Global Characterization and Genomic Stability of Human MultiStem, A Multipotent Adult Progenitor Cell.
The therapeutic benefits of adult adherent stem cells are currently being investigated in clinical trials for a variety of diseases. Data from initial clinical studies are promising and as a consequence of moving to later stage clinical studies, have resulted in larger scale clinical-grade cell production strategies. Therefore it becomes imperative to examine the epigenetic flux and genomic stability of stem cells in long-term culture to determine that minimal risk is associated with these therapies. Multipotent adult progenitor cells (MAPC) are an adherent adult stem cell population that can be derived from bone marrow and was the first of a class of adult stem cells that have broad developmental potential both in vitro and in vivo. Here, we report a panel of tests to characterize MultiStem, a multipotent adult stem cell type based on MAPC, and establish its genomic stability during culture expansion. A variety of techniques were employed that consisted of miRNA expression to characterize and define the cell population; chromosomal SNP analysis and G-banding to determine karyotypic stability; and methylation pattern and telomerase expression to examine potential changes in epigenetic and chromosomal stability with prolonged in vitro culture of cells. This panel of test was applied to cultures at early isolation stages and compared to cultures harvested at population doublings greater than those reached in current MultiStem clinical trials. These tests also provide a baseline for quality control of cells prepared from various biological donor sources for subsequent large scale propagation and preparation of cell banks for downstream applications.


Isolated Tricuspid Valve Surgery: A Single Institutional Experience with the Technique of Minimally Invasive Surgery via Right Minithoracotomy.
Background Minimally invasive cardiac surgery via right lateral minithoracotomy is a well-described approach. However, reports on isolated tricuspid valve surgery (TVS) in this technique are rare. Therefore, we like to give a contribution by reporting our experience. Methods We retrospectively reviewed 25 tricuspid valve operations via right lateral minithoracotomy with femoral cannulation between August 2009 and September 2013 (18 repairs, 7 replacements, and 72% repair rate). Three patients (12%) presented for a re-do operation, and nine patients (36%) suffered from active endocarditis at admission. All patients underwent TVS as single valve procedure. Ten patients received additional procedures such as removal of infected leads, resection of atrial tumors, or closure of atrial septal defects. An annuloplasty ring was inserted in 12 cases. We investigated the short-term morbidity and mortality with regard to the surgical procedure. Results Repair rate was 72%. Thirty-day and 1-year mortality were 4 and 20%, respectively. The only patient with early mortality received the surgical procedure on the tricuspid valve as fourth cardiac-related surgery and postoperative mortality was due to intracranial air embolism. Perioperative morbidity included reoperation for bleeding (8%) and stroke (4%). No disturbance of wound healing occurred. Durations of intensive care unit stay and hospital stay were 2.3 ± 2.4 and 17.4 ± 13.1 days, respectively. Endocarditis-caused surgery did not reveal any significant difference in the intra- or perioperative course compared with other indications. Conclusion Minimally invasive TVS via right lateral minithoracotomy is feasible with good results. Even in a cohort of patients suffering from elevated rate of active endocarditis, a high repair rate can be achieved.


Most recent developments in strategies to reduce the progression of structural changes in osteoarthritis: today and tomorrow.
Osteoarthritis (OA), the most common of all arthritic conditions, is a social and financial burden to all nations. The most recent research has significantly advanced our understanding of the cause of OA and risk factors associated with it. These findings have provided useful information that has helped in the daily management of patients with OA. Some preventative measures and a number of therapeutic agents and drugs are available, which may help to reduce the progression of OA in certain patients. Moreover, the most recent progress in research has significantly enhanced our knowledge of the factors involved in the development of the disease and of the mechanisms responsible for its progression. This has allowed identification of several new therapeutic targets in a number of pathophysiological pathways. Consequently, the field is opening up to a new era in which drugs and agents that can specifically block important mechanisms responsible for the structural changes that occur in OA can be brought into development and eventually into clinical trials.


Male prevalence for reading disability is found in a large sample of black and white children free from ascertainment bias.
Male vulnerability to neurodevelopmental disorders remains controversial. For one disorder, reading disability, this sex bias has been interpreted as an artifact of referral bias. We investigated sex differences for the incidence of reading disability within a large prospective sample of White (N = 16,910) and Black (N = 15,313) children derived from the National Collaborative Perinatal Project (NCPP). Children were classified as having either moderate or severe reading disability when they had reading scores lower than 1.5 or 2.0 standard errors of prediction, respectively, given their age and intelligence. Reading disability was about twice as common in boys than girls (p < .001), irrespective of race, severity of disability, or exclusion of children with attentional disturbances or high activity levels. We conclude that there is a clear sex bias toward males for the incidence of reading disabilities.


Action potentials without contraction in frog skeletal muscle fibers with disrupted transverse tubules.
Action potentials, with no accompanying contraction, were recorded from muscle fibers in which the transverse tubular system had been disrupted. The results show that action potentials require an intact transverse tubular system to cause contraction. Furthermore, both the after-depolarization following a single action potential and the slower, late afterpotential following a train of action potentials were absent in this preparation. Therefore, both phenomena must normally involve the transverse tubular system.


The prenatal human submandibular gland: a histological, histochemical and ultrastructural study.
The submandibular glands of 6 human fetuses, 13.5-16 weeks old, were studied using light and electron microscopic techniques. The developing gland at this stage consisted of a bush-like network of terminal buds (primitive acini) and primary ducts surrounded by a loose mesenchyme. Both components had a lumen which was surrounded by 1 or 2 layers of epithelial cells. Those cells adjacent to the lumen were attached by desmosomes but lacked well developed terminal bars. The cells were separated by an intercellular space, into which projected numerous microvilli. The cytoplasm of the epithelial cells contained the usual organelles with some cells containing large accumulations of glycogen granules. Serous granules and the luminal contents were both strongly PAS and AB positive. The function of this secretory material, at this stage of human development, is unknown. No mucus-like granules were observed. The terminal buds and primary ducts were surrounded by a well developed basal lamina and contained a few elongated cells which appeared morphologically as developing myoepithelial cells. Morphologically the development of the human submandibular gland, at 13.5-16 weeks of age, is roughly equivalent ot the developmental stage of the gland seen in the newborn rat or mouse. By birth, the human submandibular gland would likely reach a mature state, because there would be ample time remaining, in a normal gestation, for the maturation process to be completed.


A homozygous mutation in the integrin alpha6 gene in junctional epidermolysis bullosa with pyloric atresia.
The alpha6 integrin subunit participates in the formation of both alpha6beta1 and alpha6beta4 laminin receptors, which have been reported to play an important role in cell adhesion and migration and in morphogenesis. In squamous epithelia, the alpha6beta4 heterodimer is the crucial component for the assembly and stability of hemidesmosomes. These anchoring structures are ultrastructurally abnormal in patients affected with junctional epidermolysis bullosa with pyloric atresia (PA-JEB), a recessively inherited blistering disease of skin and mucosae characterized by an altered immunoreactivity with antibodies specific to integrin alpha6beta4. In this report, we describe the first mutation in the alpha6 integrin gene in a PA-JEB patient presenting with generalized skin blistering, aplasia cutis, and defective expression of integrin alpha6beta4. The mutation (791delC) is a homozygous deletion of a single base (C) leading to a frameshift and a premature termination codon that results in a complete absence of alpha6 polypeptide. We also describe the DNA-based prenatal exclusion of the disease in this family at risk for recurrence of PA-JEB. Our results demonstrate that, despite the widespread distribution of the alpha6 integrin subunit, lack of expression of the alpha6 integrin chain is compatible with fetal development, and results in a phenotype indistinguishable from that caused by mutations in the beta4 chain, which is expressed in a more limited number of tissues.


[Enhancing cultural sensitivity of psychiatrists emigrating from Russia to Israel].
The importance of understanding the local culture and enhancing cultural sensitivity became evident during supervision of immigrant psychiatrists from the former Soviet Union. The aim of the present study was to describe enhancement of this cultural sensitivity in the supervision of 2 immigrant psychiatrists. In the first, understanding the patient's cultural world helped the immigrant psychiatrist form the therapeutic alliance. In the second, the immigrant psychiatrist's understanding of the patient's cultural background led him to change both diagnosis and treatment. In both cases, development of cultural sensitivity through supervision enabled successful treatment. Enhancement of cultural sensitivity may accelerate absorption of the immigrant psychiatrists themselves. Discussing cultural issues during work may accelerate the absorption of all immigrant physicians.


[Viral and Mycoplasma-induced glomerulopathies in children].
Morphological examinations of kidneys from 227 children who had suffered from various generalized acute viral respiratory infections and mycoplasmosis established in 79 cases pathology of renalglomeruli, namely viral and mycoplasmic glomerulopathies. In 52 cases they corresponded to various forms of glomerulonephritis. The detection of deposites of immunoglobulins, virus and mycoplasma antigens suggest the association of these changes with the above-mentioned infections. Besides, 27 children showed peculiar lesions of the renal glomeruli, associated with the cytopathic effect of respiratory viruses and mycoplasma.


Factors related to perceived labor pain in primiparas.
The purpose of this study was to investigate the association between demographic-obstetric factors and perceived labor pain in primiparas. The participants in this study were 90 primiparas having normal childbirths at the Department of Obstetrics, Chi-Mei Medical Center in southern Taiwan between September 1999 and June 2000. The perceived intensity of labor pain was measured using the visual analogue scale for pain and the present behavioral intensity score in the latent phase (cervix dilated 3-4 cm), active phase (cervix dilated 5-7 cm), and transitional phase (cervix dilated 8-10 cm). The subjects' mean age was 27.82 +/- 3.64 years (range, 20-39 yr), and the mean newborn birth weight was 3,162 +/- 387 g (range, 2,340-4,120 g). The primiparas' perceived labor pain at each of the three phases of labor was positively related to expected labor pain, but had no significant association with newborn birth weight, maternal age, body mass index, confidence in labor, or duration of labor. The expected labor pain of the primiparas had a negative correlation with body mass index. The birth weight of the newborn was positively related to the duration of labor. These findings suggest that primiparas' perceived labor pain is correlated with psychogenic rather than physical factors.


