship between the bone and systemic glucose metabolism has recently been the center of attention, since the uncarboxylated form of osteocalcin (GluOC), a bone-derived protein, but not the γ-carboxylated form, is involved in glucose metabolism. However, the analysis of GluOC effect using isolated organs and related cell lines are required to understand its roles in a whole systemic metabolic status. In the present study, we examined the effect of GluOC on cell lines derived from skeletal muscle to explore the mechanisms by which GluOC regulates glucose uptake. In the differentiated C2C12 myotubes, GluOC dose-dependently induced the phosphorylation of ERK without affecting intracellular cAMP and Ca(2+) levels. This effect was inhibited by U0126, an inhibitor of ERK kinase (MEK). Additionally, U73122, an inhibitor of phospholipase C tended to inhibit it as well. Furthermore, cell treatment with GluOC for a long period promoted insulin-induced Akt phosphorylation and glucose uptake in the myotubes, which was abolished by ERK signaling inhibition. These results indicate that GluOC does not triggered Akt phosphorylation and glucose uptake by itself but promotes insulin-induced glucose uptake in myotubes, probably by up-regulating Akt signaling through ERK activation.


Determination of 3D positions of pacemaker leads from biplane angiographic sequences.
In vitro and in vivo analyses of stress on pacemaker leads and their components during the heart cycle have become especially important because of incidences of failure of some of these mechanical components. For stress analyses, the three-dimensional (3D) position, shape, and motion of the pacemaker leads must be known accurately at each time point during the cardiac cycle. We have developed a method for determination of the in vivo 3D positions of pacemaker leads during the entire heart cycle. Sequences of biplane images of patients with pacemakers were obtained at 30 frames/s for each projection. The sequences usually included at least two heart cycles. After patient imaging, biplane images of a calibration object were obtained from which the biplane imaging geometry was determined. The centerlines of the leads and unique, identifiable points on the attached electrodes were indicated manually for all acquired images. Temporal interpolation of the lead and electrode data was performed so that the temporal nonsynchronicity of the image acquisition was overcome. Epipolar lines, generated from the calculated geometry, were employed to identify corresponding points along the leads in the pairs of biplane images for each time point. The 3D positions of the lead and electrodes were calculated from the known geometry and from the identified corresponding points in the images. Using multiple image sets obtained with the calibration object at various orientations, the precision of the calculated rotation matrix and of the translation vector defining the imaging geometry was found to be approximately 0.7 degree and 1%, respectively. The 3D positions were reproducible to within 2 mm, with the error lying primarily along the axis between the focal spot and the imaging plane. Using data obtained by temporally downsampling to 15 frames/s, the interpolated data were found to lie within approximately 2 mm of the true position for most of the heart cycle. These results indicate that, with this technique, one can reliably determine pacemaker lead positions throughout the heart cycle, and thereby it will provide the basis for stress analysis on pacemaker leads.


Molecular-genetic characterization of human parvovirus B19 prevalent in Kerala State, India.
Human parvovirus B19V is a DNA virus, and a member of the family Parvoviridae, that causes various clinical manifestations, from asymptomatic to persistent infection that is associated with different autoimmune diseases. The parvovirus B19 evolves with a very high mutation rate that is closer to those of existing RNA viruses. Globally circulating B19V is currently classified into three genotypes, but their distribution is not spatially and temporally correlated. Except for a few recent reports on B19V entry into the human host and its genetic diversity, there is a lack of sufficient studies on this virus from distinct geographical locations and no clear understanding of its evolution has been documented. To better understand the evolution of the Human parvo B19V virus from India's southern part, a geographically distinct location with no reports of B19V genomes, we have screened for B19V in 456 suspected cases using VP1/2 surface marker genes, and its characteristics were studied in detail. Amongst 456 clinically suspected B19V samples, 7.2% (33/456) were found positive by nested PCR (nPCR) were subsequently validated by real-time PCR, Sanger sequencing, and metagenome analysis. Human parvovirus B19 infection was shown among 33 of 456 patients when tested by nPCR; 30 among these were also positive by qPCR and were subsequently confirmed by sequencing 75% nPCR positive samples and 76% qPCR positive samples were from patients with age. ≥ 50 years respectively (Additional file 1: Table S1). The complete VP1/2 gene assembly from the South Indian strain showed three novel mutations (T122A, V128I, I283V), which might significantly impact the stability and virulence of the B19V virus circulating in this part of the world. These mutations might be crucial for its adaptive evolutionary strategies facilitating the spread and infectivity potential of the virus. In maximum likelihood phylogeny of VP1/2 sequences, the South Indian B19V strain forms a separate clade closer to the existing genotype two strains circulating worldwide. Our study contributes to a better understanding of the human parvovirus's genetic and evolutionary characteristics in South India. Also, it highlights the possibility that a positive selection pressure acting on VP1/2 could increase the survival and replication capabilities of the viruses.


A novel dual agonist of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors attenuates fentanyl taking and seeking in male rats.
There has been a dramatic increase in illicit fentanyl use in the United States over the last decade. In 2018, more than 31,000 overdose deaths involved fentanyl or fentanyl analogs, highlighting an urgent need to identify effective treatments for fentanyl use disorder. An emerging literature shows that glucagon-like peptide-1 receptor (GLP-1R) agonists attenuate the reinforcing efficacy of drugs of abuse. However, the effects of GLP-1R agonists on fentanyl-mediated behaviors are unknown. The first goal of this study was to determine if the GLP-1R agonist exendin-4 reduced fentanyl self-administration and the reinstatement of fentanyl-seeking behavior, an animal model of relapse, in rats. We found that systemic exendin-4 attenuated fentanyl taking and seeking at doses that also produced malaise-like effects in rats. To overcome these adverse effects and enhance the clinical potential of GLP-1R agonists, we recently developed a novel dual agonist of GLP-1Rs and neuropeptide Y2 receptors (Y2Rs), GEP44, that does not produce nausea-like behavior in drug-naïve rats or emesis in drug-naïve shrews. The second goal of this study was to determine if GEP44 reduced fentanyl self-administration and reinstatement with fewer adverse effects compared to exendin-4 alone. In contrast to exendin-4, GEP44 attenuated opioid taking and seeking at a dose that did not suppress food intake or produce adverse malaise-like effects in fentanyl-experienced rats. Taken together, these findings indicate a novel role for GLP-1Rs and Y2Rs in fentanyl reinforcement and highlight a potential new therapeutic approach to treating opioid use disorders.


Nonconvulsive Status Epilepticus: Validating the Salzburg Criteria Against an Expert EEG Examiner.
Rapid and correct diagnosis of nonconvulsive status epilepticus (NCSE) is crucial for optimal treatment. However, electroencephalographic diagnosis can be challenging. Salzburg Consensus Criteria (SCC) have been proposed to facilitate correct diagnosis, but their validity needs to be further established. We retrospectively reanalyzed the first EEG in adult patients (n = 284) referred under the suspicion of NCSE at our institution in 2014. Nonconvulsive status epilepticus or possible NCSE was diagnosed according to the SCC by an examiner specifically trained in SCC and was compared with the original diagnosis made by an expert EEG examiner, which in this context served as the reference standard, to assess the validity of the criteria. Furthermore, the clinical outcome for patients not diagnosed using SCC (false-negatives) was examined. Nonconvulsive status epilepticus or possible NCSE was diagnosed in 40 patients by the inexperienced reader using the SCC, blinded to other clinical data, and in 47 patients by the experienced reader, not blinded to the clinical data, who did not use SCC. There were eight false-negatives, one false-positive, 39 true-positives, and 236 true-negatives. Concordance between SCC and the reference standard was high (k = 0.88 [95% confidence interval, 0.80 to 0.96]). Four of the eight false-negatives suffered from anoxic encephalopathy. The remainder had a history of epilepsy and returned to preictal functional state. The SCC for NCSE implemented by an inexperienced EEG reader, blinded to all other data, yielded results highly concordant with the evaluation of EEG by an experienced reader. False-negative diagnoses were associated with postictal states or anoxic encephalopathy.


