Aberrant Functional Connectivity of the Amygdala Complexes in PTSD during Conscious and Subconscious Processing of Trauma-Related Stimuli.
Post-traumatic stress disorder (PTSD) is characterized by altered functional connectivity of the amygdala complexes at rest. However, amygdala complex connectivity during conscious and subconscious threat processing remains to be elucidated. Here, we investigate specific connectivity of the centromedial amygdala (CMA) and basolateral amygdala (BLA) during conscious and subconscious processing of trauma-related words among individuals with PTSD (n = 26) as compared to non-trauma-exposed controls (n = 20). Psycho-physiological interaction analyses were performed using the right and left amygdala complexes as regions of interest during conscious and subconscious trauma word processing. These analyses revealed a differential, context-dependent responses by each amygdala seed during trauma processing in PTSD. Specifically, relative to controls, during subconscious processing, individuals with PTSD demonstrated increased connectivity of the CMA with the superior frontal gyrus, accompanied by a pattern of decreased connectivity between the BLA and the superior colliculus. During conscious processing, relative to controls, individuals with PTSD showed increased connectivity between the CMA and the pulvinar. These findings demonstrate alterations in amygdala subregion functional connectivity in PTSD and highlight the disruption of the innate alarm network during both conscious and subconscious trauma processing in this disorder.


Modulation of carbohydrate and fat utilization by diet, exercise and environment.
At rest and during exercise carbohydrate and fat are the predominant substrates. They are oxidized simultaneously but the relative contribution of these two substrates is dependent on a variety of factors including the exercise intensity and duration, diet, environmental conditions and training status. Changes in carbohydrate metabolism during the transition from rest to exercise and from low- to high-intensity exercise are mainly due to allosteric regulation. The factors that up-regulate fat metabolism in the transition to moderate-intensity exercise and the factors that result in a down-regulation of fat metabolism at higher intensities are incompletely understood. Substrate use is further modulated by the endocrine milieu (e.g. catecholamines, insulin, cortisol) and possibly cytokines (e.g. interleukin-6). With increasing duration of exercise there are marked increases in fat metabolism and decreases in carbohydrate metabolism and this has been ascribed mainly to substrate availability. Both acute food intake and chronic diets also have profound effects on substrate utilization. An increase in carbohydrate intake will rapidly suppress fat metabolism and increase carbohydrate metabolism whereas such an adaptation to a high-fat diet may take several days. The environmental conditions can also alter substrate use; high ambient temperatures can increase glycogen breakdown as a result of increased body core temperature and increased circulation catecholamines. Low temperatures can also increase carbohydrate metabolism, especially when shivering. In addition to these factors adaptation to training, in particular endurance training, will reduce the reliance on carbohydrate metabolism and increase fat oxidation, especially from intramuscular triacylglycerol stores.


[HBV status and expression of ets-2, IGF-II, C-myc and N-ras in human hepatocellular carcinoma and adjacent nontumorous tissues--a comparative study].
A comparative study on HBV status and ets-2, IGF-II, C-myc and N-ras expression in 12 pairs of human primary hepatocellular carcinoma (PHC) and adjacent non-tumorous tissues (NT) showed that integrated forms of HBV DNA were present in 91.5% PHC and 75% NT. No specific integration sites were detected. Three PHC and 4 NT were found to have free forms of HBV DNA, which were defective in 2 PHC and 3 NT, i. e., being able to replicate but not to be secreted into the blood. At least one of four oncogenes studied was overexpressed in the 12 pairs of samples. IGF-II was expressed as 5.0 and 2.0 Kb fetal transcripts in 3 pairs of samples and 1 NT. Six NT had more than one of the four oncogenes that was expressed higher than PHC. This was commonly encountered in tissues with free forms of HBV DNA. The relation between HBV status, expression of ets-2, IGF-II, C-myc and N-ras and carcinogenesis of PHC is discussed.


Expression of v-src in embryonic neural retina alters cell adhesion, inhibits histogenesis, and prevents induction of glutamine synthetase.
Using Rous sarcoma virus as the vector, v-src or c-src genes were introduced into 6-day chicken embryo retina tissue in organ culture and their effects on retina development were investigated. Overexpression of c-src in many of the cells had no noticeable effect on retina development. In contrast, infection with v-src resulted in abnormal histogenesis and inhibition of differentiation. Although only a portion of the cells in infected tissue expressed the oncogene and displayed the transformation phenotype, the other cells were also hindered from becoming normally positioned and organized. Therefore, presence of oncogene-transformed cells within the tissue hindered organization and development of adjacent nontransformed cells. Failure of normal cell relationships impeded induction by cortisol of glutamine synthetase in Muller glia, which requires contact associations of the glia cells with neurons. The transformed cells tended to assemble into chaotic clusters, suggesting that their adhesiveness and contact affinities had become altered. This was confirmed by aggregation experiments with dissociated cells which showed that adhesiveness of transformed cells was greatly reduced and that they had lost the ability to cohere with nontransformed cells. In binary mixtures of transformed and nontransformed cells, the two sorted out into separate aggregates. Transformed cells formed loose clusters devoid of tissue architecture; aggregates of nontransformed cells became organized into retinotypic structures, and glutamine synthetase was inducible. Our findings suggest that the mechanisms of cell adhesion and cell affinities are a key target of v-src activity in infected cells and that modification of the cell surface may be a leading factor in other cellular changes characteristic of the v-src transformation phenotype.


Is poliomyelitis in the tropics provoked by injections?
In the tropics and sub-tropics, poliomyelitis is characterized by a high non-seasonal case-rate, very young victims and a predominance of leg paralysis following injections. It is proposes that this could be caused by infection of immunosuppressed infants with poliovirus of low virulence following mal-nutrition, infections with malaria and measles and treatment by injections. Vaccination policies are briefly reviewed and the complete safety of inactivated and oral poliovaccines in the tropics is queried on theoretical grounds. Even if injections are coincident with and not causal of paralysis, it may be difficult to persuade parents of this .


Endothelial growth factors and extracellular matrix regulate DNA synthesis through modulation of cell and nuclear expansion.
Studies were carried out to analyze the mechanism by which extracellular matrix (ECM) molecules and soluble growth factors interplay to control capillary endothelial cell growth. Bovine adrenal capillary endothelial cells attached to purified matrix components but spread poorly and exhibited low levels of DNA synthesis in the absence of exogenous growth factors or serum. Addition of cationic, heparin-binding growth factor purified from either human hepatoma cells or normal bovine pituitary (fibroblast growth factor) induced extensive cell spreading and up to eight fold increases in DNA synthetic rates relative to levels observed in cells on similar substrata in the absence of mitogen. However, the extent of this response differed depending upon the type of ECM molecule used for cell attachment (fold increase on type III collagen greater than gelatin greater than type IV collagen greater than fibronectin greater than type V collagen much greater than laminin). Computerized morphometry demonstrated that endothelial cell DNA synthetic rates increased in an exponential fashion in direct relation to linear increases in cell and nuclear size (projected areas). Similarly sized cells always displayed the same level of DNA synthesis independent of the type of ECM molecule used for cell attachment or the presence of saturating amounts of growth factor. In all cases, DNA metabolism appeared to be coupled to physical expansion of the cell and nucleus rather than to a specific cell morphology (e.g. polygonal versus bipolar). These findings suggest that ECM may act locally as a "solid state" regulator of angiogenesis through its ability to selectively support or prohibit cell and nuclear extension in response to stimulation by soluble mitogens.