Important role for Toll-like receptor 9 in host defense against meningococcal sepsis.
Neisseria meningitidis is a leading cause of meningitis and sepsis. The pathogenesis of meningococcal disease is determined by both bacterial virulence factors and the host inflammatory response. Toll-like receptors (TLRs) are prominent activators of the inflammatory response, and TLR2, -4, and -9 have been reported to be involved in the host response to N. meningitidis. While TLR4 has been suggested to play an important role in early containment of infection, the roles of TLR2 and TLR9 in meningococcal disease are not well described. Using a model for meningococcal sepsis, we report that TLR9(-/-) mice displayed reduced survival and elevated levels of bacteremia compared to wild-type mice. In contrast, TLR2(-/-) mice controlled the infection in a manner comparable to that of wild-type mice. TLR9 deficiency was also associated with reduced bactericidal activity in vitro, which was accompanied by reduced production of nitric oxide by TLR9-deficient macrophages. Interestingly, TLR9(-/-) mice recruited more macrophages to the bloodstream than wild-type mice and produced elevated levels of cytokines at late time points during infection. At the cellular level, activation of signal transduction and induction of cytokine gene expression were independent of TLR2 or TLR9 in macrophages and conventional dendritic cells. In contrast, plasmacytoid dendritic cells relied entirely on TLR9 to induce these activities. Thus, our data demonstrate an important role for TLR9 in host defense against N. meningitidis.


The effect of SARS-CoV-2 on the development of Parkinson's disease: the role of α-synuclein.
The current coronavirus disease 2019 (COVID-19) can lead to various neurological complications in infected people. These neurological effects include problems in both central nervous system (CNS) and peripheral nervous system (PNS). Hyposmia, a PNS symptom of COVID-19, frequently manifests in the early stages of Parkinson's disease (PD) and serves as an early warning sign of the condition. In addition, the olfactory system is recognized as an early site for the onset of α-synuclein pathology, the pathological hallmark of PD. PD is characterized by accumulation and aggregation of misfolded α-synuclein (α-Syn) into Lewy bodies and Lewy neurites, resulting in the degeneration of dopaminergic neurons in substantia nigra pars compacta (SNpc). Previous research has also shown the involvement of α-Syn in the innate immune response following viral infections. Consequently, the potential link between viral infections and development of PD has gained attention in recent years. However, it's still too early to definitively conclude whether COVID-19 can cause Parkinsonism. Nevertheless, we can explore the likelihood of this connection by examining past studies and possible mechanisms to better understand how COVID-19 might potentially lead to PD following the infection. Based on the various pieces of evidence discussed in this review, we can infer that SARS-CoV-2 promotes the aggregation of α-Syn and, ultimately, leads to PD through at least two mechanisms: the stable binding of the S1 protein to proteins prone to aggregation like α-Syn, and the upregulation of α-Syn as part of the immune response to the infection.


Shifts in comparative advantages for maize, oat and wheat cropping under climate change in Europe.
Climate change is anticipated to affect European agriculture, including the risk of emerging or re-emerging feed and food hazards. Indirectly, climate change may influence such hazards (e.g. the occurrence of mycotoxins) due to geographic shifts in the distribution of major cereal cropping systems and the consequences this may have for crop rotations. This paper analyses the impact of climate on cropping shares of maize, oat and wheat on a 50-km square grid across Europe (45-65°N) and provides model-based estimates of the changes in cropping shares in response to changes in temperature and precipitation as projected for the time period around 2040 by two regional climate models (RCM) with a moderate and a strong climate change signal, respectively. The projected cropping shares are based on the output from the two RCMs and on algorithms derived for the relation between meteorological data and observed cropping shares of maize, oat and wheat. The observed cropping shares show a south-to-north gradient, where maize had its maximum at 45-55°N, oat had its maximum at 55-65°N, and wheat was more evenly distributed along the latitudes in Europe. Under the projected climate changes, there was a general increase in maize cropping shares, whereas for oat no areas showed distinct increases. For wheat, the projected changes indicated a tendency towards higher cropping shares in the northern parts and lower cropping shares in the southern parts of the study area. The present modelling approach represents a simplification of factors determining the distribution of cereal crops, and also some uncertainties in the data basis were apparent. A promising way of future model improvement could be through a systematic analysis and inclusion of other variables, such as key soil properties and socio-economic conditions, influencing the comparative advantages of specific crops.


Hairy cell leukemia 2018: Update on diagnosis, risk-stratification, and treatment.
Hairy cell leukemia (HCL) and HCL-like disorders, including HCL variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL), are a very heterogeneous group of mature lymphoid B-cell disorders, characterized by the identification of hairy cells, a specific genetic profile, a different clinical course and the need for appropriate treatment. Diagnosis of HCL is based on morphological evidence of hairy cells, an HCL immunologic score of 3 or 4 based on the CD11C, CD103, CD123, and CD25 expression, the trephine biopsy which makes it possible to specify the degree of tumoral medullary infiltration and the presence of BRAF V600E somatic mutation. Progression of patients with HCL is based on a large splenomegaly, leukocytosis, a high number of hairy cells in the peripheral blood and the immunoglobulin heavy chain variable region gene mutational status. VH4-34 positive HCL cases are associated with poor prognosis RISK ADAPTED THERAPY: Purine analogs (PNA) are indicated in symptomatic first line HCL patients. The use of PNA followed by rituximab represents an alternative option. It is based on the use of BRAF inhibitors associated or not with MEK inhibitors, recombinant immunoconjugates targeting CD22 or BCR inhibitors.


An essential non-Watson-Crick base pair motif in 3'UTR to mediate selenoprotein translation.
The SECIS element is an RNA hairpin in the 3'UTR of selenoprotein mRNAs required for decoding UGA selenocysteine codons. Our experimentally derived 2D structure model for the SECIS RNA revealed the conservation of four consecutive non-Watson-Crick base pairs, with a central G.A/A.G tandem. The present study was dedicated to gaining insight into the role of this quartet of base pairs. The effects of mutations introduced into the SECIS quartet of the glutathione peroxidase (GPx) cDNA, an enzyme with selenocysteine in its active center, were reported in vivo by the GPx activity. The detrimental consequence of an all-Watson-Crick mutant quartet disclosed the paramount importance of the non-Watson-Crick base pairs for GPx activity. Next, structure probing established that base pair changes in the central G.A/A.G tandem, predicted by the model to be structurally unfavorable, effectively led to local opening of the helix at the quartet. A concomitant abolition of GPx activity was observed, arising from translational impairment of full-length GPx. In contrast, an isosteric base pair replacement in the tandem did not affect base pairing in the quartet, leading to an almost wt GPx activity. Collectively, the data provided conclusive evidence for the functional relevance of these non-Watson-Crick base pairs in vivo, thus identifying a noncanonical RNA motif crucial to SECIS function in mediating selenoprotein translation. Within the quartet, the prominent requirement for the central G.A/A.G tandem is highlighted, our previous structural model and the mutagenesis data presented here strongly arguing in favor of a sheared arrangement for the G.A base pairs. The SECIS RNA is therefore another member to be added to the growing list of RNAs containing building blocks of non-Watson-Crick base pairs, required for structure and/or function.


Moxifloxacin releasing intraocular implant based on a cross-linked hyaluronic acid membrane.
Intraocular antibiotic delivery is an important technique to prevent bacterial infection after ophthalmic surgery, such as cataract surgery. Conventional drug delivery methods, such as antibiotic eye drops, have limitations for intraocular drug delivery due to the intrinsic barrier effect of the cornea. Therefore, frequent instillation of antibiotic eyedrops is necessary to reach a sufficient bactericidal concentration inside the eye. In this study, an intraocular implant, MXF-HA, that combines hyaluronic acid (HA) and moxifloxacin (MXF) was developed to increase the efficiency of intraocular drug delivery after surgery. MXF-HA is manufactured as a thin, transparent, yellow-tinted membrane. When inserted into the eye in a dry state, MXF-HA is naturally hydrated and settles in the eye, and the MXF contained therein is delivered by hydrolysis of the polymer over time. It was confirmed through in vivo experiments that MXF delivery was maintained in the anterior chamber of the eye at a concentration sufficient to inhibit Pseudomonas aeruginosa and Staphylococcus aureus for more than 5 days after implantation. These results suggest that MXF-HA can be utilized as a potential drug delivery method for the prevention and treatment of bacterial infections after ophthalmic surgery.


Physical activity classification with dynamic discriminative methods.
A person's physical activity has important health implications, so it is important to be able to measure aspects of physical activity objectively. One approach to doing that is to use data from an accelerometer to classify physical activity according to activity type (e.g., lying down, sitting, standing, or walking) or intensity (e.g., sedentary, light, moderate, or vigorous). This can be formulated as a labeled classification problem, where the model relates a feature vector summarizing the accelerometer signal in a window of time to the activity type or intensity in that window. These data exhibit two key characteristics: (1) the activity classes in different time windows are not independent, and (2) the accelerometer features have moderately high dimension and follow complex distributions. Through a simulation study and applications to three datasets, we demonstrate that a model's classification performance is related to how it addresses these aspects of the data. Dynamic methods that account for temporal dependence achieve better performance than static methods that do not. Generative methods that explicitly model the distribution of the accelerometer signal features do not perform as well as methods that take a discriminative approach to establishing the relationship between the accelerometer signal and the activity class. Specifically, Conditional Random Fields consistently have better performance than commonly employed methods that ignore temporal dependence or attempt to model the accelerometer features.


MCLENA-1: A Phase II Clinical Trial for the Assessment of Safety, Tolerability, and Efficacy of Lenalidomide in Patients with Mild Cognitive Impairment Due to Alzheimer's Disease.
With the general population reaching higher ages, a surge in Alzheimer's disease (AD) incidence will happen in the coming decades, putting a heavy burden on families and healthcare systems Worldwide. This emphasizes the pressing need for AD therapeutic interventions. Accumulating evidence indicates that inflammation is prominent both in the blood and central nervous system of AD sufferers. These data suggest that systemic inflammation plays a crucial role in the cause and effects of AD neuropathology. Capitalizing on our experience from a previous clinical trial with thalidomide, we hypothesize that modulating inflammation via the pleiotropic immunomodulator lenalidomide may alter AD if administered during a proper time window in the course of the disease. Thus, in this Phase II, proof-of mechanism study, 30 amnestic mild cognitive impairment (aMCI) subjects will be treated with lenalidomide at 10 mg/day for 12 months on a 1:1 ratio, followed by a 6 months washout period. The primary objective of this study is to investigate the effect of lenalidomide on cognition, which is assessed at regular intervals. The secondary objective is to assess the safety and tolerability of lenalidomide in aMCI patients evaluated through adverse events, vital signs, clinical biochemistry, and physical and neurological examinations. Tertiary objectives are to analyze the effects of lenalidomide on brain amyloid loads (Florbetapir PET imaging) and neurodegeneration (volumetric MRI) by comparing pre- and post-dosing data. Finally, exploratory objectives will investigate whether blood inflammatory markers can serve as surrogate markers of therapeutic efficacy. Our study should determine whether lenalidomide is safe in AD subjects and whether it can alter the clinical progression of AD when administered before dementia onset. If effective, lenalidomide would become the first drug capable of delaying the trajectory of AD, which could lead the way to find additional, less toxic treatments in the near future.