The Epidemiological Characteristics and Outcome of COVID-19 in Patients Undergoing Peritoneal Dialysis: A Multi-center Study in Iran.
The pandemic of COVID-19 emerged in December 2019. Although numerous features of the illness have been investigated, the impact of disease on those patients with underlying diseases, is still a major problem. The aim of this multicenter, cohort study, was to determine the clinical manifestations of COVID-19 in peritoneal dialysis (PD) patients. Five hundred and five patients, receiving PD, were enrolled in this study, out of which 3.7% had coronavirus infection. Fever was the most common symptom (63.2%). The hospitalization rate was 10.5, 21.1% required admission to intensive care units (ICU) and the mortality rate was 21%. The most common cause of infection included close contact with the infected individuals and lower rates of protective equipment use. Although the incidence of COVID-19 among PD patients is low, the severity of the disease and the mortality rate are quite high. Vaccination and adherence to preventive measures are strongly recommended in PD patients. DOI: 10.52547/ijkd.7147.


Protein Methionine Sulfoxide Dynamics in Arabidopsis thaliana under Oxidative Stress.
Reactive oxygen species such as hydrogen peroxide can modify proteins via direct oxidation of their sulfur-containing amino acids, cysteine and methionine. Methionine oxidation, studied here, is a reversible posttranslational modification that is emerging as a mechanism by which proteins perceive oxidative stress and function in redox signaling. Identification of proteins with oxidized methionines is the first prerequisite toward understanding the functional effect of methionine oxidation on proteins and the biological processes in which they are involved. Here, we describe a proteome-wide study of in vivo protein-bound methionine oxidation in plants upon oxidative stress using Arabidopsis thaliana catalase 2 knock-out plants as a model system. We identified over 500 sites of oxidation in about 400 proteins and quantified the differences in oxidation between wild-type and catalase 2 knock-out plants. We show that the activity of two plant-specific glutathione S-transferases, GSTF9 and GSTT23, is significantly reduced upon oxidation. And, by sampling over time, we mapped the dynamics of methionine oxidation and gained new insights into this complex and dynamic landscape of a part of the plant proteome that is sculpted by oxidative stress.


Oral Candida albicans isolates from nonhospitalized normal carriers, immunocompetent hospitalized patients, and immunocompromised patients with or without acquired immunodeficiency syndrome.
A total of 128 human oral isolates of Candida albicans were collected from asymptomatic healthy carriers (64 isolates); asymptomatic, nonimmunosuppressed, hospitalized patients (25 isolates); immunosuppressed transplant patients (19 isolates); and human immunodeficiency virus-infected patients with symptoms of acquired immunodeficiency syndrome and oral candidiasis (20 isolates). Isolates were serotyped as A or B and tested for reactivity with an agglutinating immunoglobulin M monoclonal antibody (H9). Immunocompetent individuals colonized by oral C. albicans were almost equally likely to carry serotype A as serotype B cells, while immunocompromised individuals were at least twice as likely to be infected by serotype B than serotype A strains. The reactivity of isolates with H9 antibody followed a similar but more distinctive pattern. Approximately half of the strains from immunocompetent individuals reacted strongly with H9, and the remainder reacted weakly. However, up to 75% of the isolates from immunocompromised patients reacted weakly with H9, while the remainder reacted strongly. A correlation between H9 reactivity and the serotypes of these isolates existed (P = 0.16). The correlation between H9 reactivity and immune status was even stronger (P = 0.025). The monoclonal antibody activities described above were determined by agglutination tests during defined phases of C. albicans growth. Expression of antigen at various times during growth of several isolates was confirmed at the cellular level by analysis using fluorescence-activated cell sorting. Despite the correlation between serotype A and H9 reactivity, H9 antigen was not identical to the serotype A antigen because four serotype A strains reacted only weakly with H9 antibody, and one strain reacted strongly with H9 but was serotype B. These data indicate that oral strains of C. albicans from immunocompetent individuals differ as a group from C. albicans isolated from those who are immunosuppressed.


Activity-Dependent Phosphorylation by CaMKIIδ Alters the Ca2+ Affinity of the Multi-C2-Domain Protein Otoferlin.
Otoferlin is essential for fast Ca2+-triggered transmitter release from auditory inner hair cells (IHCs), playing key roles in synaptic vesicle release, replenishment and retrieval. Dysfunction of otoferlin results in profound prelingual deafness. Despite its crucial role in cochlear synaptic processes, mechanisms regulating otoferlin activity have not been studied to date. Here, we identified Ca2+/calmodulin-dependent serine/threonine kinase II delta (CaMKIIδ) as an otoferlin binding partner by pull-downs from chicken utricles and reassured interaction by a co-immunoprecipitation with heterologously expressed proteins in HEK cells. We confirmed the expression of CaMKIIδ in rodent IHCs by immunohistochemistry and real-time PCR. A proximity ligation assay indicates close proximity of the two proteins in rat IHCs, suggesting that otoferlin and CaMKIIδ also interact in mammalian IHCs. In vitro phosphorylation of otoferlin by CaMKIIδ revealed ten phosphorylation sites, five of which are located within C2-domains. Exchange of serines/threonines at phosphorylated sites into phosphomimetic aspartates reduces the Ca2+ affinity of the recombinant C2F domain 10-fold, and increases the Ca2+ affinity of the C2C domain. Concordantly, we show that phosphorylation of otoferlin and/or its interaction partners are enhanced upon hair cell depolarization and blocked by pharmacological CaMKII inhibition. We therefore propose that otoferlin activity is regulated by CaMKIIδ in IHCs.


The treatment of paediatric burns using topical papaya.
Due to the limited resources for the management of burns in most regions of Africa there is a significant role for many aspects of traditional African medicine. The active component of many traditional preparations is often of plant origin and more than 25 plants have been described as useful in relations to burns and wound healing. Carica papaya is currently used in The Gambia at the Royal Victoria Hospital, Banjul in the Paediatric Unit as the major component of burns dressings, where it is well tolerated by the children. Cheap and widely available, the pulp of the papaya fruit is mashed and applied daily to full thickness and infected burns. It appears to be effective in desloughing necrotic tissue, preventing burn wound infection, and providing a granulating wound suitable for the application of a split thickness skin graft. Possible mechanisms of action include the activity of proteolytic enzymes chymopapain and papain, as well as an antimicrobial activity, although further studies are required.