Environmental exposures to lead, mercury, and cadmium among South Korean teenagers (KNHANES 2010-2013): Body burden and risk factors.
Limited information is available on the association of age and sex with blood concentrations of heavy metals in teenagers. In addition, factors such as a shared family environment may have an association. We analyzed data from the Korean National Health and Nutrition Examination Survey (KNHANES, 2010-2013) to determine whether blood levels of heavy metals differ by risk factors such as age, sex, and shared family environment in a representative sample of teenagers. This study used data obtained in the KNHANES 2010-2013, which had a rolling sampling design that involved a complex, stratified, multistage, probability-cluster survey of a representative sample of the non-institutionalized civilian population in South Korea. Our cross-sectional analysis was restricted to teenagers and their parents who completed the health examination survey, and for whom blood measurements of cadmium, lead, and mercury were available. The final analytical sample consisted of 1585 teenagers, and 376 fathers and 399 mothers who provided measurements of blood heavy metal concentrations. Male teenagers had greater blood levels of lead and mercury, but sex had no association with blood cadmium level. There were age-related increases in blood cadmium, but blood lead decreased with age, and age had little association with blood mercury. The concentrations of cadmium and mercury declined from 2010 to 2013. The blood concentrations of lead, cadmium, and mercury in teenagers were positively associated with the levels in their parents after adjustment for covariates. Our results show that blood heavy metal concentrations differ by risk factors such as age, sex, and shared family environment in teenagers.


Let's talk about sex(ual) wellbeing! Staff perceptions of implementing a novel service for people with Multiple Sclerosis.
In people with multiple sclerosis (PwMS), a complex interplay of neurological dysfunction, polypharmacy and psychological issues, contrive to impair their sexual and reproductive wellbeing. Realising an unmet need, the Tayside MS service in collaboration with a sexual health clinician (LJ), established a 'Pelvic Health Clinic' to improve quality of life for PwMS. To explore clinician's perceptions of implementing an MS Pelvic Health service with a view to establishing future outcomes for health care professionals about the utility in such a service. In this small-scale qualitative case study, we explored clinician's perceptions of such a clinic adjunct. Semi-structured interviews were conducted, transcribed, and thematically analysed in a reflexive manner. Five participants consented. Ten sub-themes emerged, which were organised into three main themes: service tensions, patient needs and practitioner feelings. Clinicians highly valued the new MS 'pelvic health clinic'. Knowing that there was a service available empowered clinicians to ask patients about sexual health needs. Specific referral criteria may help further develop the service and improve patient care. Staff welcome training and support in this area or the option to signpost onwards; either mechanism lends itself to enhancing MS patient needs.


Associations between schizotypy and cerebral laterality.
Atypical lateralization for language has been found in schizophrenia, suggesting that language and thought disorders on the schizophrenia spectrum may be due to left hemispheric dysfunction. However, research with those with non-clinical schizotypy has been inconsistent, with some studies finding reduced or reversed language laterality (particularly with positive schizotypal traits), and others finding typical left hemispheric specialization. The aim of the current study was to use both a behavioural (dual reading-finger tapping) task and an functional magnetic resonance imaging lexical decision task to investigate language laterality in a university sample of high- and low-schizotypal adults. Findings revealed no evidence for atypical lateralization in our sample for both overall schizotypy (measured by the Oxford-Liverpool Inventory of Feelings and Experiences) and positive schizotypy (measured by the Unusual Experiences subscale) groups. Our findings provide further evidence that non-clinical schizotypy is not associated with atypical language laterality.


Engineering a Conformationally Switchable Artificial Metalloprotein.
Many naturally occurring metalloenzymes are gated by rate-limiting conformational changes, and there exists a critical interplay between macroscopic structural rearrangements of the protein and subatomic changes affecting the electronic structure of embedded metallocofactors. Despite this connection, most artificial metalloproteins (ArMs) are prepared in structurally rigid protein hosts. To better model the natural mechanisms of metalloprotein reactivity, we have developed conformationally switchable ArMs (swArMs) that undergo a large-scale structural rearrangement upon allosteric effector binding. The swArMs reported here contain a Co(dmgH)2(X) cofactor (dmgH = dimethylglyoxime and X = N3-, H3C-, and iPr-). We used UV-vis absorbance and energy-dispersive X-ray fluorescence spectroscopies, along with protein assays, and mass spectrometry to show that these metallocofactors are installed site-specifically and stoichiometrically via direct Co-S cysteine ligation within the Escherichia coli glutamine binding protein (GlnBP). Structural characterization by single-crystal X-ray diffraction unveils the precise positioning and microenvironment of the metallocofactor within the protein fold. Fluorescence, circular dichroism, and infrared spectroscopies, along with isothermal titration calorimetry, reveal that allosteric Gln binding drives a large-scale protein conformational change. In swArMs containing a Co(dmgH)2(CH3) cofactor, we show that the protein stabilizes the otherwise labile Co-S bond relative to the free complex. Kinetics studies performed as a function of temperature and pH reveal that the protein conformational change accelerates this bond dissociation in a pH-dependent fashion. We present swArMs as a robust platform for investigating the interplay between allostery and metallocofactor regulation.


Geometric effect on the photocrosslinking reaction between 3-cyanovinylcarbazole nucleoside and pyrimidine base in DNA/RNA heteroduplex.
To clarify the geometric effect of the ultra-fast photocrosslinking reaction of photoreactive oligodeoxyribonucleotide containing 3-cyanovinylcarbazole nucleoside ((CNV)K) on uridine in complementary RNA strands, pseudouridine (Ψ), which is an isomer of uridine with a C5-C1' glycosidic bond, was introduced to the photocrosslink site of (CNV)K in complementary RNA instead of U. The photoreactivity of (CNV)K toward Ψ was two-fold lower than that of U, suggesting that the geometry between the vinyl moiety on (CNV)K and the reactive double bond in the pyrimidine base has a large affect on the photoreactivity of (CNV)K. Contrary to the case of U, the reactivity of the (CNV)K toward Ψ was decreased by the decrease of reaction temperature below the Tm of heteroduplex, suggesting that the flexible structure of the duplex is advantageous for the photocrosslinking reaction with Ψ, whose reactive double bond possesses unfavorable geometry for the photocrosslinking reaction with (CNV)K. These basic findings might contribute to the development of a geometry selective photocrosslinking reaction. This is the first example of a sequence specific photocrosslinking reaction toward Ψ, which is the most abundant posttranscriptionally modified nucleoside.


