Hyponatremia: management errors.
Rapid correction of hyponatremia is frequently associated with increased morbidity and mortality. Therefore, it is important to estimate the proper volume and type of infusate required to increase the serum sodium concentration predictably. The major common management errors during the treatment of hyponatremia are inadequate investigation, treatment with fluid restriction for diuretic-induced hyponatremia and treatment with fluid restriction plus intravenous isotonic saline simultaneously. We present two cases of management errors. One is about the problem of rapid correction of hyponatremia in a patient with sepsis and acute renal failure during continuous renal replacement therapy in the intensive care unit. The other is the case of hypothyroidism in which hyponatremia was aggravated by intravenous infusion of dextrose water and isotonic saline infusion was erroneously used to increase serum sodium concentration.


Nutrient concentration in sediments accumulated in pre-treatment basins of urban LID technologies.
In this study, the contribution of pre-treatment basins of low impact development (LID) technologies to nutrient reduction performance was evaluated by understanding the distribution of nutrient in sediments accumulated in each system. The captured sediments were mostly silt to medium sand ranging from 9% to 92% of the sediments collected. Greater average N and P concentrations were found in silt particles amounting to 345 mg/kg and 696 mg/kg, respectively compared to sand and gravel. Although, N concentrations in accumulated sediments were found to be highly variable at different particle sizes (CV: 0.24 to 0.77) compared to P concentration (CV: 0.08 to 0.36) attributed to effective P treatment mechanism through deposition compared to complex nitrogen removal mechanisms. In addition, the difference between N and P concentrations of sediments collected in the pre-treatment basins of LID technologies and in-situ soil was attributed to the continuous pollutant input to the LID technologies during storm events. The study proved that pre-treatment basins of stormwater LID technologies reinforced the nutrient removal performances through sediment retention. The findings of this research may be used to design pre-treatment basins of LID technologies considering nutrients as a limiting factor.


An Evolutionary Genomic Perspective on the Breeding of Dwarf Chickens.
The evolutionary history for dwarfism in chickens remains an enigma. Herein, we explore the evolution of the Serama, the smallest breed of chicken. Leveraging comparative population genomics, analyses identify several genes that are potentially associated with the growth and development of bones and muscles. These genes, and in particular both POU1F1 and IGF1, are under strong positive selection. Three allopatric dwarf bantams (Serama, Yuanbao, and Daweishan) with different breeding-histories, form distinct clusters and exhibit unique population structures. Parallel genetic mechanisms underlay their variation in body size. These findings provide insights into the multiple and complex pathways, depending on genomic variation, that chicken can take in response to aviculture selection for dwarfism.


[Comparison of European standards of swimming pool safety].
European countries follow different procedures to monitor the quality of the water of swimming pools open to the public: some use generally accepted technical standards, some officially recommended guidelines, some rules or regulations by local authorities and some have national laws or regulations. These agree insofar as in every country the water of swimming pools must be disinfected. The microbiological limits are to a certain extent identical with drinking water threshold values, e.g., no faecal coliforms must be present in 100 ml. Other microorganisms as for instance legionellae, staphylococci or Pseudomonas aeruginosa ar not uniformly considered. In all countries the water must be disinfected by chlorination. Big differences exist, however, in respect of the maximum admissible concentrations of free or total chlorine, haloforms and organic carbons. With regard to the common goals, harmonization of the regulations appears possible.


Distribution of inorganic mercury in Sacramento River water and suspended colloidal sediment material.
The concentration and distribution of inorganic Hg was measured using cold-vapor atomic fluorescence spectrometry in samples collected at selected sites on the Sacramento River from below Shasta Dam to Freeport, CA, at six separate times between 1996 and 1997. Dissolved (ultrafiltered, 0.005 microm equivalent pore size) Hg concentrations remained relatively constant throughout the system, ranging from the detection limit (< 0.4 ng/L) to 2.4 ng/L. Total Hg (dissolved plus colloidal suspended sediment) concentrations ranged from the detection limit at the site below Shasta Dam in September 1996 to 81 ng/L at the Colusa site in January 1997, demonstrating that colloidal sediment plays an important role in the downriver Hg transport. Sequential extractions of colloid concentrates indicate that the greatest amount of Hg associated with sediment was found in the "residual" (mineral) phase with a significant quantity also occurring in the "oxidizable" phase. Only a minor amount of Hg was observed in the "reducible" phase. Dissolved Hg loads remained constant or increased slightly in the downstream direction through the study area, whereas the total inorganic Hg load increased significantly downstream especially in the reach of the river between Bend Bridge and Colusa. Analysis of temporal variations showed that Hg loading was positively correlated to discharge.


Protein aggregation mechanisms in synucleinopathies: commonalities and differences.
Synucleinopathies are characterized by the presence of different types of alpha-synuclein (AS)-positive inclusion in the brain. Thus, whereas Lewy bodies are the hallmark of Parkinson disease and dementia with Lewy bodies, glial and neuronal cytoplasmic inclusions are shown by multiple system atrophy. Because the main component of all these inclusions is conformationally modified AS, aggregation of the latter is thought to be a key pathogenic event in these diseases. Although very little information has been available on AS function and aggregation mechanisms until 2 years ago, recent investigations have greatly improved our understanding of the steps involved in the pathogenesis of synucleinopathies. Additionally, important insights into the specific molecular events (e.g. differential posttranslational modifications or isoform expression profiles) underlying each of these conditions have been gained. The present review summarizes our current knowledge of the commonalities and differences shown by protein aggregation mechanisms in the various synucleinopathies.


Office-Based Three-Dimensional Printing Workflow for Craniomaxillofacial Fracture Repair.
Three-dimensional printing of patient-specific models is being used in various aspects of craniomaxillofacial reconstruction. Printing is typically outsourced to off-site vendors, with the main disadvantages being increased costs and time for production. Office-based 3-dimensional printing has been proposed as a means to reduce costs and delays, but remains largely underused because of the perception among surgeons that it is futuristic, highly technical, and prohibitively expensive. The goal of this report is to demonstrate the feasibility and ease of incorporating in-office 3-dimensional printing into the standard workflow for facial fracture repair.Patients with complex mandible fractures requiring open repair were identified. Open-source software was used to create virtual 3-dimensional skeletal models of the, initial injury pattern, and then the ideally reduced fractures based on preoperative computed tomography (CT) scan images. The virtual 3-dimensional skeletal models were then printed in our office using a commercially available 3-dimensional printer and bioplastic filament. The 3-dimensional skeletal models were used as templates to bend and shape titanium plates that were subsequently used for intraoperative fixation.Average print time was 6 hours. Excluding the 1-time cost of the 3-dimensional printer of $2500, roughly the cost of a single commercially produced model, the average material cost to print 1 model mandible was $4.30. Postoperative CT imaging demonstrated precise, predicted reduction in all patients.Office-based 3-dimensional printing of skeletal models can be routinely used in repair of facial fractures in an efficient and cost-effective manner.


Multi-Modal Biomarkers of Repetitive Head Impacts and Traumatic Encephalopathy Syndrome: A Clinicopathological Case Series.
Traumatic encephalopathy syndrome (TES) criteria were developed to aid diagnosis of chronic traumatic encephalopathy (CTE) pathology during life. Interpreting clinical and biomarker findings in patients with TES during life necessitates autopsy-based determination of the neuropathological profile. We report a clinicopathological series of nine patients with previous repetitive head impacts (RHI) classified retrospectively using the recent TES research framework (100% male and white/Caucasian, age at death 49-84) who completed antemortem neuropsychological evaluations, T1-weighted magnetic resonance imaging, diffusion tensor imaging (n = 6), (18)F-fluorodeoxyglucose-positron emission tomography (n = 5), and plasma measurement of neurofilament light (NfL), glial fibrillary acidic protein (GFAP), and total tau (n = 8). Autopsies were performed on all patients. Cognitively, low test scores and longitudinal decline were relatively consistent for memory and executive function. Medial temporal lobe atrophy was observed in all nine patients. Poor white matter integrity was consistently found in the fornix. Glucose hypometabolism was most common in the medial temporal lobe and thalamus. Most patients had elevated plasma GFAP, NfL, and total tau at their initial visit and a subset showed longitudinally increasing concentrations. Neuropathologically, five of the nine patients had CTE pathology (n = 4 "High CTE"/McKee Stage III-IV, n = 1 "Low CTE"/McKee Stage I). Primary neuropathological diagnoses (i.e., the disease considered most responsible for observed symptoms) were frontotemporal lobar degeneration (n = 2 FTLD-TDP, n = 1 FTLD-tau), Alzheimer disease (n = 3), CTE (n = 2), and primary age-related tauopathy (n = 1). In addition, hippocampal sclerosis was a common neuropathological comorbidity (n = 5) and associated with limbic-predominant TDP-43 proteinopathy (n = 4) or FTLD-TDP (n = 1). Memory and executive function decline, limbic system brain changes (atrophy, decreased white matter integrity, hypometabolism), and plasma biomarker alterations are common in RHI and TES but may reflect multiple neuropathologies. In particular, the neuropathological differential for patients with RHI or TES presenting with medial temporal atrophy and memory loss should include limbic TDP-43. Researchers and clinicians should be cautious in attributing cognitive, neuroimaging, or other biomarker changes solely to CTE tau pathology based on previous RHI or a TES diagnosis alone.


Mechanisms shaping the naïve T cell repertoire in the elderly - thymic involution or peripheral homeostatic proliferation?
The ability of the human immune system to repel infections is drastically diminished with age. Elderly individuals are more susceptible to new threats and are less able to control endogenous infections. The thymus, which is the sole source of new T cells, has been proposed as a target for regenerative efforts to improve immune competence, as thymic activity is dramatically reduced after puberty. In this review, we review the role of the thymus in the maintenance of T cell homeostasis throughout life and contrast the differences in mice and humans. We propose that in humans, lack of thymic T cell generation does not explain a decline in T cell receptor diversity nor would thymic rejuvenation restore diversity. Initial studies using next generation sequencing are beginning to establish lower boundaries of T cell receptor diversity. With increasing sequencing depth and the development of new statistical models, we are now in the position to test this model and to assess the impact of age on T cell diversity and clonality.