Inhibition of thrombin formation by active site mutated (S360A) activated protein C.
Activated protein C (APC) down-regulates thrombin formation through proteolytic inactivation of factor Va (FVa) by cleavage at Arg(506) and Arg(306) and of factor VIIIa (FVIIIa) by cleavage at Arg(336) and Arg(562). To study substrate recognition by APC, active site-mutated APC (APC(S360A)) was used, which lacks proteolytic activity but exhibits anticoagulant activity. Experiments in model systems and in plasma show that APC(S360A), and not its zymogen protein C(S360A), expresses anticoagulant activities by competing with activated coagulation factors X and IX for binding to FVa and FVIIIa, respectively. APC(S360A) bound to FVa with a K(D) of 0.11 +/- 0.05 nm and competed with active site-labeled Oregon Green activated coagulation factor X for binding to FVa. The binding of APC(S360A) to FVa was not affected by protein S but was inhibited by prothrombin. APC(S360A) binding to FVa was critically dependent upon the presence of Arg(506) and not Arg(306) and additionally required an active site accessible to substrates. Inhibition of FVIIIa activity by APC(S360A) was >100-fold less efficient than inhibition of FVa. Our results show that despite exosite interactions near the Arg(506) cleavage site, binding of APC(S360A) to FVa is almost completely dependent on Arg(506) interacting with APC(S360A) to form a nonproductive Michaelis complex. Because docking of APC to FVa and FVIIIa constitutes the first step in the inactivation of the cofactors, we hypothesize that the observed anticoagulant activity may be important for in vivo regulation of thrombin formation.


Aberrant "default mode" functional connectivity in schizophrenia.
The "default mode" has been defined as a baseline condition of brain function and is of interest because its component brain regions are believed to be abnormal in schizophrenia. It was hypothesized that the default mode network would show abnormal activation and connectivity in patients with schizophrenia. Patients with schizophrenia (N=21) and healthy comparison subjects (N=22) performed an auditory oddball task during functional magnetic resonance imaging (fMRI). Independent component analysis was used to identify the default mode component. Differences in the spatial and temporal aspects of the default mode network were examined in patients versus comparison subjects. Healthy comparison subjects and patients had significant spatial differences in the default mode network, most notably in the frontal, anterior cingulate, and parahippocampal gyri. In addition, activity in patients in the medial frontal, temporal, and cingulate gyri correlated with severity of positive symptoms. The patients also showed significantly higher frequency fluctuations in the temporal evolution of the default mode. Schizophrenia is associated with altered temporal frequency and spatial location of the default mode network. The authors hypothesized that this network may be under- or overmodulated by key regions, including the anterior and posterior cingulate cortex. In addition, the altered temporal fluctuations in patients may result from a change in the connectivity of these regions with other brain networks.


The Affordable Care Act's Medicaid Expansion and Impact Along the Cancer-Care Continuum: A Systematic Review.
Health reform and the merits of Medicaid expansion remain at the top of the legislative agenda, with growing evidence suggesting an impact on cancer care and outcomes. A systematic review was undertaken to assess the association between Medicaid expansion and the goals of the Patient Protection and Affordable Care Act in the context of cancer care. The purpose of this article is to summarize the currently published literature and to determine the effects of Medicaid expansion on outcomes during points along the cancer care continuum. A systematic search for relevant studies was performed in the PubMed/MEDLINE, EMBASE, Scopus, and Cochrane databases. Three independent observers used an abstraction form to code outcomes and perform a quality and risk of bias assessment using predefined criteria. A total of 48 studies were identified. The most common outcomes assessed were the impact of Medicaid expansion on insurance coverage (23.4% of studies), followed by evaluation of racial and/or socioeconomic disparities (17.4%) and access to screening (14.5%). Medicaid expansion was associated with increases in coverage for cancer patients and survivors as well as reduced racial- and income-related disparities. Medicaid expansion has led to improved access to insurance coverage among cancer patients and survivors, particularly among low-income and minority populations. This review highlights important gaps in the existing oncology literature, including a lack of studies evaluating changes in treatment and access to end-of-life care following implementation of expansion.


Codivergence in heteromyid rodents (Rodentia: heteromyidae) and their sucking lice of the genus Fahrenholzia (Phthiraptera: anoplura).
Although most studies of codivergence rely primarily on topological comparisons of host and parasite phylogenies, temporal assessments are necessary to determine if divergence events in host and parasite trees occurred contemporaneously. A combination of cophylogenetic analyses and comparisons of branch lengths are used in this study to understand the host-parasite association between heteromyid rodents (Rodentia: Heteromyidae) and their sucking lice of the genus Fahrenholzia (Phthiraptera: Anoplura). Cophylogenetic comparisons based on nucleotide substitutions in the mitochondrial COI gene reveal a significant, but not perfect, pattern of cophylogeny between heteromyids and their sucking lice. Regression analyses show a significant functional relationship between the lengths of analogous branches in the host and parasite trees, indicating that divergence events in hosts and parasites were approximately contemporaneous. Thus, the topological similarity observed between heteromyids and their lice is the result of codivergence. These analyses also show that the COI gene in lice is evolving two to three times faster than the same gene in their hosts (similar to the results of studies of other lice and their vertebrate hosts) and that divergence events in lice occurred shortly after host divergence. We recommend that future studies of codivergence include temporal comparisons and, when possible, use the same molecular marker(s) in hosts and parasites to achieve the greatest insight into the history of the host-parasite relationship.


Time-delay signature suppression in a chaotic semiconductor laser by fiber random grating induced random distributed feedback.
We demonstrate that a semiconductor laser perturbed by distributed feedback with random time delays from a large number of scattering centers along a fiber random grating can emit light chaotically without the time-delay signature (TDS). A theoretical model is developed based on the modified Lang-Kobayashi model to numerically explore the chaotic dynamics of the laser diode subjected to random feedback. It is predicted that the random distributed feedback destroys the phase-correlated mode condition and hence suppresses the TDS. The fiber random grating is fabricated with random index modulation periods through point-by-point inscription, which introduces large numbers of phase-uncorrelated cavity modes into the semiconductor laser, leading to high dimensional chaotic dynamics and thus the concealment of the TDS. The experimentally obtained TDS value is negligible with a minimum of 0.0088, which is the smallest to date.


Development of iminosugar-based glycosidase inhibitors as drug candidates for SARS-CoV-2 virus via molecular modelling and in vitro studies.
We developed new iminosugar-based glycosidase inhibitors against SARS-CoV-2. Known drugs (miglustat, migalastat, miglitol, and swainsonine) were chosen as lead compounds to develop three classes of glycosidase inhibitors (α-glucosidase, α-galactosidase, and mannosidase). Molecular modelling of the lead compounds, synthesis of the compounds with the highest docking scores, enzyme inhibition tests, and in vitro antiviral assays afforded rationally designed inhibitors. Two highly active α-glucosidase inhibitors were discovered, where one of them is the most potent iminosugar-based anti-SARS-CoV-2 agent to date (EC90 = 1.94 µM in A549-ACE2 cells against Omicron BA.1 strain). However, galactosidase inhibitors did not exhibit antiviral activity, whereas mannosidase inhibitors were both active and cytotoxic. As our iminosugar-based drug candidates act by a host-directed mechanism, they should be more resilient to drug resistance. Moreover, this strategy could be extended to identify potential drug candidates for other viral infections.