Acceptance and Commitment Therapy and nicotine patch for smokers with bipolar disorder: preliminary evaluation of in-person and telephone-delivered treatment.
People with bipolar disorder are two to three times more likely to smoke and 50% less likely to quit than the general population. New treatments are needed to improve smoking cessation outcomes in this group. The study aim was to develop and pilot test a novel cessation intervention for smokers with bipolar disorder using Acceptance and Commitment Therapy (ACT) combined with nicotine patches. The ten-session ACT intervention was initially evaluated as in-person, individual counseling (n = 10), then as telephone-delivered counseling (n = 6). Participants were adult smokers with no more than mild current symptoms of bipolar disorder. For the in-person protocol, end-of-treatment outcomes were: 80% retention, 40% of participants with carbon monoxide (CO)-verified seven-day point prevalence abstinence (PPA), 90% satisfied with treatment, 8.3 of ten sessions attended, and 54% increase in acceptance of cravings to smoke (i.e., ACT's theory-based change process) from baseline. The seven-day PPA at one-month follow-up was 30%. For the telephone protocol, end-of-treatment outcomes were: 67% retention, 33% reporting seven-day PPA, 100% satisfied with treatment, 6.7 of ten treatment calls completed, and 55% increase in acceptance from baseline. At one-month follow-up, seven-day PPA was 17%. The proportion of treatment completers who used at least 80% of the nicotine patches was 62.5% for the in-person protocol and 0% for the telephone protocol. Both in-person and telephone-delivered ACT were feasible. Despite low adherence to nicotine patches, the intervention showed preliminary evidence of facilitating quitting and impacting ACT's change mechanism. A randomized, controlled trial of this targeted ACT intervention is now needed.


Differential expression of chitinases identify subsets of murine airway epithelial cells in allergic inflammation.
The mammalian chitinase family includes members both with and without enzymatic activity against chitin, a product of fungal cell walls, exoskeletons of crustaceans and insects, and the microfilarial sheaths of parasitic nematodes. Two members of that family, Ym1 and acidic mammalian chitinase (AMCase), are strongly upregulated in pulmonary T helper (Th) 2 inflammation but not in Th1 inflammation. The sites of expression of these products are incompletely known. We show here that, in two different models of Th2 inflammation, Ym1 and AMCase are mutually exclusively expressed in proximal vs. distal airway epithelium, respectively, whereas both are expressed in alveolar macrophages. This regional difference along the airway corresponds to the previously noted distinction between mucus positive proximal cells and mucus negative distal cells under the same conditions. Among distal cells, AMCase colocalizes with epithelial cells expressing the Clara cell marker Clara cell secretory protein. These AMCase-expressing cells retain expression of FOXA2, a transcription factor whose downregulation in association with IL-13 signaling has previously been associated with production of mucus in proximal airway epithelial cells. These results provide evidence that secretory cells of proximal and distal airways undergo fundamentally different gene expression programs in response to allergic inflammation. Furthermore, AMCase provides the first positive molecular marker of distal Clara cell secretory protein-expressing cells under these conditions.


2D transition metal carbide MXene as a robust biosensing platform for enzyme immobilization and ultrasensitive detection of phenol.
MXene-Ti3C2, as a new class of two-dimensional (2D) transition metal carbides (or nitrides), has been synthesized by exfoliating pristine Ti3AlC2 phases with hydrofluoric acid. The SEM and XRD images show that the resultant MXene possesses a graphene-like 2D nanostructure. and the surface of MXene has been partially terminated with -OH, thus providing a favorable microenvironment for enzyme immobilization and retaining their bioactivity and stability. Considering the unique metallic conductivity, biocompatibility and good dispersion in aqueous phase, the as-prepared MXene was explored as a new matrix to immobilize tyrosinase (a model enzyme) for fabricating a mediator-free biosensor for ultrasensitive and rapid detection of phenol. The varying electrochemical measurements were used to investigate the electrochemical performance of MXene-based tyrosinase biosensors. The results revealed that the direct electron transfer between tyrosinase and electrode could be easily achieved via a surface-controlled electrochemical process. The fabricated MXene-based tyrosinase biosensors exhibited good analytical performance over a wide linear range from 0.05 to 15.5 μmol L-1, with a low detection limit of 12 nmol L-1 and a sensitivity of 414.4 mA M-1. The proposed biosensing approach also demonstrated good repeatability, reproducibility, long-term stability and high recovery for phenol detection in real water samples. With those excellent performances, MXene with graphene-like structure is proved to be a robust and versatile electrochemical biosensing platform for enzyme-based biosensors and biocatalysis, and has wide potential applications in biomedical detection and environmental analysis.


DNA methyltransferase immunohistochemical expression in odontogenic tumours.
Odontogenic tumours are a heterogeneous group of lesions formed from tissues that give rise to the tooth. DNA methylation, a covalent addition of a methyl group to the 5-carbon position of a cytosine nucleotide, is considered an important regulator of gene expression. The addition of the methyl radical is catalysed by DNA methyltransferases (DNMTs). Although some epigenetic studies have been conducted in odontogenic tumours, a study with the three types of DNMTs in several different members of this group is missing. This study analyses the expression of DNMTs in odontogenic tumours. Formalin-fixed and paraffin-embedded tissue samples of 20 ameloblastomas, 10 calcifying cystic odontogenic tumours, 10 calcifying epithelial tumours, 10 adenomatoid odontogenic tumours, 10 keratocystic odontogenic tumours, five ameloblastic fibromas, two ameloblastic fibro-odontomas, four central odontogenic fibromas, seven peripheral odontogenic fibromas and 10 odontogenic myxomas were included. Immunohistochemical expression of DNMT1, 3A and 3B was assessed using a semi-quantitative analysis, and also a correlation with p21, p27 and E-cadherin immunoexpression was made. DNMT1, 3A and 3B were expressed in the nucleus and/or cytoplasm of all odontogenic tumours. DNMT1 expression was directly correlated with p27 expression in ameloblastomas. The high expression of DNMTs in odontogenic tumour cells suggests methylation as an important mechanism for this group of tumours.