Expression patterns of sterol transporters NPC1 and NPC2 in the cnidarian-dinoflagellate symbiosis.
The symbiotic interaction between cnidarians (e.g., corals and sea anemones) and photosynthetic dinoflagellates of the genus Symbiodinium is triggered by both host-symbiont recognition processes and metabolic exchange between the 2 partners. The molecular communication is crucial for homeostatic regulation of the symbiosis, both under normal conditions and during stresses that further lead to symbiosis collapse. It is therefore important to identify and fully characterise the key players of this intimate interaction at the symbiotic interface. In this study, we determined the cellular and subcellular localization and expression of the sterol-trafficking Niemann-Pick type C proteins (NPC1 and NPC2) in the symbiotic sea anemones Anemonia viridis and Aiptasia sp. We first established that NPC1 is localised within vesicles in host tissues and to the symbiosome membranes in several anthozoan species. We demonstrated that the canonical NPC2-a protein is mainly expressed in the epidermis, whereas the NPC2-d protein is closely associated with symbiosome membranes. Furthermore, we showed that the expression of the NPC2-d protein is correlated with symbiont presence in healthy symbiotic specimens. As npc2-d is a cnidarian-specific duplicated gene, we hypothesised that it probably arose from a subfunctionalisation process that might result in a gain of function and symbiosis adaptation in anthozoans. Niemann-Pick type C proteins may be key players in a functional symbiosis and be useful tools to study host-symbiont interactions in the anthozoan-dinoflagellate association.


Key questions about the future of laboratory medicine in the next decade of the 21st century: A report from the IFCC-Emerging Technologies Division.
This review advances the discussion about the future of laboratory medicine in the 2020s. In five major topic areas: 1. the "big picture" of healthcare; 2. pre-analytical factors; 3. Analytical factors; 4. post-analytical factors; and 5. relationships, which explores a next decade perspective on laboratory medicine and the likely impact of the predicted changes by means of a number of carefully focused questions that draw upon predictions made since 2013. The "big picture" of healthcare explores the effects of changing patient populations, the brain-to-brain loop, direct access testing, robots and total laboratory automation, and green technologies and sustainability. The pre-analytical section considers the role of different sample types, drones, and biobanks. The analytical section examines advances in point-of-care testing, mass spectrometry, genomics, gene and immunotherapy, 3D-printing, and total laboratory quality. The post-analytical section discusses the value of laboratory medicine, the emerging role of artificial intelligence, the management and interpretation of omics data, and common reference intervals and decision limits. Finally, the relationships section explores the role of laboratory medicine scientific societies, the educational needs of laboratory professionals, communication, the relationship between laboratory professionals and clinicians, laboratory medicine financing, and the anticipated economic opportunities and outcomes in the 2020's.


Enhancing the quality and accuracy of national cancer registries in the Eastern Mediterranean Region.
We cannot prevent cancer, detect it early, diagnose, treat, and palliate it without reliable data. Continuous, systematic collection, analysis, and interpretation of cancer-related data are essential to effectively plan, implement and evaluate cancer control activities and policies. Enhancing routine health information systems to ensure that cancer-related data are well captured is essential, just as fostering functioning cancer surveillance systems, particularly population-based cancer registries (1,2). Population-based cancer registries play a critical role in the planning of national cancer control and prevention strategies, monitoring and evaluation of cancer care services, as well as cancer epidemiological and clinical research (1).


How Comprehensive and Efficient Are Patient-Reported Outcomes for Rotator Cuff Tears?
Increasing emphasis is placed on patient-reported outcomes (PROs) after common orthopaedic procedures as a measure of quality. When considering PRO utilization in patients with rotator cuff tears, several different PROs exist with varying levels of accuracy and utilization. Understanding which disease-specific PRO may be most efficiently administered in patients after rotator cuff repair may assist in promoting increased patient and physician adoption of these useful scores. Using a novel assessment criterion, this study assessed all commonly used rotator cuff PROs. We hypothesize that surveys with fewer numbers of questions may remain comparable (with regard to comprehensiveness) to longer surveys. Systematic review. Commonly utilized rotator cuff PROs were analyzed with regard to number of survey components, comprehensiveness, and efficiency. Comprehensiveness (maximum score, 11) was scored as the total number of pain (at rest/baseline, night/sleep, activities of daily living [ADLs], sport, and work) and functional (strength, motion/stiffness, and ability to perform ADLs, sport, and work) metrics included, along with inclusion of quality of life/satisfaction metrics. Efficiency was calculated as comprehensiveness divided by the number of survey components. Sixteen different PROs were studied. Number of components ranged from 5 (University of California at Los Angeles score [UCLA]) to 36 (Short Form-36 [SF-36], Japanese Orthopaedic Association score [JOA]). The Quality of Life Outcome Measure for Rotator Cuff Disease (RC-QoL) included all 5 pain components, while 7 PROs contained all 5 functional components. Ten PROs included a quality of life/satisfaction component. The most comprehensive scores were the RC-QoL (score, 11) and Penn (score, 10), and the least comprehensive score was the Marx (score, 3). The most efficient PROs were the UCLA, the Quick Disabilities of the Arm, Shoulder, and Hand score (QuickDASH), and Constant scores. The least efficient scores were the JOA and SF-36 scores. Many commonly utilized PROs for rotator cuff tears are lacking in comprehensiveness and efficiency. Continued critical assessment of PRO quality may help practitioners identify the most comprehensive and efficient PRO to incorporate into daily clinical practice.


Selective deficiency in IL-2 production and refractoriness to extrinsic IL-2 in immunodeficiency with hyper-IgM.
Various lymphokines are inducible by the stimulation of T-cell mitogens, phytohemagglutinin, and concanavalin A. A 32-year-old female with an atypical type of immunodeficiency with hyper-IgM was evaluated for possible defects in the production of several immunoregulatory lymphokines. Although the mitogens appeared to bind effectively to the specific surface receptors of patient peripheral blood lymphocyte (PBL), the proliferative responses were significantly decreased. The culture supernatant of patient PBL stimulated by the mitogens contained only a trace amount of interleukin 2 (IL-2) activity. Addition of recombinant IL-2 to the cultures concomitantly with the mitogens could not restore the decreased responses of patient PBL. Tac antigen expression of patient PBL induced by the mitogens was moderately impaired. These data suggest that there is a defect in both IL-2-producing and IL-2-responding cells. In contrast, the culture supernatant of mitogen-stimulated patient PBL contained B-cell growth and differentiation factors as well as interferon-gamma activities equal to those of the control. These results suggest that there are independent regulatory pathways for the production of IL-2 and other T-cell-derived lymphokines.


Vitamin C supplementation in pregnancy.
Vitamin C supplementation may help reduce the risk of pregnancy complications like pre-eclampsia, intrauterine growth restriction and maternal anaemia. There is a need to evaluate the efficacy and safety of vitamin C supplementation in pregnancy. To evaluate the effects of vitamin C supplementation, alone or in combination with other separate supplements, on pregnancy outcomes, adverse events, side-effects and use of health resources. We searched the Cochrane Pregnancy and Childbirth Group Trials Register (23 June 2004), Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2004), MEDLINE, Current Contents and EMBASE. All randomised or quasi-randomised controlled trials evaluating vitamin C supplementation in pregnant women. Interventions using a multivitamin supplement containing vitamin C or where the primary supplement was iron were excluded. Two authors independently assessed trials for inclusion, extracted data and assessed trial quality. Five trials, involving 766 women, are included in this review. No difference was seen between women supplemented with vitamin C alone or combined with other supplements compared with placebo for the risk of stillbirth (relative risk (RR) 0.87, 95% confidence intervals (CI) 0.41 to 1.87, three trials, 539 women), perinatal death (RR 1.16, 95% CI 0.61 to 2.18, two trials, 238 women), birthweight (weighted mean difference (WMD) -139.00 g, 95% CI -517.68 to 239.68, one trial, 100 women) or intrauterine growth restriction (RR 0.72, 95% CI 0.49 to 1.04, two trials, 383 women). Women supplemented with vitamin C alone or combined with other supplements were at increased risk of giving birth preterm (RR 1.38, 95% CI 1.04 to 1.82, three trials, 583 women). Significant heterogeneity was found for neonatal death and pre-eclampsia. No difference was seen between women supplemented with vitamin C combined with other supplements for the risk of neonatal death (RR 1.73, 95% CI 0.25 to 12.12, two trials, 221 women), using a random-effects model. For pre-eclampsia, women supplemented with vitamin C combined with other supplements were at decreased risk when using a fixed-effect model (RR 0.47, 95% CI 0.30 to 0.75, four trials, 710 women); however, this difference could not be demonstrated when using a random-effects model (RR 0.52, 95% CI 0.23 to 1.20, four trials, 710 women). The data are too few to say if vitamin C supplementation, alone or combined with other supplements, is beneficial during pregnancy. Preterm birth may have been increased with vitamin C supplementation.


Central nervous system complications associated with immune checkpoint inhibitors.
To describe the spectrum and outcome of central nervous system complications associated with immune checkpoint inhibitors (CNS-ICI). Patients with CNS-ICI were identified and their characteristics compared with ICI-related peripheral neuropathy (PN-ICI). We identified 19 patients with CNS-ICI. The patients were receiving nivolumab (n=8), pembrolizumab (n=6), a combination of ipilimumab-nivolumab (n=3), ipilimumab-durvalumab (n=1), or atezolizumab (n=1). Underlying malignancies included non-small-cell lung cancer (n=8), melanoma (n=3), and other less common tumours (n=8). Neurological phenotypes were limbic encephalitis (n=8), meningoencephalitis (n=4) and cerebellitis (n=4). Two patients developed isolated confusion and one parkinsonism. Associated autoantibodies included onconeural (Ma2, n=7; Hu, n=1), astrocytic (glial fibrillar acidic protein, n=2) and neuronal surface (contactin-associated protein-like 2, n=1) specificities. ICIs were withheld and corticosteroid treatment was given in all cases. Five patients received intravenous immunoglobulin, two rituximab, one plasmapheresis and one infliximab. Overall, six patients died. Readministration of ICI was attempted in three patients, without further relapses. Non-small-cell lung cancer was significantly more frequent in patients with CNS-ICI (p<0.01), while melanoma and ipilimumab treatment were more common in PN-ICI (p<0.01 and p=0.01). Conversely, CNS-ICI cases were more frequently antibody-positive than PN-ICI (p<0.01) and showed a strong trend towards poorer outcome (p=0.053). Three main clinical phenotypes characterise CNS complications of ICIs, each with distinct immunological background, disease course and response to treatment. Other clinical manifestations (including parkinsonism and steroid-responsive confusion) are also possible. Underlying cancers, antibody prevalence and outcome appear different from those of patients with PN-ICI.