Contribution of Beta-HPV Infection and UV Damage to Rapid-Onset Cutaneous Squamous Cell Carcinoma during BRAF-Inhibition Therapy.
BRAF-inhibition (BRAFi) therapy for advanced melanoma carries a high rate of secondary cutaneous squamous cell carcinoma (cSCC) and risk of other cancers. UV radiation and α-genus human papillomavirus (HPV) are highly associated with SCC, but a novel role for β-genus HPV is suspected in BRAFi-cSCC. Cutaneous β-HPV may act in concert with host and environmental factors in BRAFi-cSCC. Primary BRAFi-cSCC tissue DNA isolated from patients receiving vemurafenib or dabrafenib from two cancer centers was analyzed for the presence of cutaneous oncogenic viruses and host genetic mutations. Diagnostic specimens underwent consensus dermatopathology review. Clinical parameters for UV exposure and disease course were statistically analyzed in conjunction with histopathology. Twenty-nine patients contributed 69 BRAFi-cSCC lesions. BRAFi-cSCC had wart-like features (BRAFi-cSCC-WF) in 22% of specimens. During vemurafenib therapy, BRAFi-cSCC-WF arose 11.6 weeks more rapidly than conventional cSCC when controlled for gender and UV exposure (P value = 0.03). Among all BRAFi-cSCC, β-genus HPV-17, HPV-38, HPV-111 were most frequently isolated, and novel β-HPV genotypes were discovered (CTR, CRT-11, CRT-22). Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK, and EGFR mutations also detected. We examined clinical, histopathologic, viral, and genetic parameters in BRAFi-cSCC demonstrating rapid onset; wart-like histomorphology; β-HPV-17, HPV-38, and HPV-111 infection; UV damage; and novel ALK and CKIT mutations. Discovered β-HPV genotypes expand the spectrum of tumor-associated viruses. These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general.


Mortality in residents of the urban and rural areas of Mexico, 2002-2019.
Mortality is affected by several factors, including the place of residence. Several studies have found a gap in mortality between urban and rural residents. This study aimed to describe adjusted mortality rates in urban and rural areas of Mexico. Adjusted mortality rate per 100 000 inhabitants was estimated in urban and rural areas of Mexico, were grouped by sex, age, and main cause of death. Trend analysis was performed with a logarithmic regression of adjusted rates. Mortality was higher in urban (622.1/100 000 inhabitants) than rural (549.5/100 000 inhabitants) areas of Mexico. Males showed the highest mortality rate in both studied areas, urban and rural (737.8 and 634.4/100 000 inhabitants respectively). A significant annual decrease of 0.5% in mortality rates was observed in both areas. In Mexico, there is a gap in mortality rates based on individuals' place of residence. Those who live in urban areas present the highest mortality rates.


Enzyme synthesis in myxamoebae of the cellular slime mould Dictyostelium discoideum during growth in axenic culture.
1. The specific activities of beta-N-acetylglucosaminidase, acid phosphatase, alpha-mannosidase, beta-glucosidase, UDP-glucose pyrophosphorylase and alkaline phosphatase have been determined in myxamoebae of the cellular slime mould Dictyostelium discoideum Ax-2 grown on different media and in different phases of the growth cycle. 2. Variations in enzymic composition occur with changes in growth medium and phase of the growth cycle. 3. The intracellular location of the enzymes studied has been determined. 4. Two enzymes, beta-N-acetylglucosaminidase and alpha-mannosidase, are not only synthesized preferentially as the myxamoebae enter the stationary phase of growth but they are also excreted. The excretion process appears to be specific, because other enzymes that occur in the same intracellular fraction are not excreted.


Prevalence and consequences of patient safety incidents in general practice in the Netherlands: a retrospective medical record review study.
Patient safety can be at stake in both hospital and general practice settings. While severe patient safety incidents have been described, quantitative studies in large samples of patients in general practice are rare. This study aimed to assess patient safety in general practice, and to show areas where potential improvements could be implemented. We conducted a retrospective review of patient records in Dutch general practice. A random sample of 1,000 patients from 20 general practices was obtained. The number of patient safety incidents that occurred in a one-year period, their perceived underlying causes, and impact on patients' health were recorded. We identified 211 patient safety incidents across a period of one year (95% CI: 185 until 241). A variety of types of incidents, perceived causes and consequences were found. A total of 58 patient safety incidents affected patients; seven were associated with hospital admission; none resulted in permanent disability or death. Although this large audit of medical records in general practices identified many patient safety incidents, only a few had a major impact on patients' health. Improving patient safety in this low-risk environment poses specific challenges, given the high numbers of patients and contacts in general practice.


The oncogenic gene fusion TMPRSS2: ERG is not a diagnostic or prognostic marker for ovarian cancer.
TMPRSS2:ERG is a gene fusion resulting from the chromosomal rearrangement of the androgen-regulated TMPRSS2 gene and the ETS transcription factor ERG, leading to the over-expression of the oncogenic molecule ERG. This gene rearrangement has been found in approximately half of all prostate cancers and ERG overexpression is considered as a novel diagnostic marker for prostate carcinoma. However, little is known about the role of the TMPRSS2:ERG gene fusion in ovarian cancer. The purpose of this study was to test ERG expression in ovarian cancer and its potential as a diagnostic marker for ovarian carcinoma progression. A tissue microarray containing 180 ovarian cancer tissues of various pathological types and grades were examined by immunohistochemical analysis for expression of ERG. We also used 40 prostate carcinoma tissues and 40 normal tissues for comparison in parallel experiments. ERG-positive expression was detected in 40% of the prostate tumor cancer, as well as in internal positive control endothelial cells, confirming over-expression of ERG in prostate cancer at relatively the same rate observed by others. In contrast, all of the ovarian tumor patient tissues of varying histologic types were ERG-negative, despite some positivity in endothelial cells. These results suggest that the oncogenic gene fusion TMPRSS2:ERG does not occur in ovarian cancer relative to prostate cancer. Therefore, development of ERG expression profile would not be a useful diagnostic or prognostic marker for ovarian cancer patient screening.


Hyperexpression of HOXC13, located in the 12q13 chromosomal region, in well‑differentiated and dedifferentiated human liposarcomas.
Liposarcoma (LPS) is the most common soft tissue neoplasm in adults and is characterized by neoplastic adipocyte proliferation. Some subtypes of LPSs show aberrations involving the chromosome 12. The most frequent are t(12;16) (q13;p11) present in more than 90% of myxoid LPSs and 12q13-15 amplification in well-differentiated and dedifferentiated LPSs. In this region, there are important oncogenes such as CHOP (DDIT3), GLI, MDM2, CDK4, SAS, HMGA2, but also the HOXC locus, involved in development and tumor progression. In this study, we evaluated the expression of HOXC13, included in this chromosomal region, in a series of adipocytic tumors. We included 18 well-differentiated, 4 dedifferentiated, 11 myxoid and 6 pleomorphic LPSs as well as 13 lipomas in a tissue microarray. We evaluated the HOXC13 protein and gene expression by immunohistochemistry and quantitative PCR. Amplification/translocation of the 12q13-15 region was verified by FISH. Immunohistochemical HOXC13 overexpression was observed in all well-differentiated and dedifferentiated LPSs, all characterized by the chromosome 12q13-15 amplification, and confirmed by quantitative PCR analysis. In conclusion, our data show a deregulation of the HOXC13 marker in well‑differentiated and dedifferentiated LPSs, possibly related to 12q13-15 chromosomal amplification.