Relative contributions of distinct MHC class I-dependent cell populations in protection to tuberculosis infection in mice.
A necessary role for cytotoxic T lymphocytes in protection against Mycobacterium tuberculosis (MTB) has been suggested by studies of the beta2-microglobulin-deficient mouse, which is unable to present antigens through MHC class I and class I-like molecules and invariably succumbs early after infection. To identify the relative contributions of distinct putative MHC class I-dependent cell populations in protection against tuberculosis, we compared a variety of gene-disrupted mouse strains for susceptibility to MTB infection. Among the strains tested, the most susceptible mice, as measured by survival time and bacterial loads, were the beta2-microglobulin(-/-), followed by transporter associated with antigen processing deficient (TAP1(-/-)), CD8alpha(-/-), perforin(-/-), and CD1d(-/-) mice. These findings indicated that (i) CD8(+) T cells contribute to protection against MTB, and their protective activity is only partially dependent on perforin; (ii) beta2-microglobulin-dependent T cell populations distinct from CD8(+) T cells also contribute to anti-MTB immunity; and (iii) protective immune mechanisms are predominantly TAP-dependent, although TAP-independent mechanisms also contribute to protection. Because CD1d-deficient animals were fully resistant to MTB, other TAP-independent mechanisms must contribute to protection. We suggest here that both classical and nonclassical MHC class I-restricted T cells, distinct from CD1d-restricted cells, may be involved in protective immune responses against tuberculosis.


[Detection of Staphylococcus aureus and Staphylococcus epidermis species specific antigens and antibodies to alpha-toxin in the blood of patients with pneumonia].
Test systems for indirect hemagglutination (IHA) test for detection of S. aureus and S. epidermidis teichoic acids and S. aureus alpha-toxin in patients' sera have been developed on the basis of immunoglobulins isolated from monospecific sera. Test system for IHA test for detection of antitoxin in donor and patients' sera has been created on the basis of highly purified alpha-toxin. Thirty donor sera and 61 sera from patients with pneumonia were analyzed. Low antibody levels in the patients may be due to the fact that the sera were collected during the first days of disease. Group of patients with high content of staphylococcal antigens and antitoxin in the blood was particularly interesting. These patients developed severe pneumonia, among whose etiological agents were S. aureus and S. epidermidis. Diagnostic analysis of patients' sera by IHA test for detection of staphylococcal antigens was more effective, accurate, and rapid in comparison with the bacteriological method; moreover, it confirmed the significance of staphylococci in the pathogenesis of pneumonia.


Vagus nerve stimulation magnet activation for seizures: a critical review.
Some patients receiving VNS Therapy report benefit from manually activating the generator with a handheld magnet at the time of a seizure. A review of 20 studies comprising 859 subjects identified patients who reported on-demand magnet mode stimulation to be beneficial. Benefit was reported in a weighted average of 45% of patients (range 0-89%) using the magnet, with seizure cessation claimed in a weighted average of 28% (range 15-67%). In addition to seizure termination, patients sometimes reported decreased intensity or duration of seizures or the post-ictal period. One study reported an isolated instance of worsening with magnet stimulation (Arch Pediatr Adolesc Med, 157, 2003 and 560). All of the reviewed studies assessed adjunctive magnet use. No studies were designed to provide Level I evidence of efficacy of magnet-induced stimulation. Retrospective analysis of one pivotal randomized trial of VNS therapy showed significantly more seizures terminated or improved in the active stimulation group vs the control group. Prospective, controlled studies would be required to isolate the effect and benefit of magnet mode stimulation and to document that the magnet-induced stimulation is the proximate cause of seizure reduction. Manual application of the magnet to initiate stimulation is not always practical because many patients are immobilized or unaware of their seizures, asleep or not in reach of the magnet. Algorithms based on changes in heart rate at or near the onset of the seizure provide a methodology for automated responsive stimulation. Because literature indicates additional benefits from on-demand magnet mode stimulation, a potential role exists for automatic activation of stimulation.


Exercise-induced increase in muscle insulin sensitivity.
Exercise/muscle contraction activates glucose transport. The increase in muscle glucose transport induced by exercise is independent of insulin. As the acute effect of exercise on glucose transport wears off, it is replaced by an increase in insulin sensitivity. An increase in insulin sensitivity results in a shift in the insulin dose-response curve to the left, with a decrease in the concentration of insulin needed to induce 50% of the maximal response. This phenomenon, which plays a major role in rapid muscle glycogen accumulation after exercise, is not mediated by amplification of the insulin signal. Development of the increase in insulin sensitivity after contractions does not require protein synthesis or activation of p38 MAPK. It does require the presence of a serum protein during the period of contractile activity. The effect of exercise on muscle insulin sensitivity is mimicked by hypoxia and by treatment of muscles with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside to activate AMP-activated protein kinase. The postexercise increase in sensitivity of muscle glucose transport to activation is not specific for insulin but also involves an increased susceptibility to activation by a submaximal contraction/hypoxia stimulus. The increase in insulin sensitivity is mediated by translocation of more GLUT4 glucose transporters to the cell surface in response to a submaximal insulin stimulus. Although the postexercise increase in muscle insulin sensitivity has been characterized in considerable detail, the basic mechanisms underlying this phenomenon remain a mystery.


Exploration of clinical predictors of the degree of ventricular catheter obstruction: a multicenter retrospective study.
The aim of this study was to explore how clinical factors, including the number of lifetime revision surgeries and the duration of implantation, affect the degree of obstruction and failure rates of ventricular catheters (VCs) used to manage hydrocephalus. A total of 343 VCs and their associated clinical data, including patient demographics, medical history, and surgical details, were collected from 5 centers and used for this analysis. Each VC was classified by the degree of obstruction after macroscopic analysis. Univariate, multivariate, and binned analyses were conducted to test for associations between clinical data and degree of VC obstruction. VCs from patients with 0 to 2 lifetime revisions had a larger proportion of VC holes obstructed than VCs from patients with 10 or more revisions (p = 0.0484). VCs implanted for less than 3 months had fewer obstructed holes with protruding tissue aggregates than VCs implanted for 13 months or longer (p = 0.0225). Neither duration of implantation nor the number of lifetime revisions was a significant predictor of the degree of VC obstruction in the regression models. In the multinomial regression model, contact of the VCs with the ventricular wall robustly predicted the overall obstruction status of a VC (p = 0.005). In the mixed-effects model, the age of the patient at their first surgery emerged as a significant predictor of obstruction by protruding tissue aggregates (p = 0.002). VCs implanted through the parietal entry site were associated with more holes with nonobstructive growth and fewer empty holes than VCs implanted via other approaches (p = 0.001). The number of lifetime revisions and duration of implantation are correlated with the degree of VC obstruction but do not predict it. Contact of the VC with the ventricular wall and the age of the patient at their first surgery are predictors of the degree of VC obstruction, while the entry site of the VC correlates with it.