A comprehensive microRNA expression profile of the backfat tissue from castrated and intact full-sib pair male pigs.
It is widely known that castration has a significant effect on the accumulation of adipose tissue. microRNAs (miRNAs) are known to be involved in fat deposition and to be regulated by the androgen-induced androgen receptor (AR). However, there is little understanding of the relationship between miRNAs and fat deposition after castration. In this study, the high-throughput SOLiD sequencing approach was used to identify and characterize miRNA expression in backfat from intact and castrated full-sib male 23-week-old pigs. The patterns of adipogenesis and fat deposition were compared between castrated and intact male pigs. A total of 366 unique miRNA genes were identified, comprising 174 known pre-miRNAs and 192 novel pre-miRNAs. One hundred and sixty-seven pre-miRNAs were common to both castrated (F3) and intact (F4) male pig small RNA libraries. The novel pre-miRNAs encoded 153 miRNAs/miRNA*s and 141 miRNAs/miRNA*s in the F3 and F4 libraries, respectively. One hundred and seventy-seven miRNAs, including 45 up- and 132 down-regulated, had more than 2-fold differential expression between the castrated and intact male pigs (p-value < 0.001). Thirty-five miRNAs were further selected, based on the expression abundance and differentiation between the two libraries, to predict their targets in KEGG pathways. KEGG pathway analyses suggested that miRNAs differentially expressed between the castrated and intact male pigs are involved in proliferation, apoptosis, differentiation, migration, adipose tissue development and other important biological processes. The expression patterns of eight arbitrarily selected miRNAs were validated by stem-loop reverse-transcription quantitative polymerase chain reaction. These data confirmed the expression tendency observed with SOLiD sequencing. miRNA isomiRs and mirtrons were also investigated in this study. Mirtrons are a recently described category of miRNA relying on splicing rather than processing by the microprocessor complex to generate the RNAi pathway. The functions of miRNAs important for regulating fat deposition were also investigated in this study. This study expands the number of fat-deposition-related miRNAs in pig. The results also indicate that castration can significantly affect the expression patterns of fat-related miRNAs. The differentially expressed miRNAs may play important roles in fat deposition after castration.


Amino acid pair interchanges at spatially conserved locations.
Here we study the pattern of amino acid interchanges at spatially, locally conserved regions in globally dissimilar and unrelated proteins. By using a method which completely separates the amino acid sequence from its respective structure, this work addresses the question of which properties of the amino acids are the most crucial for the stability of conserved structural motifs. The proteins are taken from a structurally non-redundant dataset. The spatially conserved substructural motifs are defined as consisting of a "large enough" number of Calpha atoms found to provide a geometric match between two proteins, regardless of the order of the Calpha atoms in the sequence, or of the sequence composition of the substructures. This approach can apply to proteins with little or no sequence similarity but with sufficient structural similarity, and is unique in its ability to handle local, non-topological matches between pairs of dissimilar proteins. The method uses a computer-version based algorithm, the Geometric Hashing. Since the Geometric Hashing ignores sequence information it lends itself to answer the question posed above. The interchanges at geometrically similar positions that have been obtained with our method demonstrate the expected behaviour. Yet, a closer inspection reveals some distant characteristics, as compared with interchanges based upon sequence-order based techniques, or from energy-contact-based considerations. First, a pronounced division of the amino acids into two classes is displayed: Lys, Glu, Arg, Gln, Asp, Asn, Pro, Gly, Thr, Ser and His on the one hand, and Ile, Val, Leu, Phe, Met, Tyr, Trp, Cys and Ala on the other. These groups further cluster into subgroups: Lys, Glu, Arg, Gln; Asp Asn; Pro, Gly; Ile, Val, Leu, Phe. The other amino acids stand alone. Analysis of the conservation among amino acids indicates proline to be consistently, by far, the most conserved. Next are Asp, Glu, Lys and Gly. Cys is also highly conserved. Interestingly, oppositely charged amino acids are interchanged roughly as frequently as those of the same charge. These observations can be explained in terms of the three-dimensional structures of the proteins. Most of all, there is a clear distinction between residues which prefer to be on the protein surfaces, compared to those frequently buried in the interiors. Analysis of the interchanges indicates their low information content. This, together with the separation into two groups, suggest that the predictive value of the spatial positions of the Calpha+ atoms is not much greater than the sequence alone, aside from their hydrophobicity/hydrophillicity classification.


Single crystal structures and theoretical calculations of uranium endohedral metallofullerenes (U@C2n , 2n = 74, 82) show cage isomer dependent oxidation states for U.
Charge transfer is a general phenomenon observed for all endohedral mono-metallofullerenes. Since the detection of the first endohedral metallofullerene (EMF), La@C82, in 1991, it has always been observed that the oxidation state of a given encapsulated metal is always the same, regardless of the cage size. No crystallographic data exist for any early actinide endohedrals and little is known about the oxidation states for the few compounds that have been reported. Here we report the X-ray structures of three uranium metallofullerenes, U@D3h-C74, U@C2(5)-C82 and U@C2v(9)-C82, and provide theoretical evidence for cage isomer dependent charge transfer states for U. Results from DFT calculations show that U@D3h-C74 and U@C2(5)-C82 have tetravalent electronic configurations corresponding to U4+@D3h-C744- and U4+@C2(5)-C824-. Surprisingly, the isomeric U@C2v(9)-C82 has a trivalent electronic configuration corresponding to U3+@C2v(9)-C823-. These are the first X-ray crystallographic structures of uranium EMFs and this is first observation of metal oxidation state dependence on carbon cage isomerism for mono-EMFs.


Evaluation of Superparamagnetic Silica Nanoparticles for Extraction of Triazines in Magnetic in-Tube Solid Phase Microextraction Coupled to Capillary Liquid Chromatography.
The use of magnetic nanomaterials for analytical applications has increased in the recent years. In particular, magnetic nanomaterials have shown great potential as adsorbent phase in several extraction procedures due to the significant advantages over the conventional methods. In the present work, the influence of magnetic forces over the extraction efficiency of triazines using superparamagnetic silica nanoparticles (NPs) in magnetic in tube solid phase microextraction (Magnetic-IT-SPME) coupled to CapLC has been evaluated. Atrazine, terbutylazine and simazine has been selected as target analytes. The superparamagnetic silica nanomaterial (SiO₂-Fe₃O₄) deposited onto the surface of a capillary column gave rise to a magnetic extraction phase for IT-SPME that provided a enhancemment of the extraction efficiency for triazines. This improvement is based on two phenomena, the superparamegnetic behavior of Fe₃O₄ NPs and the diamagnetic repulsions that take place in a microfluidic device such a capillary column. A systematic study of analytes adsorption and desorption was conducted as function of the magnetic field and the relationship with triazines magnetic susceptibility. The positive influence of magnetism on the extraction procedure was demonstrated. The analytical characteristics of the optimized procedure were established and the method was applied to the determination of the target analytes in water samples with satisfactory results. When coupling Magnetic-IT-SPME with CapLC, improved adsorption efficiencies (60%-63%) were achieved compared with conventional adsorption materials (0.8%-3%).


Tumor Biomarkers for the Prediction of Distant Metastasis in Head and Neck Squamous Cell Carcinoma.
Distant metastases (DM) in head and neck squamous cell carcinoma (HNSCC) remain a challenge as treatment options are limited. To identify biomarkers predictive of DM in primary tumors (PT), gene expression profiling was performed in PT from patients who did, or did not develop DM (T-with and T-without, n = 25 and 24, respectively), and in matched DM. A total of 185 and 42 differentially expressed genes were identified in the T-with vs. T-without and the T-with vs. DM comparisons, respectively. The intersection between these two comparisons identified COX7A1 and TBX5 as common genes. In three independent datasets, both genes were able to significantly distinguish patients according to their DM-free survival. By functional biological analyses, the T-without group showed enrichment in immune-response pathways, whereas the T-with group showed an enrichment in B-plasma cells and Tregs. Increased enrichment of proliferation-related pathways was observed in the T-with group compared with that in the DM group. Further comparisons with/without DM are needed to confirm these data in order to improve clinical management of HNSCC.


Basic fibroblast growth factor: receptor-mediated internalization, metabolism, and anterograde axonal transport in retinal ganglion cells.
Basic fibroblast growth factor (bFGF) was radiolabeled and used in axonal transport studies to determine whether certain neuronal populations express functional receptors for bFGF. Unlike 125I-NGF, 125I-bFGF was not retrogradely transported in the adult rat sciatic nerve or from iris to trigeminal ganglion or superior cervical ganglion. However, after intraocular injection of 125I-bFGF into the posterior chamber of the eye of adult rats, radioactivity was detected within the retinal ganglion cell projections. This radioactivity was localized to the ipsilateral optic nerve and in the contralateral lateral geniculate body and the contralateral superior colliculus by using autoradiographic techniques. Direct measurement of the radioactivity in dissected brain regions was used to study the process of 125I-bFGF uptake and transport by retinal ganglion cells. The uptake and transport were specific for biologically active bFGF since neither denatured, biologically inactive 125I-bFGF nor 125I-NGF was taken up and transported. The uptake and transport of 125I-bFGF were saturable phenomena since they were blocked in the presence of excess, unlabeled bFGF. Wheat germ agglutinin, but not heparinase, blocked uptake and transport of 125I-bFGF, a finding that is consistent with the uptake being mediated by high-affinity bFGF receptors. Radioactivity from 125I-bFGF was transported in retinal ganglion cell axons in an anterograde direction at a maximum rate in excess of 1.7 mm/hr. No specific retrograde transport of bFGF to the retina was detected after 125I-bFGF was injected into the superior colliculus. The radioactivity from 125I-bFGF that accumulated in the superior colliculus was lost from this tissue with a half-life of about 22 hr. Autoradiography of proteins separated by SDS-PAGE demonstrated that 125I-bFGF was not substantially degraded in the retina after internalization within retinal ganglion cells. During anterograde transport, however, 125I-bFGF underwent limited proteolytic cleavage resulting in 3 prominent 125I-bFGF derivatives of molecular weights greater than 7000 Da. Although these were the major radioactive species recovered from the superior colliculus after intraocular injection, some intact 125I-bFGF was also detected within the innervated target. These results indicate that retinal ganglion cells express high-affinity receptors for bFGF, that these receptors mediate the internalization of bFGF, that internalized bFGF undergoes limited proteolytic cleavage, and that bFGF and its derivatives are anterogradely transported to the lateral geniculate body and the superior colliculus. These data raise the possibility that bFGF or its derivatives may act as an anterograde trophic factor in the visual system, a system that is known to undergo anterograde transneuronal cell death.


High-resolution ultrasound to diagnose melanoma metastases in patients with clinically palpable lymph nodes.
High-resolution ultrasound was used to determine if it could predict the presence of metastatic disease in 52 patients with melanoma who had developed newly palpable lymph nodes during clinical follow-up. Ultrasound proved accurate in diagnosing the presence of nodal metastases; it had a sensitivity of 94%, a specificity of 87% and an accuracy of 89%. The ultrasound features which together were diagnostic of the presence of nodal metastases were a node thickness greater than two-thirds of the node length and the presence of low-level echoes in the node. When these two features were both present on ultrasound, node metastases were present in every case. Ultrasound can be used to evaluate newly palpable lymph nodes in patients with melanoma. A normal ultrasound finding does not exclude micrometastases, but a lymph node showing the two key ultrasound features aforementioned is highly likely to contain metastatic disease and should be treated accordingly.