Development and Evaluation of Nutrition Screening Tool in Patients with Hepatitis B-Related Cirrhosis: A Cross-Sectional Study.
Malnutrition is common in cirrhotic patients; however, there is no gold standard for nutritional assessment for this population. The aim of this study was to develop a novel nutritional screening tool based on objective indicators for cirrhotic patients chronically infected with hepatitis B virus (HBV). This was a cross-sectional study. Patients with hepatitis B-related cirrhosis were recruited. Malnutrition was diagnosed by the presence of any of the following conditions: Nutrition Risk Screening 2002 score greater than 3 points, Subjective Global Assessment grade B or C, and body mass index (BMI) <18.5 kg/m2. Nomogram model and decision tree model were developed, and the area under the receiver operating characteristic curve (AUROC) was compared. Among the 231 studied cases, 92 (39%) were malnourished. Malnourished patients had significantly lower serum albumin, BMI and hand grip strength levels, but higher serum creatinine level and Child-Pugh grade. Two models were developed based on these variables. The nomogram model had a sensitivity of 0.696, a specificity of 0.820 and an accuracy of 0.813. The AUROC of nomogram model was 0.813 (95% CI: 0.758-0.869, p <0.001). For the decision tree model, the sensitivity, specificity and accuracy are 0.761, 0.885 and 0.886, respectively, with an AUROC of 0.886 (95% CI: 0842-0.930, p <0.001). The difference in AUROC between these two models was not statistically significant (p <0.001). The nomogram model and decision tree model developed in this study may aid assessing nutritional status for cirrhotic patients with HBV.


[Benefits of early nephrological management in chronic renal failure].
We evaluated whether early nephrological referral of patients with chronic renal failure (CRF) resulted in improved condition of patients at initiation of maintenance dialysis and in better outcome on dialysis. We prospectively recorded clinical status, laboratory parameters, length of hospital stay and outcome of 900 CRF patients who started maintenance dialysis at Necker hospital between January 1989 and December 1996. We compared patients who benefited regular nephrological follow-up, and patients who were referred in emergency conditions at the ultimate stage of CRF. Among the 900 patients, 731 (81.2%) had regular nephrological follow-up, including 632 (70.2%, group IA) with optimal preparation to dialysis and 99 (11%, group IB) whose clinical course was complicated due to heavy comorbidity, whereas 169 (18.8%, group II) had no previous nephrological management. Over the 8-year observation period, the proportion of the latter group did not decrease. Late referred patients had higher blood pressure level, more frequent fluid overload, higher serum levels of urea, creatinine, uric acid and phosphate, and lower levels of bicarbonate, calcium, albumin and creatinine clearance that did well-prepared patients. Mean (+/- SD) hospital stay was 29.7 +/- 15.8 days in the former compared to only 4.8 +/- 3.3 days (p < 0.001) in the latter. Early deaths within 3 months of dialysis initiation were more frequent (7.1 vs 1.6%, p < 0.05) and less patients subsequently were able to be treated out-center (20.1 vs 40.7%, p < 0.05) in group II than in group IA. The overcost induced by late referral may be estimated at 0.25 million French francs per patient. An unjustified late nephrological referral of CRF patients still is observed in nearly 20% of cases. Such late referral is detrimental to both patients in terms of altered quality of life and long hospital stay, and to the collectivity due to heavy overcost. Closer cooperation between family physicians and nephrologists is needed to provide optimal management and allow timely preparation to maintenance dialysis of CRF patients.


A novel approach of fabricating monodispersed spherical MoSiBTiC particles for additive manufacturing.
It is very challenging to fabricate spherical refractory material powders for additive manufacturing (AM) because of their high melting points and complex compositions. In this study, a novel technique, freeze-dry pulsated orifice ejection method (FD-POEM), was developed to fabricate spherical MoSiBTiC particles without a melting process. Elemental nanopowders were dispersed in water to prepare a high-concentration slurry, which was subsequently extruded from an orifice by diaphragm vibration and frozen instantly in liquid nitrogen. After a freeze-drying process, spherical composite particles with arbitrary composition ratios were obtained. The FD-POEM particles had a narrow size range and uniform elemental distribution. Mesh structures were formed within the FD-POEM particles, which was attributed to the sublimation of ice crystals. Furthermore, owing to their spherical morphology, the FD-POEM particles had a low avalanche angle of 42.6°, exhibiting good flowability. Consequently, the combination of FD-POEM and additive manufacturing has great potential for developing complex refractory components used in industrial applications.


Presence of Angiostrongylus costaricensis Morera and Céspedes 1971 in Colombia.
Angiostrongylus costaricensis, producing abdominal angiostrongyliasis, is known to occur in humans and/or rodents in the Western Hemisphere, namely in the U.S.A. (Texas), Mexico, Honduras, El Salvador, Costa Rica, Panama, Venezuela, and Brazil, Rats, Oryzomys caliginosus, in Colombia were found to harbor the parasite. First-stage larvae from one of these rats developed to third-stage larvae in the slug Veronicella occidentalis, also from Colombia.


[Steadily changing food consumption of Danes. Clear trends during the period 1995-2001].
The aim of the study was to describe trends in food habits in Denmark derived from a food frequency survey conducted by the Danish Nutrition Council in 2001 and compare it to similar surveys from 1995 and 1998. A random population sample of 1000 men and women (aged 15-91 years) were interviewed by telephone. They were asked 13 food frequency questions about nutritionally important foods (yoghurt, milk, cheese, rye bread, wheat bread, sandwiches with fish, fish as the main meal, meat as the main meal, potatoes, rice/pasta, vegetables (two questions) fruit) and about the type of milk and fat spreads most often used. Several of the changes seen from 1995 to 1998 had continued into the 1998-2001 period. The results showed increased frequencies for shredded salad/raw vegetables and rice/pasta, but reduced frequencies for meat as the main meal and potatoes. Fruit consumption had also increased between 1998 and 2001. Average frequencies differed by 13-28%. Another pronounced trend was the increased use of low-fat milk (< or = 0.5% fat) instead of whole milk (42% drinking low-fat milk in 2001 versus 28% in 1998) and the greater numbers who did not spread any kind of fat on their bread (40% versus 22% in 1995, for rye bread). In general the observed trends point in the right direction in respect of food-based dietary guidelines and other recommendations. This indicates that the Danish population has been influenced by the nutritional messages and campaigns stressing fat reduction and increased intake of fruit and vegetables. An important factor in this context is the increasing availability of low-fat milk products on the Danish market. Whether or not the positive trends for foods included are supported by the rest of the diet remains to be answered.


Phosphotransferase-mediated regulation of carbohydrate utilization in Escherichia coli K12: location of the gsr (tgs) and iex (crr) genes by specialized transduction.
A lysogen of Escherichia coli K12 with lambda cI857 S7 xis6 nin5 b515 b519 integrated into ptsI was induced and the lysates plated on a Pel- host [on which lambda strains with less than the wild-type amount of DNA form plaques at low frequency (Cameron et al., 1977)]. All of the 40 plaques examined contained phage able to transduce at least two of the genes known from bacteriophage P1 transduction experiments to be closely linked to ptsI. Assuming that each specialized transducing phage arose by a single illegitimate recombination event, the distribution of phage types showed that the gene order is cysA gsr ptsI (ptsH, iex) cysZ lig; both gsr+ and iex+ were dominant. Analysis of restriction endonuclease digests of the transducing phage confirmed that no unexpected DNA rearrangements had taken place and allowed the construction of a map of the sites of action of the restriction endonucleases EcoRI, HindIII, BamI and Kpn for over 20 kilobases of E. coli DNA. In an Appendix, we show cysA and cysZ mutants to be deficient in sulphate assimilation.


The paralogues MAGOH and MAGOHB are oncogenic factors in high-grade gliomas and safeguard the splicing of cell division and cell cycle genes.
The exon junction complex (EJC) plays key roles throughout the lifespan of RNA and is particularly relevant in the nervous system. We investigated the roles of two EJC members, the paralogs MAGOH and MAGOHB, with respect to brain tumour development. High MAGOH/MAGOHB expression was observed in 14 tumour types; glioblastoma (GBM) showed the greatest difference compared to normal tissue. Increased MAGOH/MAGOHB expression was associated with poor prognosis in glioma patients, while knockdown of MAGOH/MAGOHB affected different cancer phenotypes. Reduced MAGOH/MAGOHB expression in GBM cells caused alterations in the splicing profile, including re-splicing and skipping of multiple exons. The binding profiles of EJC proteins indicated that exons affected by MAGOH/MAGOHB knockdown accumulated fewer complexes on average, providing a possible explanation for their sensitivity to MAGOH/MAGOHB knockdown. Transcripts (genes) showing alterations in the splicing profile are mainly implicated in cell division, cell cycle, splicing, and translation. We propose that high MAGOH/MAGOHB levels are required to safeguard the splicing of genes in high demand in scenarios requiring increased cell proliferation (brain development and GBM growth), ensuring efficient cell division, cell cycle regulation, and gene expression (splicing and translation). Since differentiated neuronal cells do not require increased MAGOH/MAGOHB expression, targeting these paralogs is a potential option for treating GBM.


IL6 and IL10 are genetic susceptibility factors of periodontal disease.
Periodontitis is a disease mainly caused by a chronic infection of tissues that support the teeth. Several factors, such as diabetes, smoking and oral care, as well as genetic susceptibility can influence both the risk to develop periodontitis and its progression. The aim of the investigation was to test whether alleles of candidate genes were associated with periodontitis. A case control study was performed with a cohort of 184 patients with chronic periodontitis and 231 healthy controls from the Italian population. A total of six single nucleotide polymorphisms from five candidate genes, i.e., IL1A, IL1B, IL6, IL10 and vitamin D receptor, were investigated. Evidence of association were obtained for rs1800795 mapping in IL6 (P value = 0.01) as well as for the rs1800872 mapping in IL10 (P = 0.04). The rarer variant allele lowered the risk to develop periodontitis at IL6 (Odds Ratio [OR] = 0.69 [95% confidence interval {CI} 0.51-0.93]) and increased the risk at IL10 (OR = 1.38 [95% CI 1.01-1.86]). The present investigation indicated that polymorphisms of IL6 and IL10 constitute risk factors for chronic periodontitis, while there was no evidence implicating a specific IL1A or IL1B genotype.