A Comprehensive Genetic and Clinical Evaluation of Waardenburg Syndrome Type II in a Set of Iranian Patients.
Waardenburg syndrome (WS) is a neurocristopathy with an autosomal dominant mode of inheritance, and considerable clinical and genetic heterogeneity. WS type II is the most common type of WS in many populations presenting with sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eye, and pigmentary abnormalities of the hair and skin. To date, mutations of MITF, SOX10, and SNAI2 have been implicated in the pathogenesis of WS2. Although different pathogenic mutations have been reported in many ethnic groups, the data on Iranian WS2 patients is insufficient. 31 WS2 patients, including 22 men and 9 women from 14 families were included. Waardenburg consortium guidelines were employed for WS2 diagnosis. WS2 patients underwent screening for MITF, SOX10, and SNAI2 mutations using direct sequencing and MLPA analysis. Clinical evaluation revealed prominent phenotypic variability in Iranian WS2 patients. Sensorineural hearing impairment and heterochromia iridis were the most common features (67% and 45%, respectively), whereas anosmia was the least frequent phenotype. Molecular analysis revealed a de novo heterozygous c.640C>T (p.R214X) in MITF and a de novo heterozygous SOX10 gross deletion in the study population. Our data help illuminate the phenotypic and genotypic spectrum of WS2 in an Iranian series of patients, and could have implications for the genetic counseling of WS in Iran.


Structural diversity among some dialkyltin(IV) benzoate and related derivatives.
The molecular structures of five diorganotin(IV) carboxylates, (I)-(V), can be categorized into two main well-known structural types for such Sn complexes. One is the mononuclear dialkytin(IV) carboxylates with an [R2Sn(LH)2]-type skew-trapezoidal bipyramid, where the alkyl ligands are in pseudo-axial positions and the O atoms from two asymmetrically coordinated bidentate carboxylate ligands are in the equatorial plane. This structure type is adopted by dibutylbis{(E)-2-hydroxy-5-[(3-methylphenyl)diazenyl]benzoato}tin(IV) cyclohexane hemisolvate, [Sn(C4H9)2(C14H11N2O3)2]·0.5C6H12, (I), dibenzylbis{(E)-5-[(4-bromophenyl)diazenyl]-2-hydroxybenzoato}tin(IV), [Sn(C7H7)2(C13H8BrN2O3)2], (II), and aquadibenzylbis(4-{(E)-[(Z)-4-hydroxypent-3-en-2-ylidene]amino}benzoato)tin(IV) benzene disolvate, [Sn(C7H7)2(C12H12NO3)2(H2O)]·2C6H6, (III), although the latter has an additional water ligand to give a distorted pentagonal bipyramidal coordination geometry in which the carboxylate groups are more symmetrically coordinated to the Sn atom than in (I) and (II). The other structure motif is that of the tetranuclear bis(dicarboxylatotetraorganodistannoxanes), {[R2Sn(LH)]2O}2, which contain an Sn4O2 core decorated with four bridging carboxylate ligands, plus two alkyl ligands at each SnIV centre. The complexes octabutyltetrakis{μ-(E)-4-[(4-hydroxy-3,5-dimethylphenyl)diazenyl]benzoato}di-μ3-oxido-tetratin(IV) ethanol disolvate, [Sn4(C4H9)8(C15H13N2O3)4O2]·2C2H6O, (IV), and octabutyltetrakis{(E)-3-[(2-hydroxybenzylidene)amino]propanoato}di-μ3-oxido-tetratin(IV), [Sn4(C4H9)8(C10H10NO3)4O2], (V), display this motif. The structures obtained correlate with the 1:1 and 1:2 stoichiometric ratios of the dialkyltin(IV) and carboxylic acid starting materials in the syntheses. The supramolecular structures arising from consideration of secondary Sn...O interactions and/or classic hydrogen bonds include discrete molecules for (V), centrosymmetric dimers for (I), extended chains for (II) and (III), and sheets for (IV).


Clinicopathological characteristics and treatment of patients with high-grade endometrial stromal sarcoma: A retrospective study of 40 cases.
To investigate the clinicopathological characteristics of patients with high-grade endometrial stromal sarcoma (HG-ESS).The clinicopathological characteristics, treatments, and prognostic information of consecutive HG-ESS patients were collected from medical records and then evaluated.A total of 40 women were included in the analysis. The immunohistochemical profiles indicated that HG-ESS tumors tend to be locally or weakly positive for vimentin (100%) and CD10 (72.0%) but mostly negative for desmin (7.7%) and AE1/AE3 (9.1%). The progression-free survival intervals and the clinical benefit rates of patients receiving radiotherapy and/or chemotherapy were slightly longer and higher than those receiving simple observation (progression-free survival: 6 and 5 months vs 2 months; clinical benefit rate: 83.3% and 75.0% vs 28.6%). The 1-year disease-specific survival (DSS) rate was 62.7%. Tumor size, myometrial invasion, lymphovascular space invasion, cervical involvement, Federation International of Gynecology and Obstetrics (FIGO) stage, and residual disease all significantly affected the DSS rate (P < .001, =.002, <.001, =.004, <.001, and <.001, respectively). For patients with stage I disease, the 1-year DSS rate was as high as 91.7%, in contrast to 66.7%, 26.7%, and 0% for those with stage II, III, and IV disease, respectively.HG-ESS is associated with an adverse prognosis. FIGO stage could effectively predict the prognosis of patients with this lethal disease. Immunohistochemical markers, vimentin+/CD10+ (local or very weak), in combination with desmin-/AE1/AE3-, may be helpful for improving the diagnostic accuracy of this lethal condition. The therapeutic roles of adjuvant chemotherapy and radiotherapy warrant further investigation.


Homologs of small nucleolar RNAs in Archaea.
In eukaryotes, dozens of posttranscriptional modifications are directed to specific nucleotides in ribosomal RNAs (rRNAs) by small nucleolar RNAs (snoRNAs). We identified homologs of snoRNA genes in both branches of the Archaea. Eighteen small sno-like RNAs (sRNAs) were cloned from the archaeon Sulfolobus acidocaldarius by coimmunoprecipitation with archaeal fibrillarin and NOP56, the homologs of eukaryotic snoRNA-associated proteins. We trained a probabilistic model on these sRNAs to search for more sRNAs in archaeal genomic sequences. Over 200 additional sRNAs were identified in seven archaeal genomes representing both the Crenarchaeota and the Euryarchaeota. snoRNA-based rRNA processing was therefore probably present in the last common ancestor of Archaea and Eukarya, predating the evolution of a morphologically distinct nucleolus.


How Does Orofacial Trauma in Children Affect the Developing Dentition? Long-term Treatment and Associated Complications.
Each year, millions of children are injured and live with the consequences of those injuries. Through infancy and childhood, orofacial trauma caused by falls or being struck by or against objects occurs in children. The long-term implications on the developing permanent teeth are little known, even when the oral region is the second most frequently injured body area in children under 6 years of age. During this period, the developing permanent teeth may be directly involved after trauma, causing mild to severe hypoplasia, displacement, damage to the tooth germ, or an extended range of morphofunctional disturbances. In some cases, the effects of oral and dental injuries caused by trauma appear later with the eruption of the permanent incisors when ectopic eruption, malalignments, and other developmental disturbances become visible. Therefore, long-term follow up of the patient in order to diagnose and treat associated complications becomes essential. Critical points for facing the consequences of orofacial trauma on the developing dentition are to recognize the impact of orofacial trauma in young children and the dentist's role in providing anticipatory guidance to parents and health care professionals, differentiate between mild and severe disturbances affecting the developing permanent teeth after oral injuries in early childhood, recognize the importance of follow-up controls, and recognize the importance of early referral to a pediatric dentist and orthodontist for diagnosis and treatment planning.