Mitochondria as a target for neurotoxins and neuroprotective agents.
Mitochondrial permeability transition pores represent a multiprotein complex that includes components of both inner and outer membrane. The pores regulate transport of ions and peptides in and out of mitochondria, and their regulation is associated with a general mechanism for maintaining Ca(2+) homeostasis in the cell and apoptosis. Various pathologic factors may induce a pathologic activation of the permeability transition and an irreversible opening of mitochondria pores. This event is a major step in the development of neurotoxicity and neurodegeneration. This paper explores the effect of MPP(+) and beta-amyloid fragment 25-35, neurotoxins that are known to generate Parkinson's-like syndrome and Alzheimer's disease, on the regulation of the mitochondrial pores. Both neurotoxins induce opening of mitochondrial pores, which is prevented by cyclosporin A, a specific inhibitor of the permeability transition. The effect of MPP(+) and beta-amyloid may be also prevented by an endogenous precursor of melatonin, N-acetylserotonin, by an anti-Alzheimer's medication tacrine, and by dimebon, which is in development as an agent for the therapy of Alzheimer's disease and other types of dementia. The paper illustrates that the effect on mitochondrial pores is an important aspect of the mechanism of neurotoxicity. Substances that may prevent opening of mitochondrial pores induced by neurotoxins may preserve the mitochondrial function and, thus, may have potential as neuroprotective agents.


Exercise to prevent the negative effects of sleep deprivation: A systematic review and meta-analysis.
Ample sleep is an important basis for maintaining health, however with the pace of life accelerating in modern society, more people are using sacrificial sleep to cope with these social changes. Sleep deprivation can have negative effects on cognitive performance and psychosomatic health. It is well known that exercise, as a beneficial intervention strategy for human health, has been increasingly used in the clinic. But it's not clear if it can prevent the negative effects of sleep deprivation. In this meta-analysis, we reviewed 23 articles from PubMed and Web of Science to investigate whether moderate physical exercise can prevent the negative effects of sleep deprivation in rodents. Our findings suggest that exercise can prevent sleep deprivation-induced cognitive impairment and anxiety-like behaviors through multiple pathways. We also discuss possible molecular mechanisms involved in this protective effect, highlighting the potential of exercise as a preventive or therapeutic strategy for sleep deprivation-induced negative effects.


Calcipotriol plus betamethasone dipropionate aerosol foam vs. apremilast, methotrexate, acitretin or fumaric acid esters for the treatment of plaque psoriasis: a matching-adjusted indirect comparison.
Plaque psoriasis has significant impact on patients' quality of life. Topical therapy is considered the treatment mainstay for mild-to-moderate disease according to guidelines. Calcipotriol/betamethasone dipropionate (Cal/BD) [0.005%/0.05%] aerosol foam is indicated for psoriasis vulgaris treatment in adults. Cal/BD foam trials demonstrated improved efficacy and similar safety in this population. Psoriasis treatment is complicated by the broad range of disease presentation, variability and therapeutic options; particularly decisions on transition from topical to non-biologic systemic treatment are difficult. Assessing comparative effectiveness of treatment options provides meaningful value to treatment decisions. To compare efficacy of Cal/BD foam individual patient data from pooled trials with efficacy of non-biologic systemic treatments based on aggregated patient characteristics and treatment outcomes. Individual data from four Cal/BD foam trials in 749 psoriasis patients were pooled to conduct matching-adjusted indirect comparisons. Literature review identified non-biologic systemic treatment trials where methods, populations and outcomes align with Cal/BD foam trials. Of 3090 screened publications, four studies of apremilast, methotrexate, acitretin or fumaric acid esters (FAE) were included. After baseline matching, patients treated with 4 weeks of Cal/BD foam had greater Physician's Global Assessment 0/1 response compared to those treated with 16 weeks of apremilast (52.7% vs. 30.4%; P < 0.001). Patients treated with Cal/BD foam had significantly greater Psoriasis Area and Severity Index (PASI) 75 response at Week 4 compared to 16 weeks of apremilast treatment (51.1% vs. 21.6%; P < 0.001). Cal/BD foam patients demonstrated significantly greater PASI 75 response improvements at Week 4 vs. 12 weeks of methotrexate (50.8% vs. 33.5%; P < 0.001) or acitretin (50.9% vs. 31.7%; P = 0.009), and comparable response to FAE (42.4% vs. 47.0%; P = 0.451). Despite recent treatment advances, unmet needs for psoriasis patients remain. Cal/BD foam offers improved efficacy in baseline matched psoriasis patients compared to apremilast, methotrexate or acitretin, and comparable efficacy to FAE.


[Possibilities of transfusion therapy in surgical practice].
The up-to-date possibilities of transfusion therapy are presented in the article. The authors analyzed their own experience and made a review of literature. The study considers the mechanisms of treatment, immunological and infectious risks, indications and contraindications for application of transfusion therapy in surgical practice.


There's always something that works: principles and practices of positive support for individuals with traumatic brain injury and problem behaviors.
Behavioral and cognitive problems are among the most common and troubling consequences of traumatic brain injury Furthermore, behavioral and cognitive challenges typically develop in complex ways, necessitating an integrated approach to intervention and supports. This article summarizes literature on interventions positively affecting the behavioral outcomes for individuals with brain injury. This literature extends many of the traditional approaches to behavioral intervention and cognitive rehabilitation to include positive behavioral support and the development of personally meaningful activities for program development. In addition, the article provides a framework for intervention based on the decades-long work of Mark Ylvisaker, which is founded on positive principles of assessment and treatment and is implemented in a context-sensitive manner that integrates cognitive and behavioral intervention themes and focuses on the development of self-regulation.


Blood pressure goal in chronic kidney disease: what is the evidence?
Most guidelines recommend that seated clinic blood pressure (BP) be targeted to less than 130/80 mmHg in patients with chronic kidney disease (CKD). The evidence underlying these recommendations is the subject of this review. The best evidence to target a certain level of BP in patients with CKD comes from randomized trials. Only three trials have prospectively examined the level to which BP should be lowered. These trials conducted exclusively among patients with CKD have demonstrated that compared to a less aggressive BP goal, a BP goal of less than 130/80 mmHg neither saves lives nor protects the kidney or the cardiovascular system. It is reasonable to achieve a goal of less than 140/90 mmHg in most patients with CKD. More aggressive lowering is not firmly supported by current data. Since BP control is important, hypertension therapy should be individualized. Individualization through home BP measurements to diagnose, monitor and treat hypertension appears to be an attractive option.


Overexpression of HIF-1α, metallothionein and SLUG is associated with high TNM stage and lymph node metastasis in papillary thyroid carcinoma.
Hypoxia inducible factor-1α (HIF-1α) is upregulated by hypoxia, and involved in tumor growth and metastasis in many malignant tumors including papillary thyroid carcinoma (PTC). Metallothionein (MT) is a group of small molecular weight cysteine-rich proteins with a broad variety of functions. SLUG is a member of SNAIL superfamily of zinc finger transcriptional factors implicated in epithelial-mesenchymal transition (EMT). The purpose of this study was to examine HIF-1α, MT and SLUG expression in PTC and assess association of their expression with clinicopathological indicators. HIF-1α, MT and SLUG protein expression in 129 PTCs, 61 nodular hyperplasia and 118 normal thyroid tissue specimens were analyzed using immunohistochemistry. The protein expression levels of these three molecules were up-regulated in PTCs. High protein expression of HIF-1α, MT and SLUG was significantly correlated with high TNM stage (P=0.003, 0.002, 0.024, respectively) and lymph node metastasis (LNM) (P<0.001 for all three molecules). Furthermore, HIF-1α, MT and SLUG protein expression were correlated with one another. Concomitant high expression of any two of these three molecules had stronger correlation with high TNM stage (P≤0.001 for HIF-1α/MT, MT/SLUG and HIF-1α/SLUG) and LNM (P=0.008, 0.002, 0.019 for HIF-1α/MT, MT/SLUG and HIF-1α/SLUG, respectively) than did each alone, and concomitant high expression of all these three molecules is significantly associated with high TNM stage and LNM as compared with cases not showing such expression (P<0.001). These results demonstrated that the evaluation of HIF-1α, MT and SLUG expression in PTC may be useful in predicting the risk of LNM and high TNM stage.


Targeted antigen delivery by an anti-class II MHC VHH elicits focused αMUC1(Tn) immunity.
Unusual patterns of glycosylation on the surface of transformed cells contribute to immune modulation and metastasis of malignant tumors. Active immunization against them requires effective antigen presentation, which is complicated by a lack of access to tumor-specific posttranslational modifications through standard genetic approaches and by the low efficiency of passive antigen sampling. We found that antigen targeted to antigen presenting cells via class II MHC products can elicit a robust immune response against MUC1(Tn) bearing a defined tumor-associated glycoform, Tn. The two-component vaccine construct was prepared by sortase-mediated protein ligation of a synthetic MUC1(Tn) fragment to a class II MHC-binding single-domain antibody fragment (VHH7) as targeting moiety. We show that VHH7 targets antigen presenting cells in vivo, and when conjugated to MUC1(Tn) can elicit a strong αMUC1(Tn) immune response in mice. The resulting sera preferentially recognized the MUC1 epitope with the tumor-associated carbohydrate antigen Tn and were capable of killing cancer cells in a complement-mediated cytotoxicity assay. Immunoglobulin isotype analysis and cytokine release assays suggested a favorable Th1 response. A single boost 12 months after primary immunization triggered a recall response of the same quality, suggesting that long-term αMUC1(Tn) memory had been achieved.


A Glossary for Chemical Approaches towards Unlocking the Trove of Metabolic Treasures in Actinomycetes.
Actinobacterial natural products showed a critical basis for the discovery of new antibiotics as well as other lead secondary metabolites. Varied environmental and physiological signals touch the antibiotic machinery that faced a serious decline in the last decades. The reason was exposed by genomic sequencing data, which revealed that Actinomycetes harbor a large portion of silent biosynthetic gene clusters in their genomes that encrypt for secondary metabolites. These gene clusters are linked with a great reservoir of yet unknown molecules, and arranging them is considered a major challenge for biotechnology approaches. In the present paper, we discuss the recent strategies that have been taken to augment the yield of secondary metabolites via awakening these cryptic genes in Actinomycetes with emphasis on chemical signaling molecules used to induce the antibiotics biosynthesis. The rationale, types, applications and mechanisms are discussed in detail, to reveal the productive path for the unearthing of new metabolites, covering the literature until the end of 2020.