Acute effects of β-hydroxybutyrate on left ventricular function in young, healthy adults.
Interest in ketones as a cardiac "super fuel" has grown significantly following reports of a marked increase in cardiac output after exogenous ketone administration in heart failure. However, the extent to which this increase in cardiac output is related to changes in cardiac contractility, and dependent on the presence of heart failure, remains incompletely understood. Therefore, we performed a randomized, double-blind, placebo-controlled study of oral ketone ester in young healthy volunteers. Baseline cardiac magnetic resonance imaging was performed and repeated every 15 min for 60 min after ketone and placebo ingestion to assess changes in left ventricular function. As expected, circulating β-hydroxybutyrate increased rapidly after ketone ingestion, but did not change with placebo (interaction: P < 0.001). Consistent with prior investigations, ketone ingestion resulted in an average 1 L/min increase in cardiac output after 60 min that did not occur with placebo (interaction: P = 0.026). This increase in cardiac output was primarily driven by an increase in heart rate after ketone ingestion (interaction: P = 0.018), with only a modest increase in stroke volume (interaction: P = 0.037). Changes in left ventricular strain and twist mechanics were limited. Taken together, the increase in cardiac output following an acute elevation in circulating β-hydroxybutyrate is primarily driven by changes in cardiac chronotropy, with minimal inotropic contribution.NEW & NOTEWORTHY In this randomized, double-blind, placebo-controlled study of oral ketone ester in young healthy volunteers, we show a marked increase in cardiac output (∼1 L/min), driven primarily by changes in chronotropy. The cardiac magnetic resonance imaging data support the limited role for inotropy.


Choice theories: What are they good for?
Simonson et al. present an ambitious sketch of an integrative theory of context. Provoked by this thoughtful proposal, I discuss what is the function of theories of choice in the coming decades. Traditionally, choice models and theory have attempted to predict choices as a function of the attributes of options. I argue that to be truly useful, they need to generate specific and quantitative predictions of the effect of the choice environment upon choice probability. To do this, we need to focus on rigorously modeling and measuring the underlying processes causing these effects, and use the Simonson et al. proposal to provide some examples. I also present some examples from research in decision-making and decision neuroscience, and argue that models that fail, and fail spectacularly are particularly useful. I close with a challenge: How would consumer researcher aid the design of real world choice environments such as the health exchanges under the Patient Protection and Affordable Care Act?


Preventing the Onset of Child Sexual Abuse by Targeting Young Adolescents With Universal Prevention Programming.
Child sexual abuse (CSA) is a serious public health problem that increases risk for physical and mental health problems across the life course. Young adolescents are responsible for a substantial portion of CSA offending, yet to our knowledge, no validated prevention programs that target CSA perpetration by youth exist. Most existing efforts to address CSA rely on reactive criminal justice policies or programs that teach children to protect themselves; neither approach is well validated. Given the high rates of desistance from sexual offending following a youth's first CSA-related adjudication, it seems plausible that many youth could be prevented from engaging in their first offense. The goal of this article is to examine how school-based universal prevention programs might be used to prevent CSA perpetrated by adolescents. We review the literature on risk and protective factors for CSA perpetration and identify several promising factors to target in an intervention. We also summarize the literature on programs that have been effective at preventing adolescent dating violence and other serious problem behaviors. Finally, we describe a new CSA prevention program under development and early evaluation and make recommendations for program design characteristics, including unambiguous messaging, parental involvement, multisession dosage, skills practice, and bystander considerations.


Measurement of ischaemia-reperfusion in patients with intermittent claudication using NMR-based metabonomics.
Intermittent claudication has proved to be a good in vivo model for ischaemia-reperfusion. For assessment of ischaemia-reperfusion damage, the known biochemical markers all have disadvantages with respect to sensitivity and interference with other physiological events. In this work, we studied the metabolic effects of ischaemia-reperfusion in patients with intermittent claudication, and the effects of vitamin C and E intervention, using both traditional biochemical measurements and 1H-NMR-based metabonomics on urine and plasma. The 1H-NMR spectra were subjected to multivariate modelling using principal components discriminant analysis, and the observed clusters were validated using joint deployment of univariate analysis of variance and Tukey-Kramer honestly significant difference (HSD) testing. The study involved 14 patients with intermittent claudication and three healthy volunteers, who were monitored during a walking test, before and after a vitamin C/E intervention, and after a washout period. The effect of exercise was only observable for a limited number of biochemical markers, whereas 1H NMR revealed an effect in line with anaerobic ATP production via glycolysis in exercising (ischaemic) muscle of the claudicants. Thus, the beneficial effect of vitamins C and E in claudicants was more pronounced when observed by metabonomics than by traditional biochemical markers. The main effect was more rapid recovery from exercise to resting state metabolism. Furthermore, after intervention, claudicants tended to have lower concentrations of lactate and glucose and several other citric acid cycle metabolites, whereas acetoacetate was increased. The observed metabolic changes in the plasma suggest that intake of vitamin C/E leads to increased muscle oxidative metabolism.


Isolation of Potential Bacteria as Inoculum for Biofloc Formation in Pacific Whiteleg Shrimp, Litopenaeus vannamei Culture Ponds.
A new green technology to reduce environmental damages while optimizing production of Pacific Whiteleg shrimp, Litopenaeus vannamei was developed known as "Biofloc technology". Microbial communities in biofloc aggregates are responsible in eliminating water exchange and producing microbial proteins that can be used as supplemented feed for L. vannamei. This study aimed to isolate and identify potential bioflocculant-producing bacteria to be used as inoculum for rapid formation of biofloc. For the purpose of this study, bacterial communities during 0, 30 and 70 days of culture (DOC) of L. vannamei grow-out ponds were isolated and identified through phenotypic and 16S rDNA sequences analysis. Phylogenetic relationships between isolated bacteria were then evaluated through phylogenetic tree analysis. One-way analysis of variance (ANOVA) was used to compare the differences of microbial communities at each DOC. Out of 125 bacterial isolates, nine species of bacteria from biofloc were identified successfully. Those bacteria species were identified as Halomonas venusta, H. aquamarina, Vibrio parahaemolyticus, Bacillus infantis, B. cereus, B. safensis, Providencia vermicola, Nitratireductor aquimarinus and Pseudoalteromonas sp., respectively. Through phylogenetic analysis, these isolates belong to Proteobacteria and Firmicutes families under the genera of Halomonas sp., Vibrio sp., Bacillus sp., Providencia sp., Nitratireductor sp. and Pseudoalteromonas sp. In this study, bioflocculant-producing bacteria were successfully identified which are perfect candidates in forming biofloc to reduce water pollution towards a sustainable aquaculture industry. Presence of Halomonas sp. and Bacillus sp. in all stages of biofloc formation reinforces the need for new development regarding the ability of these species to be used as inoculum in forming biofloc rapidly.


Predictive factors for early hospital readmission and 1-year mortality in elder patients following surgical treatment of a hip fracture.
Early hospital readmission after surgically treated hip fracture is a common entity, often involving an adverse event and causing strains on an already overburdened healthcare system. The main purposes of the present study were to determine the 30-day readmission rate, analyze the predictive factors for early hospital readmissions, and assess 1-year mortality following surgical treatment of hip fracture in elderly patients. Retrospective case-control study. In total, 517 patients with a mean age of 74 years were evaluated. The rate of early readmission, age, gender, body mass index, fracture type, pre-fracture mobility status, preoperative time to surgery, American Society of Anesthesiologists score, implant type, postoperative intensive care unit stay, total length of postoperative hospital stay, comorbidities, and the main reasons for readmission were the criteria for data collection. Multivariate analysis was performed to determine the main predictors of early hospital readmission. Mortality within the first year after surgery was also assessed. A higher prevalence of chronic obstructive pulmonary disease, cardiac arrhythmia or ischemic heart disease, diabetes, and dementia or Parkinson's disease was detected in readmitted patients. Advanced age, American Society of Anesthesiologists (ASA) grade ≥3, postoperative intensive care unit (ICU) stay, and pre-existing cardiac arrhythmia or ischemic heart disease were identified as the main predictors. The 1-year mortality rate for the readmitted group was 53.9%, whereas it was 24% for those patients who were not readmitted. The readmission rate following surgical treatment of hip fracture in elder patients was 12%, and its main predictive factors were advanced age, ASA grade ≥3, postoperative ICU stay, and pre-existing cardiac arrhythmia or ischemic heart disease. Hospital readmission within the first 30-day period following initial discharge was significantly correlated with an increased 1-year mortality rate.