Dietary factors and microsatellite instability in sporadic colon carcinomas.
Microsatellite instability (MSI) occurs in 10-20% of the sporadic colon carcinomas and appears to be primarily due to alterations in hMLH1 and hMSH2. Little is known about the role of diet in MSI-related colon carcinogenesis. We used data from a Dutch population-based case-control study on sporadic colon carcinomas (184 cases and 259 controls) to evaluate associations between dietary factors previously reported as being associated with colon cancer risk and MSI, hMLH1 expression, and hMLH1 hypermethylation. Red meat intake was significantly differently related to microsatellite instability-high (MSI-H) tumors compared with microsatellite instability-low/microsatellite stable (MSI-L/MSS) [odds ratio (OR), 0.3; 95% confidence interval (CI), 0.1-0.9]. It was inversely associated with MSI-H tumors when compared with the population-based controls (OR, 0.5; 95% CI, 0.2-1.2) and positively associated with MSI-L/MSS tumors (OR, 1.5; 95% CI, 0.9-2.6). A positive association was observed for alcohol intake with MSI-H tumors (OR, 1.9; 95% CI, 0.8-4.7). Fruit consumption seemed to especially decrease the risk of MSI-H tumors with hypermethylated hMLH1 (Methyl(+) tumors) [Methyl(+) versus controls: OR = 0.4 and 95% CI = 0.2-0.9; MSI-H tumors without hypermethylated hMLH1 (Methyl(-) tumors) versus controls, OR = 1.2 and 95% CI = 0.8-1.7; Methyl(+) versus Methyl(-) tumors, OR = 0.2 and 95% CI = 0.1-0.9]. Most other evaluated dietary factors were not distinctively associated with a specific MSI or hMLH1 methylation status. Our data suggest that red meat consumption may enhance the development of MSI-L/MSS carcinomas in particular, whereas alcohol intake appears to increase the risk of MSI-H tumors. Fruit consumption may especially decrease the risk of MSI-H carcinomas exhibiting epigenetically silenced hMLH1.


The effect of connective tissue material uncertainties on knee joint mechanics under isolated loading conditions.
Although variability in connective tissue parameters is widely reported and recognized, systematic examination of the effect of such parametric uncertainties on predictions derived from a full anatomical joint model is lacking. As such, a sensitivity analysis was performed to consider the behavior of a three-dimensional, non-linear, finite element knee model with connective tissue material parameters that varied within a given interval. The model included the coupled mechanics of the tibio-femoral and patello-femoral degrees of freedom. Seven primary connective tissues modeled as non-linear continua, articular cartilages described by a linear elastic model, and menisci modeled as transverse isotropic elastic materials were included. In this study, a multi-factorial global sensitivity analysis is proposed, which can detect the contribution of influential material parameters while maintaining the potential effect of parametric interactions. To illustrate the effect of material uncertainties on model predictions, exemplar loading conditions reported in a number of isolated experimental paradigms were used. Our findings illustrated that the inclusion of material uncertainties in a coupled tibio-femoral and patello-femoral model reveals biomechanical interactions that otherwise would remain unknown. For example, our analysis revealed that the effect of anterior cruciate ligament parameter variations on the patello-femoral kinematic and kinetic response sensitivities was significantly larger, over a range of flexion angles, when compared to variations associated with material parameters of tissues intrinsic to the patello-femoral joint. We argue that the systematic sensitivity framework presented herein will help identify key material uncertainties that merit further research and provide insight on those uncertainties that may not be as relative to a given response.


The Potential Cost-Effectiveness of HIV Vaccines: A Systematic Review.
The aim of this paper was to review and compare HIV vaccine cost-effectiveness analyses and describe the effects of uncertainty in model, methodology, and parameterization. We systematically searched MEDLINE (1985 through May 2016), EMBASE, the Tufts CEA Registry, and reference lists of articles following Cochrane guidelines and PRISMA reporting. Eligibility criteria included peer-reviewed manuscripts with economic models estimating cost-effectiveness of preventative HIV vaccines. Two reviewers independently assessed study quality and extracted data on model assumptions, characteristics, input parameters, and outcomes. The search yielded 71 studies, of which 11 met criteria for inclusion. Populations included low-income (n=7), middle-income (n=4), and high-income countries (n=2). Model structure varied including decision tree (n=1), Markov (n=5), compartmental (n=4), and microsimulation (n=1). Most measured outcomes in quality adjusted life-years (QALYs) gained (n=6) while others used unadjusted (n=3) or disability adjusted life-years (n=2). HIV vaccine cost ranged from $1.54 -$75 USD in low-income countries, $55-$100 in middle-income countries, and $500-$1,000 in the United States. Base case ICERs ranged from dominant (cost-offsetting) to $91,000 per QALY gained. Most models predicted HIV vaccines would be cost-effective. Model assumptions about vaccine price, HIV treatment costs, epidemic context, and willingness to pay influenced results more consistently than assumptions on HIV transmission dynamics.


Delusions and reasoning: a study involving cognitive behavioural therapy.
Anomalies on probabilistic reasoning, theory of mind (ToM) tasks, and attributional biases have been found in delusional people. Delusions are also effectively modified by cognitive behavioural therapy (CBT). We sought to examine whether CBT reduces delusional conviction by changing such general reasoning anomalies. Sixteen patients commenced an 8-11 week CBT programme that targeted their delusions. Probabilistic reasoning, attributional biases, and ToM were assessed pre- and post-treatment. Delusional conviction, preoccupation, and distress were rated at each session. Pretreatment task performances were compared to norms. Repeated measures analyses compared pre- and posttreatment task performances and ratings of delusions. Correlational analyses were used to identify factors associated with reduced delusional conviction. At baseline, 11 patients showed some form of abnormal probabilistic reasoning, 13 excessive attributional biases, and 13 defective ToM compared to norms. Fourteen patients completed the CBT programme and showed significant reductions in delusional conviction and preoccupation. Despite some inconsistent evidence of improvement in verbal ToM tasks, reasoning styles in these 14 patients were largely unchanged by CBT. Reasoning anomalies associated with delusions in this sample mark a vulnerability that persists and is independent of the effectiveness of CBT.