Perceptions and performance of function and physical activity in assisted living communities.
The purpose of this study was to describe residents' self-efficacy and outcome expectations with regard to function and physical activity (PA); to measure functional performance and time in PA; to evaluate the fit between the resident and the environment; and to evaluate knowledge, beliefs, and care behaviors of nursing assistants (NAs) in 4 different assisted living (AL) communities. This was a descriptive study using baseline data from an ongoing intervention study, Testing the Impact of a Function Focused Care Intervention, Res-Care-AL. Four assisted living communities in Maryland. A total of 171 residents and 96 NAs consented, passed eligibility, and were included in this study. Descriptive data were obtained from NAs and residents. Resident data also included self-efficacy and outcome expectations associated with functional tasks and exercise, social support for exercise, and subjective and objective information about function and physical activity. NA data included self-efficacy and outcome expectations, knowledge, and performance of function-focused care. Residents were mostly female, white, and widowed; needed some assistance with activities of daily living; and engaged in very little PA based on subjective and objective reports. NAs were mostly female and black, had more than a decade of nursing experience, strong confidence but limited knowledge of function-focused care, and performed this care in 76% of observed care interactions. There were no site-specific differences among NAs with regard to beliefs, knowledge, or performance of function-focused care. There were site-specific differences in residents with regard to self-efficacy for functional ability; functional performance; social supports for exercise from experts; and from family, person-environment fit, and PA based on subjective surveys. There were no differences noted based on actigraphy. Residents in AL communities engage in very limited amounts of PA and staff in these sites could benefit from ongoing education about how to increase PA among residents and help them adhere to current guidelines for PA so as to optimize overall health status.


Stability of bacteriophages in burn wound care products.
Bacteriophages could be used along with burn wound care products to enhance antimicrobial pressure during treatment. However, some of the components of the topical antimicrobials that are traditionally used for the prevention and treatment of burn wound infection might affect the activity of phages. Therefore, it is imperative to determine the counteraction of therapeutic phage preparations by burn wound care products before application in patients. Five phages, representatives of two morphological families (Myoviridae and Podoviridae) and active against 3 common bacterial burn wound pathogens (Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus) were tested against 13 different products commonly used in the treatment of burn wounds. The inactivation of the phages was quite variable for different phages and different products. Majority of the anti-infective products affected phage activity negatively either immediately or in the course of time, although impact was not always significant. Products with high acidity had the most adverse effect on phages. Our findings demonstrate that during combined treatment the choice of phages and wound care products must be carefully defined in advance.


Dual EGFR and BRAF blockade overcomes resistance to vemurafenib in BRAF mutated thyroid carcinoma cells.
BRAF inhibitors are effective anticancer agents in BRAF-mutated melanomas. By contrast, evidences about sensitivity of thyroid carcinomas to BRAF inhibition are conflicting and it has been proposed that BRAF V600E thyroid carcinoma cells are less sensitive to BRAF inhibitors due to activation of parallel signaling pathways. This study evaluated the hypothesis that feedback activation of EGFR signaling counteracts the cytostatic activity of vemurafenib (PLX4032) in BRAF V600E thyroid carcinoma cells. Cell proliferation, cell cycle distribution, induction of apoptosis and EGFR and AKT signaling were evaluated in thyroid carcinoma cell lines bearing the BRAF V600E mutation in response to PLX4032. A partial and transient cytostatic response to PLX4032 was observed in thyroid carcinoma cell lines bearing the BRAF V600E mutation, with lack of full inhibition of ERK pathway. Interestingly, the exposure of thyroid carcinoma cells to PLX4032 resulted in a rapid feedback activation of EGFR signaling with parallel activation of AKT phosphorylation. Consistently, the dual inhibition of EGFR and BRAF, through combination therapy with PLX4032 and gefitinib, resulted in prevention of EGFR phosphorylation and sustained inhibition of ERK and AKT signaling and cell proliferation. Of note, the combined treatment with gefitinib and vemurafenib or the exposure of EGFR-silenced thyroid carcinoma cells to vemurafenib induced synthetic lethality compared to single agents. These data suggest that the dual EGFR and BRAF blockade represents a strategy to by-pass resistance to BRAF inhibitors in thyroid carcinoma cells.


Different-sized incisions for phacoemulsification in age-related cataract.
Age-related cataract is the principal cause of blindness and visual impairment in the world. Phacoemulsification is the main surgical procedure used to treat cataract. The comparative effectiveness and safety of different-sized incisions for phacoemulsification has not been determined. The aim of this systematic review was to assess the effectiveness and safety of smaller versus larger incisions for phacoemulsification in age-related cataract. The primary outcome of this review was surgically induced astigmatism at three months after surgery. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 10), MEDLINE Ovid (1946 to 28 October 2016), Embase Ovid (1947 to 28 October 2016), PubMed (1948 to 28 October 2016), LILACS (Latin American and Caribbean Health Sciences Literature Database) (1982 to 28 October 2016), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com; last searched 13 May 2013), ClinicalTrials.gov (www.clinicaltrials.gov; searched 28 October 2016), and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp; searched 28 October 2016). We did not use any date or language restrictions in the electronic searches for trials. We included randomized controlled trials (RCTs) comparing different-sized incisions in people with age-related cataract undergoing phacoemulsification. We used standard methodological procedures expected by Cochrane. We included 26 RCTs with a total of 2737 participants (3120 eyes). These trials were conducted in Bosnia and Herzegovina, China, France, India, Italy, Korea, Spain, Switzerland, and Turkey. Half of the 26 trials were conducted in China. We judged all trials as mostly at unclear to low risk of bias. The included RCTs compared four different-sized incisions:<= 1.5 mm, 1.8 mm, 2.2 mm, and approximately 3.0 mm. These incisions were performed using three different techniques: coaxial and biaxial microincision phacoemulsification (C-MICS and B-MICS) and standard phacoemulsification. Not all studies provided data in a form that could be included in this review. Five studies had three arms.Fifteen trials compared C-MICS (2.2 mm) with standard phacoemulsification (about 3.0 mm). Very low-certainty evidence suggested less surgically induced astigmatism in the C-MICS group at three months compared with standard phacoemulsification (mean difference (MD) -0.19 diopters (D), 95% confidence interval (CI) -0.30 to -0.09; 996 eyes; 8 RCTs). There was low-certainty evidence that both groups achieved similar best-corrected visual acuity (MD 0.00 logMAR, 95% CI -0.02 to 0.02; 242 eyes; 3 RCTs). There was low-certainty evidence of little or no difference in endothelial cell loss and central corneal thickness comparing C-MICS with standard phacoemulsification (MD -7.23 cells/mm2, 95% CI -78.66 to 64.20; 596 eyes; 4 RCTs) and (MD -0.68 μm, 95% CI -3.26 to 1.90; 487 eyes; 5 RCTs).Nine trials compared C-MICS (1.8 mm) with standard phacoemulsification (about 3.0 mm). Very low-certainty evidence suggested less astigmatism at three months in the C-MICS group compared with standard phacoemulsification group (MD -0.23 D, 95% CI -0.34 to -0.13; 561 eyes; 5 RCTs). Low-certainty evidence suggested little or no difference in best-corrected visual acuity, endothelial cell loss, and central corneal thickness in the two groups at three months (MD -0.02 logMAR, 95% CI -0.03 to -0.00; 192 eyes; 3 RCTs), (MD 7.56 cells/mm2, 95% CI -67.65 to 82.77; 380 eyes; 5 RCTs), and (MD -1.52 μm, 95% CI -6.29 to 3.25; 245 eyes; 3 RCTs).Six studies compared C-MICS (1.8 mm) with C-MICS (2.2 mm). There was low-certainty evidence that astigmatism, visual acuity, and central corneal thickness were similar in the two groups at three months (MD 0.04 D, 95% CI -0.09 to 0.16; 259 eyes; 3 RCTs), (MD 0.01 logMAR, 95% CI -0.01 to 0.04; 200 eyes; 3 RCTs), and (MD 0.45 μm, 95% CI -2.70 to 3.60; 100 eyes; 1 RCT). Very low-certainty evidence suggested higher endothelial cell loss in the 1.8 mm group (MD 213.00 cells/mm2, 95% CI 11.15 to 414.85; 70 eyes; 1 RCT).Four studies compared B-MICS (<= 1.5 mm) with standard phacoemulsification (about 3.0 mm). Astigmatism was similar in the two groups at three months (MD -0.01 D, 95% CI -0.03 to 0.01; 368 eyes; 2 RCTs; moderate-certainty evidence). There was low-certainty evidence on visual acuity, suggesting little or no difference between the two groups (MD -0.02 logMAR, 95% CI -0.04 to -0.00; 464 eyes; 3 RCTs). Low-certainty evidence on endothelial cell loss and central corneal thickness also suggested little or no difference between the two groups (MD 55.83 cells/mm2, 95% CI -34.93 to 146.59; 280 eyes; 1 RCT) and (MD 0.10 μm, 95% CI -14.04 to 14.24; 90 eyes; 1 RCT).None of the trials reported on quality of life. One trial reported that no participants experienced endophthalmitis or posterior capsule rupture; they also reported little or no difference between incision groups regarding corneal edema (risk ratio 1.02, 95% CI 0.40 to 2.63; 362 eyes). Phacoemulsification with smaller incisions was not consistently associated with less surgically induced astigmatism compared with phacoemulsification with larger incisions. Coaxial microincision phacoemulsification may be associated with less astigmatism than standard phacoemulsification, but the difference was small, in the order of 0.2 D, and the evidence was uncertain. Safety outcomes and quality of life were not adequately reported; these should be addressed in future studies.