Transformation and tumorigenic properties of a mutant polyomavirus containing a middle T antigen defective in Shc binding.
Polyomavirus middle T antigen is phosphorylated on several tyrosine residues which act as binding sites for cellular proteins, including phosphatidylinositol 3-kinase, Shc, and phospholipase C-gamma. In this report we describe the transforming properties and tumor-inducing ability of a polyomavirus that contains a single-site mutation in middle T antigen which changes a tyrosine residue at amino acid position 250 to serine. This mutation disrupts the association of middle T with the transforming protein Shc. The mutant virus is weakly transforming, inducing foci which are smaller and of different morphology than those of the wild type. Although the virus induced tumors in close to 100% of inoculated mice, the spectrum of tumors and their morphology were altered compared to those of wild-type virus. The mutant virus induced a reduced frequency of kidney and thymic tumors. Both the mammary gland and the thymic tumors that were induced were histologically distinct from those induced by wild-type polyomavirus. These results demonstrate that the signal transduction pathway that is deregulated by the middle T-Shc association is important for full transformation of cells in culture and for tumor induction in some target tissues in the mouse-polyomavirus system.


Integrating Genomics Into Clinical Pediatric Oncology Using the Molecular Tumor Board at the Memorial Sloan Kettering Cancer Center.
Pediatric oncologists have begun to leverage tumor genetic profiling to match patients with targeted therapies. At the Memorial Sloan Kettering Cancer Center (MSKCC), we developed the Pediatric Molecular Tumor Board (PMTB) to track, integrate, and interpret clinical genomic profiling and potential targeted therapeutic recommendations. This retrospective case series includes all patients reviewed by the MSKCC PMTB from July 2014 to June 2015. Cases were submitted by treating oncologists and potential treatment recommendations were based upon the modified guidelines of the Oxford Centre for Evidence-Based Medicine. There were 41 presentations of 39 individual patients during the study period. Gliomas, acute myeloid leukemia, and neuroblastoma were the most commonly reviewed cases. Thirty nine (87%) of the 45 molecular sequencing profiles utilized hybrid-capture targeted genome sequencing. In 30 (73%) of the 41 presentations, the PMTB provided therapeutic recommendations, of which 19 (46%) were implemented. Twenty-one (70%) of the recommendations involved targeted therapies. Three (14%) targeted therapy recommendations had published evidence to support the proposed recommendations (evidence levels 1-2), eight (36%) recommendations had preclinical evidence (level 3), and 11 (50%) recommendations were based upon hypothetical biological rationales (level 4). The MSKCC PMTB enabled a clinically relevant interpretation of genomic profiling. Effective use of clinical genomics is anticipated to require new and improved tools to ascribe pathogenic significance and therapeutic actionability. The development of specific rule-driven clinical protocols will be needed for the incorporation and evaluation of genomic and molecular profiling in interventional prospective clinical trials.


[A cost-effectiveness study of hepatic venous pressure gradient measurement in the secondary prevention of variceal bleeding].
variceal rebleeding is common following a first episode of hemorrhage in cirrhotic patients. The objective of this study was to determine the cost-effectiveness of monitoring hepatic venous pressure gradient (HVPG) to guide secondary prophylaxis. we created a Markov decision model to calculate cost-effectiveness for two strategies: Group 1: HVPG monitoring to decide treatment -when portal pressure was reduced by at least 20 percent or HVPG was less than 12 mmHg after beta-blocker administration, patients received beta-blockers; when portal pressure did not meet these criteria therapy was endoscopic band ligation. Group 2: in this group there was no monitoring of HVPG. Patients with large varices received treatment with beta-blockers combined with EBL; patients with small varices received beta-blockers plus isosorbide mononitrate. there was no recurrent variceal bleeding in group 1 for good responders, and for 17% of poor responders. In group 2 a 25% rebleeding rate was detected in patients with small varices and 13% for those with big varices. Overall cost in group 1 was 14,100.49 euros, and 14,677.16 in group 2. HVPG measurement is cost-effective for the secondary prophylaxis of variceal bleeding.


Metabolism of properdin in normal subjects and patients with renal disease.
Properdin deposition has been recognized in glomeruli of patients with acute and chronic nephritis and lupus nephritis, and low serum properdin levels have been found in these disorders. These findings suggest that properdin may be involved in the production of glomerular damage and that low properdin levels may be due to hypercatabolism. The study was designed to examine the metabolism of properdin in normal subjects and to look for an abnormality in five patients with systemic lupus erythematosus with renal involvement and in six patients with membranoproliferative glomerulonephritis or dense deposit disease (MPGN). Highly purified human properdin was prepared by elution from zymosan, followed by DEAE-cellulose and carboxymethyl-Sephadex chromatography, and labeled with 125I by the iodine monochloride method. Parameters of metabolism were determined by monitoring plasma and urinary radioactivity at frequent intervals after the intravenous injection of 1-2 muCi of labeled material. The fractional catabolic rate (FCR) of properdin in normal subjects was found to have a very narrow range of 0.78-1.0,% of the plasma pool per hour (mean 0.95%). In systemic lupus erythematosus, the FCR was regularly elevated with a range of 1.21-2.30% (mean 1.70%). In MPGN, FCR was elevated in three patients (1.22, 1.94, and 2.08%) and within or below the normal range in three (0.78, 1.00, and 1.00%). Properdin levels were reduced in two patients who had the highest FCR's noted in the study. Properdin synthetic rates in normals varied from 4.1 to 14.3 mug/kg per h (mean 9.1) and was not found to be reduced in any patient. Properdin catabolism was found to be normal in a patient deficient in the C3b inactivator. These studies show that properdin is hypercatabolized in patients with renal disease and that decreased properdin levels when they occur in these patients can be entirely explained on the basis of this hypercatabolism.


Microalbuminuria prevalence study in hypertensive patients with type 2 diabetes mellitus in Singapore.
Microalbuminuria is a marker of increased cardiovascular morbidity and mortality. It represents the earliest clinical evidence of diabetic nephropathy. Its early detection allows for implementation of individually-tailored cardiovascular risk reduction management programmes. Despite this, information on the prevalence of microalbuminuria in hypertensive patients with type 2 diabetes mellitus in Singapore is limited. The Microalbuminuria Prevalence Study (MAPS) assessed the prevalence of macroalbuminuria and microalbuminuria in consecutively-screened hypertensive adult patients with type 2 diabetes mellitus in ten Asian countries. This paper presents the results of a sub-analysis of data from patients in Singapore. Singapore contributed seven percent of the overall enrolment into MAPS; a total of 499 patients were enrolled and 388 constituted the per-protocol population (patients with bacteriuria and haematuria were excluded). Overall, the prevalence of diabetic kidney disease was high. In our study population, 23.5 percent of patients had macroalbuminuria (95 percent confidence interval [CI] 21.3-25.6), and 48.5 percent of patients had microalbuminuria (95 percent CI 45.9-51.0). Only 28.1 percent (95 percent CI 25.8-30.4) of patients were normoalbuminuric. Associated factors were poor glycaemic control and poor blood pressure control. The high prevalence (72 percent) of microalbuminuria and macroalbuminuria found in hypertensive patients with type 2 diabetes mellitus in Singapore is a cause for concern. These findings highlight the need to screen for microalbuminuria and better manage hypertensive patients with type 2 diabetes mellitus, if we are to avoid a major increase in end-stage renal disease.


Direct Three-Dimensional Shape Measurement by Digital Light-in-Flight Holography.
A method for direct shape measurement with short laser light pulses and digital holography with a CCD array is proposed. An in-line holographic setup is used in which the reference beam is reflected from a blazed reflection grating, i.e., a Littrow setup. By this method a relatively large optical delay is created between the reference and the object beams even with a small object-reference angle, which is necessary because of the limited resolution of the CCD. The delay varies continuously across one axis of the CCD array. In this way different object sections are reconstructed from different parts of the CCD, which in turn correspond to a certain path length from the object. By putting the sections together, one can evaluate the three-dimensional shape. Theoretical as well as experimental results are presented.


Cell-free miR-17-5p as a diagnostic biomarker for gastric cancer inhibits dendritic cell maturation.
Gastric cancer (GC) patients display aberrant miRNA expression and defective dendritic cell function. However, the role of cancer cell-derived oncomiR in GC detection and dendritic cell (DC) maturation remains largely elusive. Candidate miRNAs were selected by deep sequencing (8 GC plasma samples vs 8 control plasma samples; 8 GC tissues vs 8 adjacent normal gastric tissues) and confirmed by PCR with 164 plasma samples and 72 formalin-fixed paraffin-embedded GC tissue samples. Their diagnostic performance was evaluated by receiver operating characteristic curve. Cy3 fluorescence signals in DCs, exposed to conditioned medium obtained from BGC-823 cells pre-transfected with Cy3-miR-17-5p, were determined by flow cytometry and visualized by confocal microscopy. Functional and phenotypical alterations of DCs were assayed when DCs were transfected with miR-17-5p in vitro. Deep sequencing and RT-PCR confirmed that five shared miRNAs were upregulated in plasma and tissue samples of GC patients. Cell-free miR-17-5p was superior to others in GC detection with an area under the curve of 0.82, and correlated with lymphatic metastasis and poor overall survival. GC cell-shuttled miR-17-5p can be delivered to immature DCs, and they significantly inhibited LPS-stimulated phenotypic maturation by diminishing the expression of maturation markers (MHC II, CD80 and CD86 molecules). In line with those alterations in the phenotypic markers, functional experiments demonstrated that miR-17-5p triggered an inhibitory effect on DCs endocytic activity and decreased tumor necrosis factor-α and IL-12 secretion, while enhancing IL-10 production. Mixed lymphocyte reaction showed that miR-17-5p inhibited the T cell stimulating effect of DCs and favored regulatory T cells expansion. GC cell-derived miR-17-5p is a potential biomarker for GC detection. Taken up by DCs, miR-17-5p weakened antitumor immune responses via inhibiting the maturation of dendritic cells.