SARS-CoV-2 RNA contamination on surfaces of a COVID-19 ward in a hospital of Northern Italy: what risk of transmission?
SARS-CoV-2 can reportedly exist on inanimate surfaces for a long duration, but there is limited data available from Italian COVID-19 hospital wards, especially for non-intensive care units hosting patients that do not require mechanical ventilation. Identification of the extent of environmental contamination can help in understanding possible virus transmission routes, limit hospital infections and protect healthcare workers. Thus, we investigated virus contamination on surfaces of the acute COVID-19 ward of an Italian hospital. Ward surfaces, including four points inside and six points outside the patients' rooms were sampled by swabs, seven hours after routine sanitation. To minimize the risk of underestimation of virus detection, two different sensitive molecular methods were used comparatively, and specific internal controls were added to enhance the efficiency of all the analysis steps. SARS-CoV-2 contamination was detected in only three out of all the collected samples, i.e., on two floors and one-bathroom sink, likely reflecting aerosol and saliva contamination, respectively. The overall level of contamination was low, and the floors exhibited a very low level of SARS-CoV-2 presence, evidenced by only one of the two methods used. The existence of SARS-CoV-2 on hospital surfaces may be limited, although it was reported to persist for a longer duration on surfaces under controlled laboratory conditions. Thus, effective transmission of SARS-CoV-2 by surfaces/fomites within the hospital ward may be a rare event. However, the results highlight the importance of assessing method sensitivity and including controls when investigating low-level virus contamination so as to avoid the risk of underestimation of virus presence.


Cognitive rehabilitation for Parkinson's disease dementia: a study protocol for a pilot randomised controlled trial.
There is growing interest in developing non-pharmacological treatments to address the cognitive deficits apparent in Parkinson's disease dementia and dementia with Lewy bodies. Cognitive rehabilitation is a goal-oriented behavioural intervention which focuses on improving everyday functioning through management of cognitive difficulties; it has been shown to be effective in Alzheimer's disease. To date, no studies have assessed its potential efficacy for addressing the impact of cognitive impairment in people with Parkinson's disease or dementia with Lewy bodies. Participants (n = 45) will be recruited from movement disorders, care for the elderly and memory clinics. Inclusion criteria include: a diagnosis of Parkinson's disease, Parkinson's disease dementia or dementia with Lewy bodies according to consensus criteria and an Addenbrooke's Cognitive Examination - III score of ≤ 82. Exclusion criteria include: a diagnosis of any other significant neurological condition; major psychiatric disorder, including depression, which is not related to the patient's Parkinson's disease and unstable medication use for their physical or cognitive symptoms. A single-blind pilot randomised controlled trial, with concurrent economic evaluation, will compare the relative efficacy of cognitive rehabilitation with that of two control conditions. Following a goal-setting interview, the participants will be randomised to one of the three study arms: cognitive rehabilitation (eight weekly sessions), relaxation therapy (eight weekly sessions) or treatment as usual. Randomisation and treatment group allocation will be carried out by a clinical trials unit using a dynamic adaptive sequential randomisation algorithm. The primary outcomes are patients' perceived goal attainment at a 2-months post-intervention assessment and a 6-months follow-up. Secondary outcomes include patients' objective cognitive performance (on tests of memory and executive function) and satisfaction with goal attainment, carers' perception of patients' goal attainment and patients' and carers' health status and psychosocial well-being, measured at the same time points. Cost-effectiveness will be examined to explore the design of a larger cost-effectiveness analysis alongside a full trial. This pilot study will evaluate the application of cognitive rehabilitation for the management of cognitive difficulties associated with Parkinson's disease dementia and dementia with Lewy bodies. The results of the study will inform the design of a fully powered randomised controlled trial. ISRCTN16584442 DOI 10.1186/ISRCTN16584442 13 April 2015.


Invasion as target for therapy of glioblastoma multiforme.
The survival of cancer patients suffering from glioblastoma multiforme is limited to just a few months even after treatment with the most advanced techniques. The indefinable borders of glioblastoma cell infiltration into the surrounding healthy tissue prevent complete surgical removal. In addition, genetic mutations, epigenetic modifications and microenvironmental heterogeneity cause resistance to radio- and chemotherapy altogether resulting in a hardly to overcome therapeutic scenario. Therefore, the development of efficient therapeutic strategies to combat these tumors requires a better knowledge of genetic and proteomic alterations as well as the infiltrative behavior of glioblastoma cells and how this can be targeted. Among many cell surface receptors, members of the integrin family are known to regulate glioblastoma cell invasion in concert with extracellular matrix degrading proteases. While preclinical and early clinical trials suggested specific integrin targeting as a promising therapeutic approach, clinical trials failed to deliver improved cure rates up to now. Little is known about glioblastoma cell motility, but switches in invasion modes and adaption to specific microenvironmental cues as a consequence of treatment may maintain tumor cell resistance to therapy. Thus, understanding the molecular basis of integrin and protease function for glioblastoma cell invasion in the context of radiochemotherapy is a pressing issue and may be beneficial for the design of efficient therapeutic approaches. This review article summarizes the latest findings on integrins and extracellular matrix in glioblastoma and adds some perspective thoughts on how this knowledge might be exploited for optimized multimodal therapy approaches.


"El lado oscuro": "the dark side" of social capital in Mexican American heroin using men.
This article describes social capital in a cohort of 227 Mexican American men who are long-term injection heroin users. Social capital scores for current and former users were similar, suggesting equal absolute values of capital, but associated with illicit activities in current users and with cessation efforts in former users. Stable drug-using relationships provided high negative capital, whereas conventional relationships provided positive capital. Thus, social capital functions dichotomously in positive and negative contextualized roles. This study provides an alternative understanding of the dynamic interactions between individuals, environment, and drug abuse and can inform prevention and treatment interventions for an important demographic group.


Effect of body mass index on functional outcomes following arthroplasty procedures.
To evaluate the body mass index (BMI) change in arthroplasty patients and its impact on the patients' functional results. Between October 2010 and May 2013, 606 patients who were operated due to gonarthrosis, coxarthrosis, aseptic loosening of the total knee and hip prosthesis were evaluated prospectively. Patients were operated by three surgeons in three medical centers. Patients who were between 30-90 years of age and who were underwent total knee arthroplasty, total hip arthroplasty, revision knee arthroplasty, or revision hip arthroplasty were included in the study. We excluded the patients who cannot tolerate our standard postoperative rehabilitation program. Additionally, patients who had systemic inflammatory diseases, diabetes mellitus, or endochrinopathies were excluded from the study. The remaining 513 patients comprised our study group. Preoperative functional joint scores, height, weight and BMI of all patients were recorded. We used the Knee Society Score (KSS) for knee and Harris Hip Score (HHS) for hip patients. Postoperative functional scores were measured at 1(st), 6(th) and 12(th) months and recorded separately at outpatient visits. The mean age of the patients was 64.7 (range: 30-90) years (207 males/306 females) and the mean follow-up duration was 14.3 (range: 12-26) mo. We found that arthroplasty patients had weight gain and had an increase in BMI at the postoperative 1(st), 6(th) and 12(th) months. The mean BMI of the patients was 27.7 preoperatively, 27.8 at the postoperative 1(st) month, 28.1 at the 6(th) month and 28.6 at the 12(th) month (P < 0.01). At the last visit, the mean postoperative HHS of the hip arthroplasty patients was 82.2 ± 7.12 (preoperatively, 52.3; 1(st) month, 78.2; 6(th) month, 81.1; 12(th) month, 82.2), and the mean KSS of the knee arthroplasty patients was 79.3 ± 4.31 (preoperatively, 35.8; 1(st) month, 75.2; 6(th) month, 79.1; 12(th) month, 79.3). Worse functional results were noted in the patients who had a BMI increase, however, this correlation was statistically significant only at the postoperative 6(th) month (P = 0.03). To prevent the negative functional effects of this weight gain during the postoperative period, arthroplasty patients should be advised for weight control and risky patients should consult with a dietician.