Arterial internal elastic lamina holes: relationship to function?
Internal elastic lamina (IEL) hole (fenestration) characteristics and myoendothelial gap junction (MEGJ) density were examined in selected resistance and conduit arteries of normal and diseased rat and mouse models, using conventional, ultrastructural and confocal microscopy methods. Selected vessels were those commonly used in functional studies: thoracic aorta, proximal and distal mesenteric, caudal, saphenous, middle-cerebral and caudal cerebellar artery. Rat and mouse strains and treatment groups examined were Dahl, Sprague Dawley, Wistar Kyoto, Wistar, spontaneously hypertensive (SHR), deoxycorticosterone (DOC) treated rat; and apolipoprotein E knockout, C57/BL6 and BALB/c mice. Vessel size (as IEL circumference), IEL hole and MEGJ density were quantified. In mesenteric arteries, the width of IEL holes and the percent of IEL occupied by holes were also determined. IEL hole density varied significantly within and between mesenteric artery beds, even among normotensive rat strains. Among the hypertensive rats (SHR and DOC), hole density in some vessels was higher in the normotensives than in the hypertensives within each strain, whereas in Dahl rats, hole density was similar between hypertensives and normotensives. Hole density was not correlated with the formation of intimal lesions in superior mesenteric artery. There was no positive general correlation between IEL hole and MEGJ density in resistance and conduit vessels. However, there was a positive correlation between the size of some resistance arteries and MEGJ density, although such a relationship did not hold for conduit vessels or during development, and there was no such relationship between vessel size and IEL hole density. Whilst IEL holes are obviously required for MEGJ communication, their presence is not an indication of contact-mediated communication, but rather may be related to the presence of sites for the low resistance passage of diffusion-mediated release of vasoactive endothelial and smooth muscle substances.


β-1,4-Galactosyltransferase III suppresses extravillous trophoblast invasion through modifying β1-integrin glycosylation.
Glycosylation controls diverse protein functions and regulates various cellular phenotypes. Trophoblast invasion is essential for normal placental development. However, the role of glycosylation in human placenta throughout pregnancy is still unclear. The β-1,4-galactosyltransferase III (B4GALT3) has been found to regulate cancer cell invasion. We therefore investigated the expression of B4GALT3 in placenta and its roles in trophoblast. B4GALT3 protein expression was examined by quantitative Western blotting analysis in human placentas. For identification of B4GALT3-positive cells in normal human placenta, immunohistochemistry and immunofluorescence methods were used. To investigate effects of B4GALT3 on extravillous trophoblast (EVT)-like cell and primary EVT cells, we analyzed cell growth, adhesion, migration, and invasion in mock and B4GALT3-transfected cell. B4GALT3 expression significantly increased in third trimester human placenta. Immunostaining revealed that B4GALT3 expressed in placental villous cytotrophoblast, syncytiotrophoblast, and a subpopulation of EVT cells throughout pregnancy. Interestingly, we found increases in the expression level and percentage of B4GALT3-positive cells in third trimester EVT, but not in syncytiotrophoblasts and cytotrophoblasts of placental villi. Overexpression of B4GALT3 in HTR8/SVneo cells and primary trophoblast cells significantly suppressed cell migration. In addition, B4GALT3 suppressed cell invasion, and enhanced cell adhesion to laminin in HTR8/SVneo cells. Notably, we found that B4GALT3 modified glycans on β1-integrin, suppressed focal adhesion kinase (FAK) signaling, and enhanced β1-integrin degradation. We propose that B4GALT3-mediated glycosylation change not only enhances β1-integrin binding to laminin, but also attenuates β1-integrin stability. Our findings suggest that B4GALT3 is a critical regulator for suppressing EVT invasion in the late stages of pregnancy.


Hip pain referral patterns in patients with labral tears: analysis based on intra-articular anesthetic injections, hip arthroscopy, and a new pain "circle" diagram.
Fluoroscopically guided intra-articular (FGIA) anesthetic hip joint injections have been used to determine whether the hip joint is the source of a patient's hip pain. However, there have been no reports documenting the efficacy of their use for defining the pain referral patterns (PRPs) of patients with labral tears. The aim of this study was to determine the PRPs of patients with labral tears and evaluate a new pain "circle" diagram (PCD) developed for this analysis. Fifty-two patients were evaluated at our institution who had: 1) a preoperative FGIA anesthetic hip joint injection; 2) completed our PCD and a visual analog pain scale pre- and postinjection; 3) significant (≥ 80%) pain reduction after their FGIA injection; and 4) a labral tear and minimal (≤ grade II) degenerative joint disease, as documented by hip arthroscopy. The PCD had circles in which patients put an "X" in to indicate pain in the following locations: anterior superior spine, lateral peritrochanteric area, central groin, symphysis pubis, proximal inner thigh, anterior thigh, posterior iliac crest, sacroiliac joint, sciatic notch, and ischial tuberosity. Based on the percentage of patients with significant (≥ 80%) pain reduction after administration of FGIA, 2 areas demonstrated substantially more and consistent presence of pain, which improved after injection. These were the central groin (P < 0.001) and the lateral peritrochanteric area (P = 0.02). The most common locations of pain were the central groin and the lateral peritrochanteric area. The least common were the ischial tuberosity and the anterior thigh, which are 2 areas often associated with osteoarthritis of the hip. The use of the PCD combined with an FGIA anesthetic injection may help physicians reconcile the expectations of those patients with labral tears who believe that hip arthroscopy will treat their multiple areas of "hip" pain.


Clinical, molecular, and cell biological aspects of Chediak-Higashi syndrome.
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by variable degrees of oculocutaneous albinism, easy bruisability, and bleeding as a result of deficient platelet dense bodies, and recurrent infections, with neutropenia, impaired chemotaxis and bactericidal activity, and abnormal NK cell function. Neurologic involvement is variable, but often includes peripheral neuropathy. Most patients also undergo an "accelerated phase," which is a nonmalignant lymphohistiocytic infiltration of multiple organs resembling lymphoma. Death often occurs in the first decade from infection, bleeding, or development of the accelerated phase. The hallmark of CHS is the presence of huge cytoplasmic granules in circulating granulocytes and many other cell types. These granules are peroxidase-positive and contain lysosomal enzymes, suggesting that they are giant lysosomes or, in the case of melanocytes, giant melanosomes. The underlying defect in CHS remains elusive, but the disorder can be considered a model for defects in vesicle formation, fusion, or trafficking. Because the beige mouse demonstrates many characteristics similar to those of human CHS patients, including dilution of coat color, recurrent infections, and the presence of giant granules, it is considered the animal homologue of CHS. The beige gene, Lyst, was mapped and sequenced in 1996, prompting identification of the human LYST gene on chromosome 1q42. Lyst and LYST show 86.5% sequence homology. LYST encodes a 429 kDa protein with a function that remains unknown, but the source of extensive speculation among students of cell biology.


[A focus of Huntington's chorea in Peru].
Since 1970, 91 patients with Huntington's chorea have been identified in Peru, the majority of them, 42 cases, living in Cañete, a valley 140 km from Lima. The precise origin of the disease is unknown, but these patients are mostly half-bred from a mixture of White and Indian rather than from a mixture of Chinese, Japanese or Black.


Adipocytes Promote Early Steps of Breast Cancer Cell Dissemination via Interleukin-8.
Fat is a major tissue component in human breast cancer (BC). Whether breast adipocytes (BAd) affect early stages of BC metastasis is yet unknown. BC progression is dependent on angiogenesis and inflammation, and interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) are key regulators of these events. Here, we show that BAd increased the dissemination of estrogen receptor positive BC cells (BCC) in vivo in the zebrafish model of metastasis, while dissemination of the more aggressive and metastatic BCC such as estrogen receptor negative was unaffected. While anti-VEGF and anti-IL-8 exhibited equal inhibition of angiogenesis at the primary tumor site, anti-IL-8 reduced BCC dissemination whereas anti-VEGF had minor effects on this early metastatic event. Mechanistically, overexpression of cell-adhesion molecules in BCC and neutrophils via IL-8 increased the dissemination of BCC. Importantly, the extracellular in vivo levels of IL-8 were 40-fold higher than those of VEGF in human BC. Our results suggest that IL-8 is a clinical relevant and promising therapeutic target for human BC.


Mutational analysis of the potato virus Y 5' untranslated region for alteration in translational enhancement in tobacco protoplasts.
The 185 nucleotide 5' untranslated region (5'UTR) of potato virus Y ordinary strain (PVY-O) showed translation-enhancing activity on the beta-glucuronidase (GUS) gene in tobacco protoplasts. Mutational analysis of the 5'UTR was done to find sequence motifs necessary for the enhancement. Deletions within the 1-130 nucleotide region of 5'UTR stimulated the GUS expression in some cases, while the GUS activity declined with deletions in the 131-185 nucleotide region. The results indicated that the last 55 nucleotides of PVY-O 5'UTR might play the much important role in the translational enhancement in plant cells.


Diagnostic approach in parenchymal lung diseases: transbronchial lung biopsy or cryobiopsy?
Diagnosis of interstitial lung diseases requires a multidisciplinary approach, and a gold standard for histological diagnosis is open lung biopsy. Transbronchial lung biopsy (TBLB) and in recent years an alternative method, cryobiopsy (TBLC), are used for the diagnosis of parenchymal lung lesions. The aim of this study is to compare the efficacy of concomitant conventional TBLB and TBLC. A total of 82 patients who underwent TBLC for diagnosis of diffuse parenchymal lung diseases at Dr. Suat Seren Chest Diseases and Surgery Training and Research Hospital between 2015 and 2018 were screened retrospectively and included in the study. Of the patients, 53.7% (n: 44) were male, and 46.4% (n:38) of them were female. The mean age was 58.37 (±9.33) years. First TBLB and then TBLC were performed to all patients in the same session and their diagnostic performances were compared. Although both procedures were done in the same session, 45 patients (54.9%) were diagnosed with TBLB and 75 patients (91.5%) were diagnosed with TBLC (P ˂ 0.001). Hemorrhage was observed in 39 patients (47.6%), but only one had a massive hemorrhage. Pneumothorax was observed in 6 patients (7.3%) and none of them required tube drainage. Transbronchial lung cryobiopsy is a promising technique for the diagnosis of parenchymal lung diseases compared to transbronchial lung biopsy.