Frequent overexpression of Aurora Kinase A in upper gastrointestinal adenocarcinomas correlates with potent antiapoptotic functions.
Upper gastrointestinal adenocarcinomas are a common cause of cancer-related deaths. In this study, the authors investigated the prevalence and biological significance of Aurora Kinase A (AURKA) overexpression in upper gastrointestinal adenocarcinomas. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemical staining on tumor tissue microarrays (TMA) were used to study the expression of AURKA in upper gastrointestinal adenocarcinomas. To investigate the biological and signaling impact of AURKA, the authors used multiple in vitro assays that included 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT), TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling), cytochrome C release, flow cytometry, luciferase reporter, and Western blot analysis. Frequent overexpression of AURKA transcript in upper gastrointestinal adenocarcinomas was detected compared with normal samples (47%; P= .001). The immunohistochemical analysis of 130 tumors demonstrated moderate-to-strong immunostaining of AURKA in >50% of upper gastrointestinal adenocarcinomas. By using camptothecin as a drug-induced apoptosis in vitro model, the authors demonstrated that the expression of AURKA provided protection against apoptosis to gastrointestinal cancer cells (AGS and RKO) (P= .006) and RIE-1 primary intestinal epithelial cells (P= .001). The AURKA overexpression mediated an increase in phosphorylation of AKT(Ser473) with an increase in HDM2 level. The shRNA-knockdown of AKT in AURKA-overexpressing cells reversed this effect and showed a significant increase in the p53 protein level, indicating a possible nexus of AURKA/AKT/p53. Indeed, overexpression of AURKA led to a remarkable reduction in the transcription activity of p53, with subsequent reductions in transcript and protein levels of its downstream proapoptotic transcription targets (p21, BAX, NOXA, and PUMA). Study results indicated that AURKA provides potent antiapoptotic properties to gastrointestinal cells by regulating levels of p53 through the AKT/HDM2 axis.


Impaired intestinal immunity and microbial diversity in common carp exposed to cadmium.
Waterborne cadmium (Cd) accumulates in the fish intestine and causes irreversible toxicity by disrupting intestinal immunity and microbial diversity. To explore the toxicity of environmentally available high Cd concentration on intestinal immunity and microbial diversity of fish, we selected the widely used bioindicator model species, Common carp (Cyprinus carpio). Literature review and Cd pollution data supported sequential doses of 0.2, 0.4, 0.8, 1.6, 3.2, and 6.4 mg/L Cd for 30 days. Based on intestinal tissue Cd accumulation, previous studies, and environmentally available Cd data, 0.4 and 1.6 mg/L Cd were selected for further studies. Intestinal Cd bioaccumulation increased significantly to ~100 times in fish exposed to 1.6 mg/L Cd. We observed villous atrophy, increased goblet cells with mucus production, muscularis erosion, and thickened lamina propria due to intense inflammatory cell infiltration in the intestine at this Cd concentration. Cd-induced immunosuppression occurred with increased lysozyme, alkaline phosphate (AKP), and acid phosphate (ACP). High levels of catalase (CAT), total antioxidant capacity (T-AOC), malondialdehyde (MDA), and hydrogen peroxide (H2O2) suggested induced oxidative stress and poor metabolism by α-amylase and lipase suppression for Cd toxicity. Proteobacteria (41.2 %), Firmicutes (21.8 %), and Bacteroidetes (17.5 %) were the dominant bacterial phyla in the common carp intestine. Additionally, potential pathogenic Cyanobacteria increased in Cd-treated fish. The decrease of beneficiary bacteria like Aeromonas, and Cetobacterium indicated Cd toxicity. Overall, these findings indicate harmful consequences of high Cd concentration in the intestinal homeostasis and health status of fish.


METALLIZED FOOD IN THE REGENERATION OF HEMOGLOBIN IN RAT AND MAN.
(1) Metals dissolve enough in milk to supply the requirements for rapid regeneration of hemoglobin in rat and man. (2) Copper alone is effective but less so than when accompanied by other metals, especially iron. (2) Much less mortality occurs among rats fed on metallized milk than when salts of the metals are used in anemia tests. (4) These metals produce no odor, color, taste or other observed change in milk with the quantities used unless they are exposed to air and milk.


Monte Carlo calculation of dosimetry parameters for the IR08-103Pd brachytherapy source.
For the treatment of some cancerous tumors using brachytherapy methods and low-energy photon sources, such as 125I and 103Pd, the American Association of Physicists in Medicine Task Group No. 43U1 report recommends that the dosimetric parameters of a new brachytherapy source must be determined in two experimental and Monte Carlo theoretical methods before using each new source clinically. This study presents the results of Monte Carlo calculations of the dosimetric parameters for IR08-103Pd brachytherapy source design. IR08-103Pd seed has been manufactured at the Agricultural, Medical and Industrial Research School. Version 5 of the (MCNP) Monte Carlo radiation transport code was used to calculate the dosimetry parameters around the source. Three geometric models of the seed, based on different locations of beads inside the titanium capsule, were simulated. The seed contains five resin beads of 0.6 mm diameter having 103Pd uniformly absorbed in the bead volume, which were contained within a cylindrical titanium capsule having 0.8 mm outside diameter and 4.8 mm length. The Monte Carlo calculated dose rate constant of the IR08-103Pd seed was found to be 0.695 +/- 0.021 cGyU(-1) h(-1). Also in this study, the geometry function G(r, theta), line and point-source radial dose functions gL(r) and gP(r), and the anisotropy function F(r, theta), have been calculated at distances from 0.25 to 7 cm. The results of these calculations have been compared with measured values for an actual IR08-103Pd seed. There are no statistical significant dosimetric differences among the three seed orientations in this study (i.e., ideal, vertical, and diagonal). However, the observed differences between the calculated and measured values could be explained by the measurement uncertainty and the configuration of the resin beads within the capsule and capsule orientation.


p53 dependent centrosome clustering prevents multipolar mitosis in tetraploid cells.
p53 abnormality and aneuploidy often coexist in human tumors, and tetraploidy is considered as an intermediate between normal diploidy and aneuploidy. The purpose of this study was to investigate whether and how p53 influences the transformation from tetraploidy to aneuploidy. Live cell imaging was performed to determine the fates and mitotic behaviors of several human and mouse tetraploid cells with different p53 status, and centrosome and spindle immunostaining was used to investigate centrosome behaviors. We found that p53 dominant-negative mutation, point mutation, or knockout led to a 2∼ 33-fold increase of multipolar mitosis in N/TERT1, 3T3 and mouse embryonic fibroblasts (MEFs), while mitotic entry and cell death were not significantly affected. In p53-/- tetraploid MEFs, the ability of centrosome clustering was compromised, while centrosome inactivation was not affected. Suppression of RhoA/ROCK activity by specific inhibitors in p53-/- tetraploid MEFs enhanced centrosome clustering, decreased multipolar mitosis from 38% to 20% and 16% for RhoA and ROCK, respectively, while expression of constitutively active RhoA in p53+/+ tetraploid 3T3 cells increased the frequency of multipolar mitosis from 15% to 35%. p53 could not prevent tetraploid cells entering mitosis or induce tetraploid cell death. However, p53 abnormality impaired centrosome clustering and lead to multipolar mitosis in tetraploid cells by modulating the RhoA/ROCK signaling pathway.