Provider perspectives on demand creation for maternal vaccines in Kenya.
Background . Expansion of maternal immunization, which offers some of the most effective protection against morbidity and mortality in pregnant women and neonates, requires broad acceptance by healthcare providers and their patients. We aimed to describe issues surrounding acceptance and demand creation for maternal vaccines in Kenya from a provider perspective. Methods . Nurses and clinical officers were recruited for semi-structured interviews covering resources for vaccine delivery, patient education, knowledge and attitudes surrounding maternal vaccines, and opportunities for demand creation for new vaccines. Interviews were conducted in English and Swahili, transcribed verbatim from audio recordings, and analyzed using codes developed from interview guide questions and emergent themes. Results . Providers expressed favorable attitudes about currently available maternal immunizations and introduction of additional vaccines, viewing themselves as primarily responsible for vaccine promotion and patient education. The importance of educational resources for both patients and providers to maintain high levels of maternal immunization coverage was a common theme. Most identified barriers to vaccine acceptance and delivery were cultural and systematic in nature. Suggestions for improvement included improved patient and provider education, including material resources, and community engagement through religious and cultural leaders. Conclusions . The distribution of standardized, evidence-based print materials for patient education may reduce provider overwork and facilitate in-clinic efforts to inform women about maternal vaccines. Continuing education for providers should address communication surrounding current vaccines and those under consideration for introduction into routine schedules. Engagement of religious and community leaders, as well as male decision-makers in the household, will enhance future acceptance of maternal vaccines.


The interaction between smoking and Epstein-Barr virus as multiple sclerosis risk factors may depend on age.
The multiple sclerosis (MS) risk factors smoking and remote Epstein-Barr virus (EBV) infection have been suggested to interact statistically, but the results are conflicting. In a prospective study on 192 MS cases and 384 matched controls, we analysed levels of cotinine as a marker of smoke exposure, and Epstein-Barr Nuclear Antigen-1 antibody reactivity. We assessed interaction on the additive and multiplicative scales, and estimated the effects of the risk factors across strata of each other. The results suggest that a negative interaction may be present in samples drawn at a young age, and a positive interaction among older subjects.


Implementation of interdisciplinary neurosurgery morning huddle: cost-effectiveness and increased patient satisfaction.
OBJECTIVE Morning discharge huddles consist of multiple members of the inpatient care team and are used to improve communication and patient care and to facilitate patient flow through the hospital. However, the effect of huddles on hospital costs and patient satisfaction has not been clearly elucidated. The authors investigated how a neurosurgeryled interdisciplinary daily morning huddle affected various costs of patient care and patient satisfaction. METHODS Huddles were conducted at 8:30 am Monday through Friday, and lasted approximately 30 minutes. The authors retrospectively looked at the average monthly costs per patient for a variety of variables (e.g., average ICU days, average step-down days, average direct cost, average laboratory costs, average pharmacy costs, hospital ratings, and hospital recommendations) and compared the results from before and after implementation of the huddle. RESULTS There was a significant decrease in the number of ICU days, average laboratory costs, and average pharmacy costs per patient after the huddle was implemented; decreased laboratory and pharmacy costs produced $1,408,047.66 in savings. There was no significant difference found for the average direct cost. The percentage of patients who rated the hospital as a 9 or 10 significantly increased. The percentage who answered "strongly agree" when asked whether they would recommend the hospital also significantly increased. CONCLUSIONS A short morning huddle consisting of key members of the inpatient team may result in substantial hospital savings derived from reduced ICU days and laboratory and pharmacy costs as well as increased patient satisfaction.


[Drug interactions between coumarin derivatives and antimycotics: also with topical antifungal agents].
The imidazole derivative miconazole is often used to treat fungal infections of the skin, mouth and gastrointestinal tract. Used concomitantly with coumarin derivatives, it may enhance their anticoagulant effects by inhibiting the CYP2C9 isoenzyme; an interaction which has been well described for oral and vaginal administrations of miconazole. In daily practice, however, cutaneous formulations can also cause clinically relevant drug interactions after having been absorbed through the skin. We describe 4 patients in whom topically applied miconazole enhanced the effect of coumarin derivatives. These cases concern reports received by the Netherlands Pharmacovigilance Centre Lareb between April 2001 and April 2012.


Changes in BMI before and during economic development and subsequent risk of cardiovascular disease and total mortality: a 35-year follow-up study in China.
It is unclear whether changes in BMI during rapid economic development influence subsequent mortality. We analyzed whether BMI in 1976 and 1994 and changes in BMI during 1976-1994 predict cardiovascular disease (CVD) and all-cause mortality in a 35-year follow-up cohort of 1,696 Chinese (1,124 men and 572 women, aged 35-65 years) in Xi'an, China. Participants were categorized as underweight (<18.5 kg/m(2)), normal weight (18.5-24.9 kg/m(2)), and overweight (≥25.0 kg/m(2)). During 51,611 person-years of follow-up, we identified 655 deaths from all causes and 234 from CVD. From 1976 to 1994, the prevalence of overweight rose from 9.2 to 27.8%. With each unit increment in 1976 BMI, multivariate hazard ratios (HRs) (95% CI) were 0.78 (0.72-0.84) for CVD and 0.91 (0.87-0.95) for all-cause mortality. In contrast, corresponding HRs were 1.14 (1.08-1.19) and 1.05 (1.01-1.08) in 1994 BMI. The HRs for each unit increment in BMI change from 1976 to 1994 were 1.35 (1.25-1.41) for CVD and 1.09 (1.05-1.13) for all-cause mortality. Compared with participants with stable normal weight in 1976 and 1994, HRs of all-cause mortality for those who had normal weight in 1976 but became overweight in 1994 and for those who were persistently overweight during 1976-1994 were 1.42 (1.12-1.80) and 1.80 (1.04-3.14), respectively. Gaining weight with increased BMI at middle age in Chinese during economic development was associated with elevated risks of all-cause and CVD mortality. Higher BMI measured before economic development was associated with lower mortality risk, whereas BMI measured afterward was associated with increased mortality.


Cortical Thinning and Cognitive Impairment in Parkinson's Disease without Dementia.
Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized clinically by motor dysfunction (bradykinesia, rigidity, tremor, and postural instability), and pathologically by the loss of dopaminergic neurons in the substantia nigra of the basal ganglia. Growing literature supports that cognitive deficits may also be present in PD, even in non-demented patients. Gray matter (GM) atrophy has been reported in PD and may be related to cognitive decline. This study investigated cortical thickness in non-demented PD subjects and elucidated its relationship to cognitive impairment using high-resolution T1-weighted brain MRI and comprehensive cognitive function scores from 71 non-demented PD and 48 control subjects matched for age, gender, and education. Cortical thickness was compared between groups using a flexible hierarchical multivariate Bayesian model, which accounts for correlations between brain regions. Correlation analyses were performed among brain areas and cognitive domains as well, which showed significant group differences in the PD population. Compared to Controls, PD subjects demonstrated significant age-adjusted cortical thinning predominantly in inferior and superior parietal areas and extended to superior frontal, superior temporal, and precuneus areas (posterior probability >0.9). Cortical thinning was also found in the left precentral and lateral occipital, and right postcentral, middle frontal, and fusiform regions (posterior probability >0.9). PD patients showed significantly reduced cognitive performance in executive function, including set shifting (p = 0.005) and spontaneous flexibility (p = 0.02), which were associated with the above cortical thinning regions (p < 0.05).


Detection of deleterious genotypes in multigenerational studies. I. Disruptions in individual Arabidopsis actin genes.
Plant actins are involved in numerous cytoskeletal processes effecting plant development, including cell division plane determination, cell elongation, and cell wall deposition. Arabidopsis thaliana has five ancient subclasses of actin with distinct patterns of spatial and temporal expression. To test their functional roles, we identified insertion mutants in three Arabidopsis actin genes, ACT2, ACT4, and ACT7, representing three subclasses. Adult plants homozygous for the act2-1, act4-1, and act7-1 mutant alleles appear to be robust, morphologically normal, and fully fertile. However, when grown as populations descended from a single heterozygous parent, all three mutant alleles were found at extremely low frequencies relative to the wild-type in the F2 generation. Thus, all three mutant alleles appear to be deleterious. The act2-1 mutant allele was found at normal frequencies in the F1, but at significantly lower frequencies than expected in the F2 and F3 generations. These data suggest that the homozygous act2-1/act2-1 mutant adult plants have a reduced fitness in the 2N sporophytic portion of the life cycle, consistent with the vegetative expression of ACT2. These data are interpreted in light of the extreme conservation of plant actin subclasses and genetic redundancy.


[A 70-year-old controversial discussion: spleen and gonad function in medical literature].
The development of a protein-free spleen-dialysate has led to a new discussion arguing about the old question as to whether there is a link between the spleen and the endocrine system. Experimental animal-trials demonstrate that the therapy with spleen dialysate is regarded superior to an adequate dose of gonadotropins. The present contradictory results in the field of spleen research cannot yet offer a valid model of the mechanisms how it works. The therapy with spleen-dialysate in various fields of indications demonstrates first remarkable results without any serious side-effects.


[Congenital forms of brachydactyly and dermatoglyphics].
Relative length and ridge count in dermatoglyphs of patients with various forms of brachydactyly were compared to those of the corresponding controls. In most cases of brachydactyly, fingers shortening was associated with the decreased ridge count, and only in two patients with brachydactyly D this relationship wasn't detected. It appears that brachydactyly may be due either to the abnormal positional information or disturbed function of certain growth factors responsible for the expression of inborn growth potential.


Public health interventions: reaching Latino adolescents via short message service and social media.
Adolescents are substantial users of short message service (SMS) and social media. The public health community now has more opportunities to reach this population with positive youth development and health messages through these media. Latinos are a growing and youthful population with significant health risks and needs. This population may benefit from SMS and social media health interventions. To examine (1) SMS and social media utilization and behavior among Latino youth, and (2) how SMS and social media can be effectively used as a component of public health interventions focused on decreasing sexual risk taking among Latino youth. A mixed-methods approach, using both quantitative survey data and qualitative interview data, was used to provide a robust understanding of SMS and social media use and behavior for public health interventions. We recruited 428 ninth and tenth grade, self-identifying Latino adolescents to participate in a quantitative survey. Additionally, we conducted five key informant interviews with staff and 15 youth. We found that 90.8% (355/391) of respondents had access to a mobile phone either through having their own or through borrowing or sharing one. Of those who had access to a mobile phone, 94.1% (334/355) used SMS, with 41.1% (113/275) sending and receiving more than 100 text messages per day. Of 395 respondents, 384 (97.2%) had at least one social media account, and the mean number of accounts was 3.0 (range 0-8). A total of 75.8% (291/384) of adolescents logged in to their account daily. Of those with a social media account, 89.1% (342/384) had a Facebook account. Youth who took the survey in English were significantly more likely than those who took it in Spanish to have access to a mobile phone (χ(2) (1 )= 5.3; 93.3% vs 86.3%; P = .02); to be high-volume texters (χ(2) (2 )= 16.8; 49.4% vs 25.3%; P < .001); to use the Internet daily (χ(2) (1 )= 5.0; 76.6% vs 66.0%; P = .03); to have a Facebook account (χ(2) (1 )= 9.9; 90.9% vs 79.7%; P = .002); and to have a greater mean number of social media accounts (t(387 )= 7.9; 3.41 vs 2.07; P < .001). SMS and social media are pervasive among Latino youth. Program staff and youth perceive these as credible and essential methods of communication in the context of public health programs. Public health interventions must continue to innovate and maximize new ways to reach young people to reinforce public health messages and education.