Longitudinal evaluation of the biodistribution and cellular internalization of the bispecific CD3xTRP1 antibody in syngeneic mouse tumor models.
CD3 bispecific antibodies (CD3-bsAbs) require binding of both a tumor-associated surface antigen and CD3 for their immunotherapeutic effect. Their efficacy is, therefore, influenced by the tumor uptake and the extracellular dose. To optimize their currently limited efficacy in solid tumors, increased understanding of their pharmacokinetics and in vivo internalization is needed. Here, were studied the pharmacokinetics and in vivo internalization of CD3xTRP1, a fully murine Fc-inert bsAb, in endogenous TRP1-expressing immunocompetent male C57BL/6J mice bearing TRP1-positive and negative tumors over time. Matching bsAbs lacking TRP1-binding or CD3-binding capacity served as controls. BsAbs were radiolabeled with 111In to investigate their pharmacokinetics, target binding, and biodistribution through SPECT/CT imaging and ex vivo biodistribution analyses. Co-injection of 111In- and 125I-labeled bsAb was performed to investigate the in vivo internalization by comparing tissue concentrations of cellular residing 111In versus effluxing 125I. Antitumor therapy effects were evaluated by monitoring tumor growth and immunohistochemistry. SPECT/CT and biodistribution analyses showed that CD3xTRP1 specifically targeted TRP1-positive tumors and CD3-rich lymphoid organ and uptake peaked 24 hours pi (KPC3-TRP1: 37.7%ID/g±5.3%ID/g, spleen: 29.0%ID/g±3.9%ID/g). Studies with control bsAbs demonstrated that uptake of CD3xTRP1 in TRP1-positive tumors and CD3-rich tissues was primarily receptor-mediated. Together with CD3xTRP1 in the circulation being mainly unattached, this indicates that CD3+ T cells are generally not traffickers of CD3-bsAbs to the tumor. Additionally, target-mediated clearance by TRP1-expressing melanocytes was not observed. We further demonstrated rapid internalization of CD3xTRP1 in KPC3-TRP1 tumors (24 hours pi: 54.9%±2.3% internalized) and CD3-rich tissues (spleen, 24 hours pi: 79.7%±0.9% internalized). Therapeutic effects by CD3xTRP1 were observed for TRP1-positive tumors and consisted of high tumor influx of CD8+ T cells and neutrophils, which corresponded with increased necrosis and growth delay. We show that CD3xTRP1 efficiently targets TRP1-positive tumors and CD3-rich tissues primarily through receptor-mediated targeting. We further demonstrate rapid receptor-mediated internalization of CD3xTRP1 in TRP1-positive tumors and CD3-rich tissues. Even though this significantly decreases the therapeutical available dose, CD3xTRP1 still induced effective antitumor T-cell responses and inhibited tumor growth. Together, our data on the pharmacokinetics and mechanism of action of CD3xTRP1 pave the way for further optimization of CD3-bsAb therapies.


Phenotypic correction and long-term expression of factor VIII in hemophilic mice by immunotolerization and nonviral gene transfer using the Sleeping Beauty transposon system.
Hemophilia A is a lead candidate for treatment by gene therapy because small increments in the missing secreted protein product, coagulation factor VIII (FVIII), would result in substantial clinical amelioration. Clinically relevant therapy might be achieved by stably delivering a human FVIII cDNA to correct the bleeding disorder. We used the Sleeping Beauty (SB) transposon, delivered as naked plasmid DNA by tail-vein injection, to integrate B-domain-deleted FVIII genes into the chromosomes of hemophilia A mice and correct the phenotype. Since FVIII protein is a neoantigen to these mice, sustaining therapeutic plasma FVIII levels was problematic due to inhibitory antibody production. We circumvented this problem by tolerizing 82% of neonates by a single facial-vein injection of recombinant FVIII within 24 hours of birth (the remaining 18% formed inhibitors). Achievement of high-level (10%-100% of normal) FVIII expression and phenotypic correction required co-injection of an SB transposase-expressing plasmid to facilitate transgene integration in immunotolerized animals. Linker-mediated polymerase chain reaction was used to clone FVIII transposon insertion sites from liver genomic DNA, providing molecular evidence of transposition. Thus, SB provides a nonviral means for sustained FVIII gene delivery in a mouse model of hemophilia A if the immune response is prevented.


A Diagnosis to Consider in an Adult Patient with Facial Features and Intellectual Disability: Williams Syndrome.
Williams syndrome (OMIM #194050) is a rare, well-recognized, multisystemic genetic condition affecting approximately 1/7,500 individuals. There are no marked regional differences in the incidence of Williams syndrome. The syndrome is caused by a hemizygous deletion of approximately 28 genes, including ELN on chromosome 7q11.2. Prenatal-onset growth retardation, distinct facial appearance, cardiovascular abnormalities, and unique hypersocial behavior are among the most common clinical features. Here, we report the case of a patient referred to us with distinct facial features and intellectual disability, who was diagnosed with Williams syndrome at the age of 37 years. Our aim is to increase awareness regarding the diagnostic features and complications of this recognizable syndrome among adult health care providers. Williams syndrome is usually diagnosed during infancy or childhood, but in the absence of classical findings, such as cardiovascular anomalies, hypercalcemia, and cognitive impairment, the diagnosis could be delayed. Due to the multisystemic and progressive nature of the syndrome, accurate diagnosis is critical for appropriate care and screening for the associated morbidities that may affect the patient's health and well-being.


Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice.
Schisandrin B (Sch B), a dibenzocyclooctadiene compound, is isolated from schisandrae fructus (SF). This study was conducted to compare the time- and dose-response between Sch B- and SF oil (SFO)-induced changes in hepatic and serum parameters in mice. Institute of Cancer Research (ICR) mice were given a single oral dose of Sch B (0.125-2 g/kg) or SFO (0.3-5 g/kg). Serum alanine aminotransferase (ALT) activity, hepatic malondialdehyde, and triglyceride (TG) levels were measured at increasing time intervals within 6-120 hours postdosing. Serum ALT activity was elevated by 60%, with maximum effect (E(max)) = 45.77 U/L and affinity (K(D)) = 1.25 g/kg at 48-96 hours following Sch B, but not SFO, treatment. Sch B and SFO treatments increased hepatic malondialdehyde level by 70% (E(max) =2.30 nmol/mg protein and K(D) =0.41 g/kg) and 22% (E(max) = 1.42 nmol/mg protein and K D = 2.56 g/kg) at 72 hours postdosing, respectively. Hepatic index was increased by 16%-60% (E max = 11.01, K(D) = 0.68 g/kg) and 8%-32% (E(max) = 9.88, K D = 4.47 g/kg) at 12-120 hours and 24-120 hours after the administration of Sch B and SFO, respectively. Hepatic TG level was increased by 40%-158% and 35%-85%, respectively, at 12-96 hours and 6-48 hours after Sch B and SFO treatment, respectively. The values of E max and K D for Sch B/SFO-induced increase in hepatic TG were estimated to be 22.94/15.02 μmol/g and 0.78/3.03 g/kg, respectively. Both Sch B and SFO increased serum TG (up to 427% and 123%, respectively), with the values of E(max) = 5.50/4.60 mmol/L and K D = 0.43/2.84 g/kg, respectively. The findings indicated that Sch B/SFO-induced increases in serum/hepatic parameters occurred in a time-dependent manner, with the time of onset being serum TG level < hepatic TG level < hepatic index < serum ALT activity. However, the time of recovery of these parameters to normal values varied as follow: serum TG level < hepatic TG level and liver injury < hepatic index. The E max and affinity of Sch B on tissue/enzyme/receptor were larger than those of SFO.


CDX2 as a marker for intestinal differentiation: Its utility and limitations.
CDX2 is a nuclear homeobox transcription factor that belongs to the caudal-related family of CDX homeobox genes. The gene encoding CDX2 is a nonclustered hexapeptide located on chromosome 13q12-13. Homeobox genes play an essential role in the control of normal embryonic development. CDX2 is crucial for axial patterning of the alimentary tract during embryonic development and is involved in the processes of intestinal cell proliferation, differentiation, adhesion, and apoptosis. It is considered specific for enterocytes and has been used for the diagnosis of primary and metastatic colorectal adenocarcinoma. CDX2 expression has been reported to be organ specific and is normally expressed throughout embryonic and postnatal life within the nuclei of epithelial cells of the alimentary tract from the proximal duodenum to the distal rectum. In this review, the authors elaborate on the diagnostic utility of CDX2 in gastrointestinal tumors and other neoplasms with intestinal differentiation. Limitations with its use as the sole predictor of a gastrointestinal origin of metastatic carcinomas are also discussed.


Serum ghrelin levels in papillary thyroid carcinoma.
Ghrelin plays a role in several processes of cancer progression, and numerous cancer types express ghrelin and its receptor. We aimed to investigate serum levels of ghrelin in patients with papillary thyroid carcinoma (PTC) and its association with the prognostic factors in PTC. We enrolled 54 patients with thyroid cancer (7 male, 47 female) and 24 healthy controls (6 male, 18 female) in the study. We compared demographic, anthropometric, and biochemical data, and serum ghrelin levels between the groups. Serum ghrelin levels were measured using as enzyme-linked immunosorbent assay. Ghrelin levels were similar between the groups, but plasma ghrelin levels were significantly higher in tumors larger than 1 cm diameter compared with papillary microcarcinomas. Serum ghrelin levels also correlated with tumor size (r = 0.499; p < 0.001). Body mass index, thyroid-stimulating hormone, and HOMA-IR levels were similar between the groups. There were no statistically significant differences regarding average age and other prognostic parameters including lymph node invasion, capsule invasion, multifocality and surgical border invasion between patients with microcarcinoma and tumors larger than 1 cm. In our study, no significant difference in serum ghrelin levels was determined between patients with papillary thyroid cancer and healthy controls however, serum ghrelin levels were higher in tumors larger than 1 cm compared to in those with thyroid papillary microcarcinoma.


The effect of non-organophosphate household pesticides exposure during pregnancy on infants birth sizes and growth rate: a cohort study.
To date, there is limited evidence on the effect of antenatal exposure to non-organophosphate household pesticides on infant health. Our hypothesis is that antenatal exposure to non-organophosphate household pesticides will be associated with birth sizes and infant growth rate. In this prospective cohort study, 284 mother-infant pairs were studied. Mothers were recruited at the third trimester in two primary care centers and one private hospital in Jakarta, Indonesia. Mothers filled out questionnaires about exposure to non-organophosphate household pesticides at the 3rd trimester of pregnancy. Birth weight and length were measured at birth. Afterwards, the weight, height, and head circumference (HC) were measured at 7 days, 1, 2, 4, and 6 months of age. Linear mixed modeling and linear regression was performed to calculate growth rate of each infant. Multivariable linear regression adjusted for confounders was used to assess the association between household pesticides exposure and birth sizes and infant growth rate. Based on self-report questionnaires, 133 (46.8%) mothers were exposed to household pesticides during pregnancy. The mean HC at day 7 in the exposed group was - 7.1 mm (95%CI -13.1;-1.2) lower than in the non-exposed group. The difference was more prominent in the non-mosquito pesticide group (linear regression coefficient: - 22.1 mm, 95%CI -36.5;-7.6). No material associations were found between antenatal exposure to household pesticides with other growth measures, including weight gain, length gain, HC increment and weight-to-length gain rates. No modification of effects by breastfeeding was found. Our findings suggest that antenatal exposure to household non-organophosphate pesticides is associated with smaller head circumference at birth.