Value of Intratumoral Metabolic Heterogeneity and Quantitative 18F-FDG PET/CT Parameters in Predicting Prognosis for Patients With Cervical Cancer.
OBJECTIVE. The purpose of this study is to evaluate the prognostic value of quantitative metabolic parameters from pretreatment PET/CT scans of patients with squamous cell cervical cancer. MATERIALS AND METHODS. This retrospective study included 120 patients with biopsy-proven squamous cell carcinoma of the cervix who underwent FDG PET/CT for initial tumor staging. The primary tumor maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean), tumor glycolytic activity, metabolic tumor volume (MTV), and metabolic intratumoral heterogeneity index (calculated as the AUC for the cumulative standardized uptake value [SUV]-volume histogram [CSH] index) were obtained. Information on patient demographic characteristics and tumor staging were collected. Median follow-up was 27.5 months. Overall survival (OS) and progression-free survival (PFS) were calculated using a multivariate Cox proportional hazards regression model and log-rank (Mantel-Cox) test to generate Kaplan-Meier survival plots. RESULTS. The mean (± SD) age of the patients was 54.4 ± 13.1 years. Twenty-two patients had stage I disease; 58, stage II; 23, stage III; and 17, stage IV. Thirty-three patients died, 82 were living, and five were lost to follow-up and were censored; 29 patients had disease progression. The median survival was 74.9 months (95% CI, 63.6-86.9 months). A higher MTV was significantly associated with reduced OS in multivariate analysis (hazard ratio, 1.085; 95% CI, 1.036-1.136; p = 0.0005). A higher AUC-CSH index (denoting lower tumor heterogeneity) was significantly associated with increased OS (hazard ratio, 0.662; 95% CI, 0.448-0.979; p = 0.04) and PFS (hazard ratio, 0.683; 95% CI, 0.471-0.991; p = 0.045) in multivariate analysis. Kaplan-Meier survival analysis using the median value for MTV (61 mL) significantly predicted OS (p = 0.0009). CONCLUSION. Tumor heterogeneity on pretreatment PET/CT is associated with OS and PFS in patients with cervical cancer. MTV is significantly associated with OS.


Age-related thymic involution in C57BL/6J x DBA/2J recombinant-inbred mice maps to mouse chromosomes 9 and 10.
A comprehensive analysis of initial thymus size and involution rate has not been quantitated for different genetic backgrounds of mice, thus genetic linkage analysis of thymic involution has not been possible. Here, we have used a mathematical method to analyze the age-related decline in thymocyte count in C57BL/6 and DBA/2 mice and have observed that thymic involution could be best fit with a negative exponential curve N(t)=beta(0) x exp(-beta(1)t), where t represents the age (day). This regression model was applied to C57BL/6 x DBA/2 (B x D) recombinant inbred strains of mice to identify the genetic loci influencing age-related thymic involution. There was a dramatic genetic effect of B and D alleles on thymocyte count at young age and the age-related thymic involution rate. The strongest quantitative trait loci (QTL) influencing the rate of thymic involution were mapped to mouse chromosome (Chr) 9 (D9Mit20 at 62 cM) and Chr 10 (D10Mit61 at 32 cM). The strongest QTLs influencing the initial thymocyte count were mapped to ChrX (DXMit324 at 26.5 cM) and Chr 3 (D3Mit127 at 70.3 cM). The present study suggests that the initial thymus size and the rate of thymic involution may be influenced by a relatively small number of genetic loci.


Multiple spatial and kinetic subpopulations of CaMKII in spines and dendrites as resolved by single-molecule tracking PALM.
Calcium/calmodulin-dependent protein kinase II (CaMKII) is essential for synaptic plasticity underlying memory formation. Some functions of CaMKII are mediated by interactions with synaptic proteins, and activity-triggered translocation of CaMKII to synapses has been heavily studied. However, CaMKII actions away from the postsynaptic density (PSD) remain poorly understood, in part because of the difficulty in discerning where CaMKII binds in live cells. We used photoactivated localization microscopy (PALM) in rat hippocampal neurons to track single molecules of CaMKIIα, mapping its spatial and kinetic heterogeneity at high resolution. We found that CaMKIIα exhibits at least three kinetic subpopulations, even within individual spines. Latrunculin application or coexpression of CaMKIIβ carrying its actin-binding domain strongly modulated CaMKII diffusion, indicating that a major subpopulation is regulated by the actin cytoskeleton. CaMKII in spines was typically more slowly mobile than in dendrites, consistent with presence of a higher density of binding partners or obstacles. Importantly, NMDA receptor stimulation that triggered CaMKII activation prompted the immobilization and presumed binding of CaMKII in spines not only at PSDs but also at other points up to several hundred nanometers away, suggesting that activated kinase does not target only the PSD. Consistent with this, single endogenous activated CaMKII molecules detected via STORM immunocytochemistry were concentrated in spines both at the PSD and at points quite distant from the synapse. Together, these results indicate that CaMKII mobility within spines is determined by association with multiple interacting proteins, even outside the PSD, suggesting diverse mechanisms by which CaMKII may regulate synaptic transmission.


Laparoscopy for Rectal Cancer.
It is evident that the use of laparoscopy in the management of rectal cancer has gained popularity in the last few years. It is still, however, not widely accepted as the standard of care. Multiple randomized trials have shown that short-term outcomes and perioperative morbidity and mortality of laparoscopic proctectomy are equivalent to open surgery. However, data regarding long-term oncologic outcomes are still scarce, with only a few randomized trials reporting similar outcomes in both laparoscopic and open group. A more recent trial failed to replicate those results in patients with locally advanced rectal cancer. In this article, we will look at the most recent evidence regarding the use of laparoscopy for patients with rectal cancer. We will also briefly discuss the different approaches and new minimally invasive techniques used in this field, and we will talk about the challenges facing the widespread adoption of laparoscopic surgery in the management of rectal cancer.


RUNX3 negatively regulates CD36 expression in myeloid cell lines.
CD36 is a member of the scavenger receptor type B family implicated in the binding of lipoproteins, phosphatidylserine, thrombospondin-1, and the uptake of long-chain fatty acids. On mononuclear phagocytes, recognition of apoptotic cells by CD36 contributes to peripheral tolerance and prevention of autoimmunity by impairing dendritic cell (DC) maturation. Besides, CD36 acts as a coreceptor with TLR2/6 for sensing microbial diacylglycerides, and its deficiency leads to increased susceptibility to Staphylococcus aureus infections. The RUNX3 transcription factor participates in reprogramming DC transcription after pathogen recognition, and its defective expression leads to abnormally accelerated DC maturation. We present evidence that CD36 expression is negatively regulated by the RUNX3 transcription factor during myeloid cell differentiation and activation. In molecular terms, RUNX3 impairs the activity of the proximal regulatory region of the CD36 gene in myeloid cells through in vitro recognition of two functional RUNX-binding elements. Moreover, RUNX3 occupies the CD36 gene proximal regulatory region in vivo, and its overexpression in myeloid cells results in drastically diminished CD36 expression. The down-regulation of CD36 expression by RUNX3 implies that this transcription factor could impair harmful autoimmune responses by contributing to the loss of pathogen- and apoptotic cell-recognition capabilities by mature DCs.