Discrepancy in perception of infertility and attitude towards treatment options: Indonesian urban and rural area.
In Indonesia infertility affects 10-15% of reproductive-age couples. In addition to medical problem, infertility in Indonesia poses significant social problem. Childlessness is often stigmatized as a failure which victimizes couples, moreover the females. Despite the high prevalence, there is no fertility awareness education which further passes down the common myth, misperception, and negative attitude towards infertility treatment in Indonesian society. This study aims to reveal the knowledge, myth, and attitude towards infertility, likewise acceptance towards infertility treatment options. Cross-sectional study using standardized questionnaire was done to 272 individuals consisted of two parallel groups: Jakarta and Sumba representing urban and rural population respectively. Participants were all outpatients above 18 years old who visited the healthcare centers from February 2017 to June 2017. Knowledge on biological and lifestyle risk factors of infertility among Jakarta and Sumba groups were comparable. However, belief in supernatural causes of infertility is remarkable in Sumba population. There is a common misconception on the use of contraception as risk factors of infertility in both groups. Half respondents from both groups think infertility is a disease. In Jakarta 93.4% respondents consider both female and male should be investigated for infertility; in Sumba only 55.4% agree while 33.1% consider only female should be investigated. Infertility is an acceptable reason for polygamy for 41.3% respondents in Sumba, with 34.7% blaming maternal side for childlessness. Most respondents from both groups accept the use of Assisted Reproductive Technology and fertility enhancing drugs as treatment options. Lack of understanding, misleading myths, and negative attitude towards infertility have been illustrated in the sample population.


Challenges and pragmatic solutions for assessing the reliability of HIV-1 viral load monitoring in resource-constrained settings.
HIV-1 RNA detection is the most reliable method for monitoring treatment response among people living with HIV (PLHIV). Effective quality control measures that include internal quality control (IQC) are challenging in resource-constrained settings. We ascertained the utility of the assay low positive control (LPC) as an effective internal quality control (IQC) to monitor the reliability of the HIV-1 viral load assay. Variations in LPC values were measured for 390 different runs over ten years (2011-2021) and compared to in-house IQC data using Levey-Jennings control chart. Overall, the Levey-Jennings analysis showed minimal variation (± 0.5 log) for both the LPC and IQC data. The mean LPC value for first 20 runs (20 days) was 2.91. The mean LPC value for the 390 runs comprising of 35 different lots, was 3.01± 0.1 log. Our decadal data reveals that Abbott real-time HIV-1 assay (Abbott Molecular Inc., IL, USA) LPC exhibited no significant biological variation over 390 runs distributed over ten years. Hence, assay LPC can supplant the IQC for monitoring assay trends as a stable and commutable material in resource-constrained settings.


Perceived fatigue and energy are independent unipolar states: Supporting evidence.
Persistent fatigue is a common problem (∼20-45% of U.S. population), with higher prevalence and severity in people with medical conditions such as cancer, depression, fibromyalgia, heart failure, sleep apnea and multiple sclerosis. There are few FDA-approved treatments for fatigue and great disagreement on how to measure fatigue, with over 250 instruments used in research. Many instruments define fatigue as "a lack of energy", thus viewing energy and fatigue states as opposites on a single bipolar continuum. In this paper, we hypothesize that energy and fatigue are distinct perceptual states, should be measured using separate unipolar scales, have different mechanisms, and deficits should be treated using tailored therapies. Energy and fatigue independence has been found in both exploratory and confirmatory factor analysis studies. Experiments in various fields, including behavioral pharmacology and exercise science, often find changes in energy and not fatigue, or vice versa. If the hypothesis that energy and fatigue are independent is correct, there are likely different mechanisms that drive energy and fatigue changes. Energy could be increased by elevated dopamine and norepinephrine transmission and binding. Fatigue could be increased by elevated brain serotonin and inflammatory cytokines and reduced histamine binding. The hypothesis could be tested by an experiment that attempts to produce simultaneously high ratings of energy and fatigue (such as with two drugs using a randomized, double-blind, placebo-controlled design), which would offer strong evidence against the common viewpoint of a bipolar continuum. If the hypothesis is correct, prior literature using bipolar instruments will be limited, and research on the prevalence, mechanisms, and treatment of low energy and elevated fatigue as separate conditions will be needed. In the immediate future, measuring both energy and fatigue using unipolar measurement tools may improve our understanding of these states and improve therapeutic outcomes.


When Culture Matters: Using Compliments and Complaints to Define and Influence Chinese Patients' Satisfaction.
Despite patients' cultural background influencing their satisfaction with medical care the majority of studies draw on assumptions and models from the Western world. We move attention to the East Asian world by investigating the attributes of Chinese patients' satisfaction with their hospital in-patient care. Our research design is an exploratory qualitative study of 577 incidents of Chinese hospital in-patients' complaints and compliments. The data were drawn from a sample of reports of patients' satisfaction with their care in a district general hospital over a five-year period. Analysis focused on satisfactory and dissatisfactory events to derive attributes involved. We find patients in Chinese culture evaluate satisfaction with their care using eight attributes: professionalism, efficiency, chīn-chièh, respect, patience, responsibility, value and ethics. We explore how Chinese patients' values and beliefs toward medicine and care-giving construct distinct meanings around these attributes. By synthesizing our findings with those in the literature we propose generic attributes which can form the basis of measures of Chinese patient satisfaction and inform training in cultural competence.


Extracorporeal photopheresis as second-line treatment for acute graft-versus-host disease: impact on six-month freedom from treatment failure.
Second-line therapy for corticosteroid-refractory or -dependent acute graft-versus-host disease remains ill-defined, due to limited efficacy of drugs and evolving clinical trial endpoints. Six-month freedom from treatment failure has been proposed as a novel clinical trial endpoint and is defined by the absence of death, malignancy relapse/progression, or addition of a next line of systemic immunosuppressive therapy within 6 months of intervention and prior to diagnosis of chronic graft-versus-host disease. We analyzed the 6-month freedom from treatment failure endpoint in 128 patients enrolled from three centers who were treated with extracorporeal photopheresis as second-line therapy for acute graft-versus-host disease. The incidence of 6-month freedom from treatment failure was 77.3% with a 2-year survival rate of 56%. Corticosteroid dose or response status at onset of second-line therapy did not influence outcome. Higher grade of acute graft-versus-host disease (grade 2 versus grades 3-4) at onset of photopheresis predicted for poor outcome as measured by survival (hazard ratio 2.78, P<0.001), non-relapse mortality (hazard ratio 2.78, P=0.001) and 6-month freedom from treatment failure (hazard ratio 3.05, P<0.001). For the 91 patients who achieved 6-month freedom from treatment failure, 1-year, 2-year and 3-year survival rates were 78.9%, 70.8% and 69.5%, respectively. Six-month freedom from treatment failure is a reasonable early surrogate for outcome and should be considered as a clinical trial endpoint. This study demonstrates the durable effect of photopheresis as second-line therapy for corticosteroid-refractory or -dependent acute graft-versus-host disease using 6-month freedom from treatment failure as the primary endpoint.


Srsf1 and Elavl1 act antagonistically on neuronal fate choice in the developing neocortex by controlling TrkC receptor isoform expression.
The seat of higher-order cognitive abilities in mammals, the neocortex, is a complex structure, organized in several layers. The different subtypes of principal neurons are distributed in precise ratios and at specific positions in these layers and are generated by the same neural progenitor cells (NPCs), steered by a spatially and temporally specified combination of molecular cues that are incompletely understood. Recently, we discovered that an alternatively spliced isoform of the TrkC receptor lacking the kinase domain, TrkC-T1, is a determinant of the corticofugal projection neuron (CFuPN) fate. Here, we show that the finely tuned balance between TrkC-T1 and the better known, kinase domain-containing isoform, TrkC-TK+, is cell type-specific in the developing cortex and established through the antagonistic actions of two RNA-binding proteins, Srsf1 and Elavl1. Moreover, our data show that Srsf1 promotes the CFuPN fate and Elavl1 promotes the callosal projection neuron (CPN) fate in vivo via regulating the distinct ratios of TrkC-T1 to TrkC-TK+. Taken together, we connect spatio-temporal expression of Srsf1 and Elavl1 in the developing neocortex with the regulation of TrkC alternative splicing and transcript stability and neuronal fate choice, thus adding to the mechanistic and functional understanding of alternative splicing in vivo.


The positive effects of positive coping on mental health in college students during the COVID-19 campus lockdown.
Isolation has been an effective method to control the spread of COVID-19 over the past 3 years. However, lifestyle changes may have a negative impact on mental health. To examine the effects of positive coping on mental health in college students during the COVID-19 campus lockdown, this study conducted an online cross-sectional survey. In October 2022, following a prolonged campus lockdown of nearly 3 years, 313 university students from a university in Shandong Province, China, were invited to complete an online questionnaire. The questionnaire comprised a self-administered general situation questionnaire, the Simple Coping Style Scale, and the Hospital Depression and Anxiety Scale. (1) The analysis of variance revealed a significant main effect of coping Style on depression [F(4,300) = 2.446, p = 0.047] during the COVID-19 campus lockdown. A post-hoc test indicated that college students who engaged in study (p = 0.012) or sports (p = 0.027) during their free time had significantly lower depression scores than those who used the Internet. (2) Independent sample t-tests showed significant differences in positive and negative coping styles among college students in terms of depression (t = 6.891, p < 0.001) and anxiety scores (t = 7.745, p < 0.001). (3) Pearson correlation analysis demonstrated a negative correlation between positive coping style and anxiety (r = -0.378, p < 0.001), and between positive coping style and depression (r = 0.427, p < 0.001). Positive correlations were also found between the negative coping style and anxiety (r = 0.155, p = 0.007), and between the negative coping style and depression (r = 0.190, p < 0.001). The study suggested that fostering positive coping in students can mitigate mental health issues during crises, providing a blueprint for university mental health initiatives during epidemics.