The course of Schistosoma mansoni infection in thymectomized rats.
Inbred rats were thymectomized, irradiated, and reconstituted with T cell-free bone marrow cells. Thymectomized-reconstituted (B rats) and control rats were infected with Schistosoma mansoni cercariae and the number of worms recovered was determined at various times after infection. The extent of immunosuppression was assessed by two criteria: 1) response to an injection of sheep erythrocytes (plaque assay, hemagglutination, hemolysis); 2) response to schistosome antigens (passive hemagglutination). Humoral responses to worm antigens were completely suppressed in almost all instances and anti-sheep erythrocyte responses showed a more variable but always very definite depression in B rats. The number of worms in B rats was about 4 times higher than in control animals at 5 weeks and about 3 times higher at 6 weeks. In a different experiment, rats were perfused at 4, 6, and 9 weeks after infection and the number of worms was found to be consistently higher in B rats, by a factor of about 2 at 4 weeks to a factor of about 4 or 6 at subsequent times. Although B rats had more worms than controls even at 9 weeks, a slow drop in their worm burden was noticeable with time in both experiments. Moreover, the size of worms in B rats was smaller than in controls and even 9-week-old worms failed to develop to normal size and appearance and could not be shown to produce fertile eggs. These experiments show a definite involvement of the immune system in the "self-cure" phenomenon, but may at the same time suggest that other non-immune mechanisms are involved in determining the pattern of S. mansoni infection in the rat.


Lysosomal Acid Lipase Deficiency: Therapeutic Options.
Lysosomal acid lipase (LAL) deficiency is a metabolic (storage) disorder, encompassing a severe (Wolman disease) and attenuated (Cholesterol ester storage disease) subtype; both inherited as autosomal recessive traits. Cardinal clinical features include the combination of hepatic dysfunction and dyslipidemia, as a consequence of cholesteryl esters and triglyceride accumulation, predominately in the liver and vascular and reticuloendothelial system. Significant morbidity can arise, due to liver failure and/or atherosclerosis; in part related to the severity of the underlying gene defect and corresponding enzyme deficiency. Diagnosis is based on demonstration of decreased LAL enzyme activity, complemented by analysis of the cognate gene defects. Therapeutic options include dietary manipulation and the use of lipid-lowering drugs. Sebelipase alfa, a recombinant enzyme replacement therapy, has garnered regulatory approval, following demonstration of improvements in disease-relevant markers and clinical benefit in clinical trials, which included increased survival in the most severe cases.


Prinzmetal's variant angina.
Two patients are described with a typical Prinzmetal's variant angina. Both patients were young, active males with angina of recent onset. They experienced angina only at rest and in one patient the angina had a cyclic character appearing only between 4 and 10 a.m. In both patients there was no correlation whatsoever between the angina pectoris and effort, emotion or change in temperature and the angina reacted promptly to nitroglycerine sublingually. The number of attacks and the intensity of the pain were increasing rapidly over a short period of time in both cases. The stenoses in both patients did not exceed 50% of the lumen of the coronary arteries, but coronary surgery has been performed on clinical grounds because both patients were completely disabled and one of them suffered from life-threatening dysrhythmias. For respectively 18 and 6 months after saphenous vein bypass surgery both patients have been symptom-free and able to resume their work. The problems concerning the diagnosis Prinzmetal's variant of angina pectoris are discussed.


Tmod3 Phosphorylation Mediates AMPK-Dependent GLUT4 Plasma Membrane Insertion in Myoblasts.
Insulin and muscle contractions mediate glucose transporter 4 (GLUT4) translocation and insertion into the plasma membrane (PM) for glucose uptake in skeletal muscles. Muscle contraction results in AMPK activation, which promotes GLUT4 translocation and PM insertion. However, little is known regarding AMPK effectors that directly regulate GLUT4 translocation. We aim to identify novel AMPK effectors in the regulation of GLUT4 translocation. We performed biochemical, molecular biology and fluorescent microscopy imaging experiments using gain- and loss-of-function mutants of tropomodulin 3 (Tmod3). Here we report Tmod3, an actin filament capping protein, as a novel AMPK substrate and an essential mediator of AMPK-dependent GLUT4 translocation and glucose uptake in myoblasts. Furthermore, Tmod3 plays a key role in AMPK-induced F-actin remodeling and GLUT4 insertion into the PM. Our study defines Tmod3 as a key AMPK effector in the regulation of GLUT4 insertion into the PM and glucose uptake in muscle cells, and offers new mechanistic insights into the regulation of glucose homeostasis.


Comparison of Clinical and Echocardiographic Outcomes After Surgical Redo Mitral Valve Replacement and Transcatheter Mitral Valve-in-Valve Therapy.
There are minimal data regarding clinical outcomes and echocardiographic findings after transcatheter mitral valve-in-valve replacement (TMVR) compared with redo surgical mitral valve replacement (SMVR). TMVR therapy has emerged as therapy for a degenerated bioprosthetic valve failure. The authors retrospectively identified patients with degenerated mitral bioprostheses who underwent redo SMVR or TMVR at 3 U.S. institutions. The authors compared clinical and echocardiographic outcomes of patients who had TMVR with those of patients who underwent redo SMVR. Sixty-two patients underwent TMVR and 59 patients underwent SMVR during the study period. Mean age and the Society of Thoracic Surgeons Predicted Risk of Mortality (STS PROM) scores were significantly higher in patients with TMVR than in those with SMVR (age 74.9 ± 9.4 years vs. 63.7 ± 14.9 years; p < 0.001; STS PROM 12.7 ± 8.0% vs. 8.7 ± 10.1%; p < 0.0001). Total procedure time, intensive care unit hours, and post-procedure length of stay were all significantly shorter in the TMVR group. There was no difference in mortality at 1 year between the 2 groups (TMVR 11.3% vs. SMVR 11.9%; p = 0.92). Mean mitral valve pressure gradient and the grade of mitral regurgitation (MR) were similar between the TMVR group and the SMVR group (mitral valve pressure gradient 7.1 ± 2.5 mm Hg vs. 6.5 ± 2.5 mm Hg; p = 0.42; MR [≥moderate] 3.8% vs. 5.6%; p = 1.00) at 30 days. At 1 year, the mitral valve pressure gradient was higher in the TMVR group (TMVR 7.2 ± 2.7 vs. SMVR 5.5 ± 1.8; p = 0.01), although there was no difference in the grade of MR. Despite the higher STS PROM in TMVR patients, there was no difference in 1-year mortality between the TMVR and SMVR groups. Echocardiographic findings after TMVR were similar to SMVR at 30 days. There was a statistically significant difference in mitral gradient at 1 year, though this is likely not clinically important. TMVR may be an alternative to SMVR in patients with previous mitral bioprosthetic valves.


Metallothioneins I/II expression in rat strains with genetically different susceptibility to experimental autoimmune encephalomyelitis.
Compared to the Dark Agouti (DA), the Albino Oxford (AO) rat strain exhibits lower susceptibility to the induction of experimental autoimmune encephalomyelitis (EAE). Here, we investigated the potential contribution of the heavy metal-binding proteins metallothioneins (MTs) I/II to these effects. Rats were immunized with bovine brain homogenate emulsified in complete Freund's adjuvant or only with complete Freund's adjuvant. The expression patterns of MTs mRNA and proteins and tissue concentrations of Zn2+ and Cu2+ were estimated in the brain and in the liver on days 7 and 12 after immunization, by real-time PCR, immunohistochemistry and inductively coupled plasma spectrometry, respectively. Additionally, the hepatic transforming growth factor beta and nuclear factor kappa B immunoreactivities were tested. Clinical signs of EAE were not induced in AO rats, but they upregulated the expression of MT I/II proteins in the brain (hippocampus and cerebellum) and in the liver, similarly as DA rats. The transcriptional activation of MT-I occurred, however, only in DA rats, which accumulated also more zinc in the brain and in the liver. In contrast, intact AO rats had greater hepatic MT-I mRNA immunoreactivity and more Cu2+ in the hippocampus. Besides, in immunized AO rats a high upregulation of transforming growth factor beta and nuclear factor kappa B immunoreactivities was found in several hepatic structures (vascular endothelium, Kupffer cells and hepatocytes). Our data show that AO and DA rats differ in constitutive and inductive MT-I gene expression in the brain and in the liver, as well as in the hepatic cytokine profile, suggesting that these mechanisms may contribute to the discrepancy in the susceptibility to EAE.


The cleaner shrimp Lysmata amboinensis adjusts its behaviour towards predatory versus non-predatory clients.
In cleaning mutualisms, small cleaner organisms remove ectoparasites and dead skin from larger clients. Because cheating by predatory clients can result in cleaner death, cleaners should assess the potential risk of interacting with a given client and adjust their behaviour accordingly. Cleaner shrimp are small marine crustaceans that interact with numerous client fish species, many of which are potential predators. We use in situ observations of cleaner-client interactions to show that the cleaner shrimp Lysmata amboinensis adjusts several behaviours when interacting with predatory versus non-predatory clients. Predatory clients were cleaned in a significantly lower proportion of interactions than non-predatory clients, and cleaners also exhibited a leg rocking behaviour-potentially signalling their identity or intent to clean-almost exclusively toward predatory clients. Incidence of leg rocking was positively correlated with client size, and laboratory experiments showed that it can be elicited by dark visual stimuli and decreases in illumination level. Thus, cleaners clean less frequently when predation risk is higher, and may use leg rocking as a signal advertising cleaning services and directed specifically at predators.


Range of motion and leg rotation affect electromyography activation levels of the superficial quadriceps muscles during leg extension.
Leg extension (LE) is commonly used to strengthen the quadriceps muscles during training and rehabilitation. This study examined the effects of limb position (POS) and range of motion (ROM) on quadriceps electromyography (EMG) during 8 repetitions (REP) of LE. Twenty-four participants performed 8 LE REP at their 8 repetition maximum with lower limbs medially rotated (TI), laterally rotated (TO), and neutral (NEU). Each REP EMG was averaged over the first, middle, and final 0.524 rad ROM. For vastus medialis oblique (VMO), a REP × ROM interaction was detected (p < 0.02). The middle 0.524 rad produced significantly higher EMG than the initial 0.524 rad for REP 6-8 and the final 0.524 rad produced higher EMG than the initial 0.524 rad for REP 1, 2, 3, 4, 6, and 8 (p ≤ 0.05). For rectus femoris (RF), EMG activity increased across REP with TO generating the greatest activity (p < 0.001). For vastus lateralis (VL), EMG increased across REP (p < 0.001) with NEU and TO EMG increasing linearly throughout ROM and TI activity greatest during the middle 0.524 rad. We conclude that to target the VMO, the optimal ROM is the final 1.047 rad regardless of POS, while maximum EMG for the RF is generated using TO regardless of ROM. In contrast, the VL is maximally activated using TI over the first 1.047 rad ROM or in NEU over the final 0.524 rad ROM.