Structural prerequisites for CRM1-dependent nuclear export signaling peptides: accessibility, adapting conformation, and the stability at the binding site.
Nuclear export signal (NES) motifs function as essential regulators of the subcellular location of proteins by interacting with the major nuclear exporter protein, CRM1. Prediction of NES is of great interest in many aspects of research including cancer, but currently available methods, which are mostly based on the sequence-based approaches, have been suffered from high false positive rates since the NES consensus patterns are quite commonly observed in protein sequences. Therefore, finding a feature that can distinguish real NES motifs from false positives is desired to improve the prediction power, but it is quite challenging when only using the sequence. Here, we provide a comprehensive table for the validated cargo proteins, containing the location of the NES consensus patterns with the disordered propensity plots, known protein domain information, and the predicted secondary structures. It could be useful for determining the most plausible NES region in the context of the whole protein sequence and suggests possibilities for some non-binders of the annotated regions. In addition, using the currently available crystal structures of CRM1 bound to various classes of NES peptides, we adopted, for the first time, the structure-based prediction of the NES motifs bound to the CRM1's binding groove. Combining sequence-based and structure-based predictions, we suggest a novel and more straight-forward approach to identify CRM1-binding NES sequences by analysis of their structural prerequisites and energetic evaluation of the stability at the CRM1's binding site.


Central nervous system-immune reconstitution inflammatory syndrome presenting as varicella zoster virus-mediated vasculitis causing stroke.
Varicella zoster virus (VZV)-mediated vasculitis is a rare cause of stroke, but should be considered in HIV patients where vasculitis can occur in association with central nervous system - immune reconstitution inflammatory syndrome (CNS-IRIS). A literature search revealed 7 reports of VZV vasculitis over the years with no unifying management strategy, highlighting the difficulty in managing rare conditions in the absence of clear guidelines. This is the first documented case of VZV-mediated vasculitis presenting as stroke in the United Kingdom. Our patient made a full recovery with multidisciplinary input from HIV, neurology and radiology specialists.


Helping other alcoholics in alcoholics anonymous and drinking outcomes: findings from project MATCH.
Although Alcoholics Anonymous (AA) is the largest mutual-help organization for alcoholics in the world, its specific mechanisms that mobilize and sustain behavior change are poorly understood. The purpose of this study is to examine prospectively the relationship between helping other alcoholics and relapse in the year following treatment for alcohol use disorders. Data were derived from Project MATCH, a longitudinal prospective investigation of the efficacy of three behavioral treatments for alcohol abuse and dependence. Kaplan-Meier survival estimates were used to calculate probabilities of time to alcohol relapse. To identify the unique value of helping other alcoholics when controlling for the number of AA meetings attended, proportional hazards regressions were conducted to determine whether the likelihood of relapse was lower for those who were helping other alcoholics. There were no demographic differences that distinguished participants in regard to involvement in helping other alcoholics, with the exception of age; those who were helping other alcoholics were, on average, 3 years older than those who were not helping alcoholics. Those who were helping were significantly less likely to relapse in the year following treatment, independent of the number of AA meetings attended. These findings provide compelling evidence that recovering alcoholics who help other alcoholics maintain long-term sobriety following formal treatment are themselves better able to maintain their own sobriety. Clinicians who treat persons with substance abuse disorders should encourage their clients to help other recovering alcoholics to stay sober.


Synthesis and Cytotoxicity Studies of Wood-Based Cationic Cellulose Nanocrystals as Potential Immunomodulators.
Polysaccharides have been shown to have immunomodulatory properties. Modulation of the immune system plays a crucial role in physiological processes as well as in the treatment and/or prevention of autoimmune and infectious diseases. Cellulose nanocrystals (CNCs) are derived from cellulose, the most abundant polysaccharide on the earth. CNCs are an emerging class of crystalline nanomaterials with exceptional physico-chemical properties for high-end applications and commercialization prospects. The aim of this study was to design, synthesize, and evaluate the cytotoxicity of a series of biocompatible, wood-based, cationic CNCs as potential immunomodulators. The anionic CNCs were rendered cationic by grafting with cationic polymers having pendant +NMe3 and +NH3 moieties. The success of the synthesis of the cationic CNCs was evidenced by Fourier transform infrared spectroscopy, dynamic light scattering, zeta potential, and elemental analysis. No modification in the nanocrystals rod-like shape was observed in transmission electron microscopy and atomic force microscopy analyses. Cytotoxicity studies using three different cell-based assays (MTT, Neutral Red, and LIVE/DEAD®) and three relevant mouse and human immune cells indicated very low cytotoxicity of the cationic CNCs in all tested experimental conditions. Overall, our results showed that cationic CNCs are suitable to be further investigated as immunomodulators and potential vaccine nanoadjuvants.


Infant antibiotic use and wheeze and asthma risk: a systematic review and meta-analysis.
Our aim was to systematically review and meta-analyse longitudinal studies on antibiotic use and subsequent development of wheeze and/or asthma with regards to study quality, outcome measurement, reverse causation (RC; wheezing/asthma symptoms have caused prescription of antibiotics) and confounding by indication (CbI; respiratory tract infections leading to antibiotic use may be the underlying cause triggering asthma symptom development). English-language papers and studies published before November 1, 2010 with longitudinal observational design were included. Study quality was assessed using the Newcastle-Ottawa scale. We identified 21 longitudinal studies. The effect of antibiotic use on wheeze/asthma risk varied between studies. 18 studies were eligible for meta-analysis showing pooled OR 1.27 (95% CI 1.12-1.43) for wheeze/asthma. When we eliminated studies with possible RC and CbI, the pooled risk estimate in the nine remaining studies was attenuated to OR 1.12 (95% CI 0.98-1.26). Definition of wheeze/asthma and age at follow-up differed between studies. Three studies focused on wheeze/asthma beyond 5-6 yrs of age with the presence of active symptoms and/or medication (pooled OR 1.08, 95% CI 0.93-1.23; dominated by one study). RC and CbI lead to overestimation of the association between antibiotic use and subsequent development of wheeze/asthma. Association was weak when fully adjusted for these types of bias. Heterogeneity of disease definition between studies could affect the results.


Neurocognitive and Academic Outcomes at Age 10 Years of Extremely Preterm Newborns.
Despite reductions in mortality and morbidity among children born extremely preterm, they remain at high risk of neurocognitive deficits, with up to 40% having significant cognitive deficits at school age. We assessed the rate of neurocognitive impairment in a contemporary US cohort of 873 children aged 10 years who were born <28 weeks' gestation. The families of 889 of 966 (92%) children enrolled from 2002 to 2004 at 14 sites in 5 states returned at age 10 years for a comprehensive assessment of IQ, language, attention, executive function, processing speed, visual perception, visual-motor function, and academic achievement. A total of 873 children were assessed with well-validated tests of cognitive and academic function. Distributions of test scores were consistently and markedly shifted below normative expectation, with one-third to two-thirds of children performing >1 SD below age expectation. The most extreme downward shifts were on measures of executive control and processing speed. Multivariate analyses, adjusted for socioeconomic status, growth restriction, and other potential confounders, revealed that the risk of poor outcome was highest at the lowest gestational age across all 18 measures. More than half of our extremely preterm cohort exhibited moderate or severe neurocognitive deficits at age 10 years, with the most extensive impairments found among those born at the lowest gestational age. Children born extremely preterm continue to be at significant risk of persistent impairments in neurocognitive function and academic achievement, underscoring the need for monitoring and remediating such outcomes beginning in early childhood.