Tissue sulfomucin and sialomucin content in colon mucosa without intestinal transit subjected to intervention with Curcuma longa (curcumin).
To measure the tissue sulfomucin and sialomucin content of the colon mucosa without fecal flow, subjected to intervention with curcumin, and the influence of the concentration used and the intervention time. Thirty-six rats were subjected to proximal right colostomy and distal mucous fistula. They were divided into two groups according to whether sacrifice was performed two or four weeks after the intervention. Each group was divided into three subgroups according to the enema applied daily: saline alone; curcumin at 50 mg/kg/day or curcumin at 200 mg/kg/day. Acid mucins were diagnosed using the Alcian blue technique. The mucin content was quantified by means of computer-assisted image analysis. The significance level of 5% was used throughout (p < 0.05). There were dose-related increases in the quantities of sulfomucins in the animals subjected to interventions with curcumin, both after two weeks (p < 0.00001) and after four weeks (p < 0.00001). There were increases in sialomucin quantity that were concentration-related (p < 0.00001) and time-related (p < 0.00001). Curcumin enemas increase the quantity of acid mucins in the intestinal flow in the excluded colon, with dose and time dependency.


The Significance of CXCL1 and CXCL8 as Well as Their Specific Receptors in Colorectal Cancer.
Every year, almost 2 million people develop colorectal cancer (CRC), which makes it the fourth most common malignancy worldwide. It is also estimated that approximately 48% of CRC patients will die from the disease. Thus, noninvasive and accurate methods for early detection and prevention of CRC are sorely needed. It is suggested that C-X-C motif ligand 1 (CXCL1) and C-X-C motif ligand 8 (CXCL8) as well as their cognate receptors can mediate tumor growth, proliferation, survival, neoangiogenesis and metastasis of malignant cells, including CRC. However, little is known about the clinical significance of these proteins as potential biomarkers for CRC. Therefore, in our review, we performed a comprehensive literature search using the PubMed database to identify original articles that investigated whether CXCL1 and CXCL8 and their receptors play a role in CRC pathogenesis. In summary, our review highlighted the potential significance of CXCL1/CXCR2 and CXCL8/CXCR1,-2 in the diagnosis and progression of CRC as well as indicated their potential therapeutic significance. However, given the non-specific nature of analyzed chemokines and a small number of studies concerning the assessment of blood concentration of these proteins in CRC patients, investigations need to be continued in the future before selected chemokines could be established as biomarkers for CRC.


Mucinous borderline ovarian tumor: a case report with diagnostic insights on ultrasound findings.
Borderline ovarian tumors represent about 10% of all epithelial ovarian cancers, but in contrast to epithelial ovarian cancers, they constitute a group of tumors with a much better prognosis. An assessment of clinical presentation, physical examination, radiological and biochemical findings is necessary to tailor management strategies for patients with ovarian tumors. The article, which is based on a case report, describes different approaches for preoperative diagnosis as well as discusses approaches that might bring some insights on tumor histology. Furthermore, it raises a question about which imaging techniques should be proposed for a reliable diagnosis of borderline ovarian tumors to ensure safe surgery planning.


Combination of quercetin and cisplatin enhances apoptosis in OSCC cells by downregulating xIAP through the NF-κB pathway.
While cisplatin is a first-line chemotherapeutic drug commonly used to treat patients with oral squamous cell carcinoma (OSCC), the cisplatin-resistance poses a major challenge for its clinical application. Recent studies have shown that quercetin, a natural flavonoid found in various plants and foods possesses an anti-cancer effect. The following study examined the combined effect of quercetin and cisplatin on OSCC apoptosis in vitro and in vivo (using a mice tumor model). We found that quercetin promotes cisplatin-induced apoptosis in human OSCC (cell lines Tca-8113 and SCC-15) by down-regulating NF-κB. Pretreatment of cancer cells with quercetin inhibited the phosphorylation Akt and IKKβ, and led to the suppression of NF-κB and anti-apoptotic protein xIAP. In addition, we observed that the pretreatment of cancer cells with quercetin improves extrinsic and intrinsic apoptosis by activating caspase-8 and caspase-9, respectively. Our in vivo data also indicated that the combination of quercetin and cisplatin may inhibit the xenograft growth in mice. To sum up, our results provide a new evidence for the application of quercetin and cisplatin in OSCC therapy.


Fluorescence lifetime distributions of diphenylhexatriene-labeled phosphatidylcholine as a tool for the study of phospholipid-cholesterol interactions.
Fluorescence lifetimes of 1-palmitoyl-2-diphenylhexatrienylpro-pionyl-phosphatidylc hol ine in vesicles of palmitoyloleoyl phosphatidylcholine (POPC) (1:300, mol/mol) in the liquid crystalline state were determined by multifrequency phase fluorometry. On the basis of statistic criteria (chi 2red) the measured phase angles and demodulation factors were equally well fitted to unimodal Lorentzian, Gaussian, or uniform lifetime distributions. No improvement in chi 2red could be observed if the experimental data were fitted to bimodal Lorentzian distributions or a double exponential decay. The unimodal Lorentzian lifetime distribution was characterized by a lifetime center of 6.87 ns and a full width at half maximum of 0.57 ns. Increasing amounts of cholesterol in the phospholipid vesicles (0-50 mol% relative to POPC) led to a slight increase of the lifetime center (7.58 ns at 50 mol% sterol) and reduced significantly the distributional width (0.14 ns at 50 mol% sterol). Lifetime distributions of POPC-cholesterol mixtures containing greater than 20 mol% sterol were within the resolution limit and could not be distinguished from monoexponential decays on the basis of chi 2red. Cholesterol stabilizes and rigidifies phospholipid bilayers in the fluid state. Considering its effect on lifetime distributions of fluorescent phospholipids it may also act as a membrane homogenizer.


Interleukin 3- receptor targeted exosomes inhibit in vitro and in vivo Chronic Myelogenous Leukemia cell growth.
Despite Imatinib (IM), a selective inhibitor of Bcr-Abl, having led to improved prognosis in Chronic Myeloid Leukemia (CML) patients, acquired resistance and long-term adverse effects is still being encountered. There is, therefore, urgent need to develop alternative strategies to overcome drug resistance. According to the molecules expressed on their surface, exosomes can target specific cells. Exosomes can also be loaded with a variety of molecules, thereby acting as a vehicle for the delivery of therapeutic agents. In this study, we engineered HEK293T cells to express the exosomal protein Lamp2b, fused to a fragment of Interleukin 3 (IL3). The IL3 receptor (IL3-R) is overexpressed in CML blasts compared to normal hematopoietic cells and thus is able to act as a receptor target in a cancer drug delivery system. Here we show that IL3L exosomes, loaded with Imatinib or with BCR-ABL siRNA, are able to target CML cells and inhibit in vitro and in vivo cancer cell growth.


Fusarium polycaprolactone depolymerase is cutinase.
Polycaprolactone (PCL), a synthetic polyester, is degraded by a variety of microorganisms, including some phytopathogens. Many phytopathogens secrete cutinase, a serine hydrolase that degrades cutin, the structural polymer of the plant cuticle. We compared wild-type strains and a cutinase-negative gene replacement mutant strain of Fusarium solani f. sp. pisi (D. J. Stahl and W. Schäfer, Plant Cell 4:621-629, 1992) and a wild-type strain of Fusarium moniliforme to show that Fusarium cutinase is a PCL depolymerase. The wild-type strains, but not the mutant strain, (i) degraded PCL and used it as a source of carbon and energy, (ii) showed induction of secreted PCL depolymerase and an esterase activity of cutinase when grown in the presence of cutin, and (iii) showed induction of PCL depolymerase and an esterase activity of cutinase when grown in the presence of a hydrolysate of PCL, which contains PCL oligomers that are structurally similar to the natural inducers of cutinase. These results together with other details of regulation and conditions for optimal enzyme activity indicate that the Fusarium PCL depolymerase, required for degradation and utilization of PCL, is cutinase.


Decision-making in burst fractures of the thoracolumbar and lumbar spine.
The most common site of injury to the spine is the thoracolumbar junction which is the mechanical transition junction between the rigid thoracic and the more flexible lumbar spine. The lumbar spine is another site which is more prone to injury. Absence of stabilizing articulations with the ribs, lordotic posture and more sagitally oriented facet joints are the most obvious explanations. Burst fractures of the spine account for 14% of all spinal injuries. Though common, thoracolumbar and lumbar burst fractures present a number of important treatment challenges. There has been substantial controversy related to the indications for nonoperative or operative management of these fractures. Disagreement also exists regarding the choice of the surgical approach. A large number of thoracolumbar and lumbar fractures can be treated conservatively while some fractures require surgery. Selecting an appropriate surgical option requires an in-depth understanding of the different methods of decompression, stabilization and/or fusion. Anterior surgery has the advantage of the greatest degree of canal decompression and offers the benefit of limiting the number of motion segments fused. These advantages come at the added cost of increased time for the surgery and the related morbidity of the surgical approach. Posterior surgery enjoys the advantage of being more familiar to the operating surgeons and can be an effective approach. However, the limitations of this approach include inadequate decompression, recurrence of the deformity and implant failure. Though many of the principles are the same, the treatment of low lumbar burst fractures requires some additional consideration due to the difficulty of approaching this region anteriorly. Avoiding complications of these surgeries are another important aspect and can be achieved by following an algorithmic approach to patient assessment, proper radiological examination and precision in decision-making regarding management. A detailed understanding of the mechanism of injury and their unique biomechanical propensities following various forms of treatment can help the spinal surgeon manage such patients effectively and prevent devastating complications.


Evolution of droplets in subsea oil and gas blowouts: development and validation of the numerical model VDROP-J.
The droplet size distribution of dispersed phase (oil and/or gas) in submerged buoyant jets was addressed in this work using a numerical model, VDROP-J. A brief literature review on jets and plumes allows the development of average equations for the change of jet velocity, dilution, and mixing energy as function of distance from the orifice. The model VDROP-J was then calibrated to jets emanating from orifices ranging in diameter, D, from 0.5 mm to 0.12 m, and in cross-section average jet velocity at the orifice ranging from 1.5 m/s to 27 m/s. The d50/D obtained from the model (where d50 is the volume median diameter of droplets) correlated very well with data, with an R(2)=0.99. Finally, the VDROP-J model was used to predict the droplet size distribution from Deepwater Horizon blowouts. The droplet size distribution from the blowout is of great importance to the fate and transport of the spilled oil in marine environment.


[The saphenous vein graft diseases].
Graft occlusions are the main problems that may arise during long-term follow-up period after coronary artery bypass surgery. Knowledge of pathologies developed in saphenous grafts and attempts to reduce their frequency are important for reduction of the incidence of saphenous graft vein occlusions. For today the patency rate for 10 years saphenous vein grafts are about 60%. Along with intraoperative technical factors, there are a lot of factors contributed to the development occlusion during long-term follow-up period. In this review we aimed to analyze the factors affecting saphenous vein pathologies and propose preventive measures.


Fluorescent and paramagnetic chitosan nanoparticles that exhibit high magnetic resonance relaxivity: synthesis, characterization and in vitro studies.
We report water-in-oil (W/O) microemulsion synthesis of fluorescently bright and paramagnetically strong bimodal chitosan nanoparticles (BCNPs). The W/O microemulsion system provides a confined environment for producing monodispersed BCNPs. Average particle size as estimated by the Transmission Electron Microscopy was 28 nm. The water to surfactant molar ratio of 22 produced small size fairly monodispersed BCNPs. Fluorescein isothiocyanate (FITC, a fluorescent dye) and Gd-DOTA (a paramagnetic Gd ion chelating agent) were covalently attached to chitosan polymer backbone prior to BCNP synthesis. The purpose of the covalent attachment of fluorescent and paramagnetic labels to chitosan is to prevent leakage of these labels from the BCNPs. The BCNPs were cross-linked with tartaric acid using water-soluble carbodiimide coupling chemistry in order to maintain particulate integrity. Zeta potential value of +27.6 mV confirmed positive surface charge of cross-linked BCNPs. Fluorescence excitation and emission spectra of BCNPs were similar to that of bare FITC spectra, showing characteristic 520 nm emission at the 490 excitation. Paramagnetic gadolinium ion (Gd3+) concentration in the BCNPs was determined by inductively coupled plasma (ICP) emission spectroscopy. The longitudinal (T1) and transverse (T2) proton relaxation times were determined as a function of Gd3+ concentration in the BCNPs at 4.7 Tesla. Proton relaxivity (R1 value) of BCNPs was calculated to be 41.1 mM Gd(-1)s(-1). The reported R1 value of Gd-DOTA chelates is however 5.8 mM Gd(-1)s(-1). High proton relaxivity of BCNPs is attributed to hydrated chitosan environment around Gd chelates which additionally contributed to overall water exchange process. To demonstrate in vitro bioimaging capability, J774 macrophage cells were incubated with BCNPs. Confocal images clearly showed BCNP uptake by J774 cells. Internalization of BCNPs was confirmed by co-labeling J774 cells with a red-emitting membrane dye. BCNP green emission was mostly observed from middle of cells and within the red-emitting membrane boundary.


Potential role of galactokinase in neonatal carbohydrate assimilation.
Glucose given to the newborn human may result in hyperglycemia, suggesting that its utilization is impaired at this developmental stage. Galactose is thought to be a more appropriate carbohydrate source for the newborn. The enzymes involved in hexose phosphorylation may, in part, be responsible for these observations. A key regulatory enzyme of hepatic glucose assimilation, glucokinase, is diminished in newborns compared to adults, whereas galactokinase activity is increased. When newborn dogs were fasted and then fed either glucose or galactose, their plasma insulin responses to glucose were similar, but the pups fed galactose demonstrated an attenuated systemic appearance rate of glucose. Hexose incorporation into hepatic glycogen and net glycogen synthesis was augmented in the galactose-fed dogs. In vitro, liver from neonatal dogs showed enhanced galactokinase activity relative to that for hexokinase or glucokinase. Neonatal hexose assimilation may be independent of insulin action and, instead, be related to the developmental presence of hexose phosphorylating enzymes.


Molecular dynamics simulations of DiI-C18(3) in a DPPC lipid bilayer.
We performed a 40 ns simulation of 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI-C18(3)) in a 1,2-dipalmitoyl-sn-glycero-3-phosphatidyl choline (DPPC) bilayer in order to facilitate interpretation of lipid dynamics and membrane structure from fluorescence lifetime, anisotropy, and fluorescence correlations spectroscopy (FCS). Incorporation of DiI of 1.6 to 3.2 mol% induced negligible changes in area per lipid but detectable increases in bilayer thickness, each of which are indicators of membrane structural perturbation. The DiI chromophore angle was 77 +/- 17 degrees with respect to the bilayer normal, consistent with rotational diffusion inferred from polarization studies. The DiI headgroup was located 0.63 nm below the lipid head group-water interface, a novel result in contrast to some popular cartoon representations of DiI but consistent with DiI's increase in quantum yield when incorporated into lipid bilayers. Importantly, the fast component of rotational anisotropy matched published experimental results demonstrating that sufficient free volume exists at the sub-interfacial region to support fast rotations. Simulations with non-charged DiI head groups exhibited DiI flip-flop, demonstrating that the positively-charged chromophore stabilizes the orientation and location of DiI in a single monolayer. DiI induced detectable changes in interfacial properties of water ordering, electrostatic potential, and changes in P-N vector orientation of DPPC lipids. The diffusion coefficient of DiI (9.7 +/- 0.02 x 10(-8) cm2 s(-1)) was similar to the diffusion of DPPC molecules (10.7 +/- 0.04 x 10(-8) cm2 s(-1)), supporting the conclusion that DiI dynamics reflect lipid dynamics. These results provide the first atomistic level insight into DiI dynamics, results essential in elucidating lipid dynamics through single molecule fluorescence studies.


Early neuropsychological tests as correlates of return to driving after traumatic brain injury.
To assess the ability of neuropsychometric tests administered during inpatient rehabilitation to predict return to driving after traumatic brain injury (TBI). Retrospective, matched case-controlled study. Sixty-seven participants with TBI, drawn from an existing database, completed a questionnaire that assessed return to driving post-TBI, as measured by reinstatement of the driver's license. Drivers were individually case-matched to non-drivers on age, Glasgow Coma Scale (GCS), Disability Rating Scale (DRS) and the rehabilitation admission interval (RAI). Scores on four neuropsychological tests (Trail-Making A, Trail Making B, Digit Span-forward and Digit Span-backward), administered during the rehabilitation stay, were compared between case-matched drivers and non-drivers. Return to driving, as defined by reinstatement of the driver's license. Participants who had returned to driving were comparable to those who had not returned to driving with respect to demographic variables, initial injury severity and baseline functioning. Scores on two neuropsychological assessments were significantly better in participants who had returned to driving than in those who had not: Trail-making A (p < 0.01) and Trail-making B (p < 0.01). The results suggest that neuropsychological measures of processing speed and cognitive flexibility may predict return to driving after TBI.


Hyperbolic Topological Band Insulators.
Recently, hyperbolic lattices that tile the negatively curved hyperbolic plane emerged as a new paradigm of synthetic matter, and their energy levels were characterized by a band structure in a four- (or higher-) dimensional momentum space. To explore the uncharted topological aspects arising in hyperbolic band theory, we here introduce elementary models of hyperbolic topological band insulators: the hyperbolic Haldane model and the hyperbolic Kane-Mele model; both obtained by replacing the hexagonal cells of their Euclidean counterparts by octagons. Their nontrivial topology is revealed by computing topological invariants in both position and momentum space. The bulk-boundary correspondence is evidenced by comparing bulk and boundary density of states, by modeling propagation of edge excitations, and by their robustness against disorder.


HLA-G gene editing in tumor cell lines as a novel alternative in cancer immunotherapy.
Cancer immunotherapies based mainly on the blockade of immune-checkpoint (IC) molecules by anti-IC antibodies offer new alternatives for treatment in oncological diseases. However, a considerable proportion of patients remain unresponsive to them. Hence, the development of novel clinical immunotherapeutic approaches and/or targets are crucial.W In this context, targeting the immune-checkpoint HLA-G/ILT2/ILT4 has caused great interest since it is abnormally expressed in several malignancies generating a tolerogenic microenvironment. Here, we used CRISPR/Cas9 gene editing to block the HLA-G expression in two tumor cell lines expressing HLA-G, including a renal cell carcinoma (RCC7) and a choriocarcinoma (JEG-3). Different sgRNA/Cas9 plasmids targeting HLA-G exon 1 and 2 were transfected in both cell lines. Downregulation of HLA-G was reached to different degrees, including complete silencing. Most importantly, HLA-G - cells triggered a higher in vitro response of immune cells with respect to HLA-G + wild type cells. Altogether, we demonstrated for the first time the HLA-G downregulation through gene editing. We propose this approach as a first step to develop novel clinical immunotherapeutic approaches in cancer.


Human serotonectin: a blood glycoprotein that binds serotonin and is associated with platelets and white blood cells.
A glycoprotein that circulates in blood, binds to the surface of platelets, and also binds serotonin with high avidity and specificity, has previously been found in rats. This glycoprotein has been called serotonectin. We now report the purification and characterization of a similar circulating glycoprotein in human blood that we propose be called human serotonectin, to distinguish it from the rat protein. Human serotonectin binds serotonin with high affinity (Kd1 = 36 nM; Kd2 = 1.1 microM). Monospecific antisera were raised in rabbits to purified human serotonectin. These antibodies were used to locate human serotonectin immunocytochemically, for quantitative estimation of the glycoprotein, and for rapid preparation of material purified by affinity chromatography. Evidence was obtained that indicated that human serotonectin circulates in plasma and also binds to the surfaces of white blood cells and platelets but not to red blood cells. In bone marrow it is found on megakaryocytes and on developing white cells of the eosinophil line. The protein can be completely removed by washing with isotonic sucrose or salt solutions from the surfaces of white cells but similar treatment only partially (63% sucrose wash/73% salt wash) removes human serotonectin from platelets. Antibodies to human serotonectin antagonize the uptake of serotonin by platelets but do not inhibit platelet aggregation. These data show that humans, like rats, have a circulating serotonin-binding glycoprotein that is also present as a peripheral membrane protein on platelets. The human also differs from the rat serotonectin in binding to white cells. The material may function in platelet serotonin uptake in both humans and rats; however, its function, if any, with respect to white cells is obscure.