Low-level laser therapy attenuates the myeloperoxidase activity and inflammatory mediator generation in lung inflammation induced by gut ischemia and reperfusion: a dose-response study.
Intestinal ischemia and reperfusion (i-I/R) is an insult associated with acute respiratory distress syndrome (ARDS). Herein we evaluate the dose-response effect of low-level laser therapy (LLLT) on lung inflammation induced by i-I/R. Mice were subjected to mesenteric artery occlusion (45 min) and killed after clamp release and intestinal reperfusion (2h). Increasing doses (1, 3, 5 and 7,5 J/cm(2)) of laser irradiation (660 nm) was carried out on the mice skin over the upper bronchus for 5 min after initiating reperfusion. Neutrophils activation was determined by myeloperoxidase (MPO) activity. The mRNA expression and protein concentration of inflammatory mediators IL-1β, IL-6, TNF and IL-10 in lung were measured by RT-PCR and ELISA, respectively. With exception of 1J/cm(2), LLLT reduced MPO activity as well as IL-1β levels in the lungs from inflamed mice. LLLT was also markedly effective in reducing both IL-6 and TNF expression and levels in the lungs from mice submitted to i-I/R in all laser doses studied. Otherwise, LLLT significantly increased the protein levels of IL-10 in inflamed mice by i-I/R; however only in the dose of 1J/cm(2). We conclude that the LLLT is able to control the neutrophils activation and proinflammatorycytokines release into the lungs in a model of i-I/R in mice.


Major trauma in elderly adults receiving lipid-lowering medications.
Some clinical trials, laboratory experiments, and in vitro studies suggest that lipid-lowering medications predispose a person to traumatic injury. We used population-based administrative database analysis to study adults age 65 years or more over a 5-year interval (n = 1,348,259). About 12% of the cohort received a prescription for a lipid-lowering medication and about 88% did not. The two groups had similar distributions of age, gender, and income. Overall, 2,557 (0.2%) were hospitalized for major trauma. Those who received a lipid-lowering medication were 39% less likely to sustain a major trauma than those who did not receive such medication (95% confidence interval, 29 to 47). Similar results were observed after adjustment for age, gender, and income; cardiac and neurologic medications; and lethality. No other cardiac or neurologic medication was associated with an apparent safety advantage. Lipid-lowering medications do not lead to a clinically important increase in the absolute risk of major trauma for elderly patients in the community.


Characterization of a stable, major DNA polymerase alpha species devoid of DNA primase activity.
We have purified from Xenopus laevis ovaries a major DNA polymerase alpha species that lacked DNA primase activity. This primase-devoid DNA polymerase alpha species exhibited the same sensitivity as the DNA polymerase DNA primase alpha to BuAdATP and BuPdGTP, nucleotide analogs capable of distinguishing between DNA polymerase delta and DNA polymerase DNA primase alpha. The primase-devoid DNA polymerase alpha species also lacked significant nuclease activity indicative of the alpha-like (rather than delta-like) nature of the DNA polymerase. Using a poly(dT) template, the primase-devoid DNA polymerase alpha species elongated an oligo(rA10) primer up to 51-fold more effectively than an oligo(dA10) primer. In direct contrast, the DNA polymerase DNA primase alpha complex showed only a 4.6-fold preference for oligoribonucleotide primers at the same template/primer ratio. The catalytic differences between the two DNA polymerase alpha species were most dramatic at a template/primer ratio of 300. The primase-devoid DNA polymerase alpha species was found at high levels throughout oocyte and embryonic development. This suggests that the primase-devoid DNA polymerase alpha species could play a physiological role during DNA chain elongation in vivo, even if it is chemically related to DNA polymerase DNA primase alpha.


Perinatal and long-term outcomes in fetuses diagnosed with isolated unilateral ventriculomegaly: systematic review and meta-analysis.
The majority of studies on fetal ventriculomegaly have focused on the perinatal and long-term outcomes in fetuses with an antenatal diagnosis of bilateral ventriculomegaly. The aim of this study was to undertake a systematic review and meta-analysis to quantify the perinatal and long-term outcomes in fetuses diagnosed in the second or third trimester of pregnancy with isolated unilateral ventriculomegaly. MEDLINE, EMBASE and The Cochrane Library were searched electronically. Outcomes investigated included incidence of aneuploidy, congenital infection, progression of ventriculomegaly, associated brain and extracerebral abnormalities in the apparently isolated cases and neurodevelopmental delay in both apparently and truly isolated cases. Sensitivity analysis was performed according to whether the ventriculomegaly was mild/moderate (atrial width < 15 mm) or severe (atrial width ≥ 15 mm). Reference lists within relevant articles and reviews were hand-searched for additional reports. Cohort and case-control studies were included. Meta-analysis of proportions was used, and between-study heterogeneity was assessed using the I2 test. The search yielded 2053 citations. The full text was retrieved for 202, and 11 studies were included in the systematic review. In fetuses with apparently isolated unilateral ventriculomegaly, no chromosomal abnormalities were identified and the pooled prevalence of congenital infection was 8.2% (95% CI, 3.6-14.5%). The pooled prevalence of additional brain abnormalities detected prenatally and postnatally by magnetic resonance imaging was 5.1% (95% CI, 0.2-16.1%) and 6.4% (95% CI, 0.3-19.4%), respectively. The pooled prevalence of abnormal neurodevelopment was 5.9% (95% CI, 2.2-11.2%) in apparently isolated cases with an atrial width of < 15 mm, and it was 7.0% (95% CI, 3.2-12.2%) in fetuses with truly isolated unilateral ventriculomegaly. Most cases with apparently isolated ventriculomegaly were classified as mild/moderate (93.5%) and therefore the outcomes in this group were similar to those in the whole cohort of apparently isolated ventriculomegaly. The prevalence of aneuploidy, congenital infection and neurodevelopmental delay in fetuses with a prenatal diagnosis of isolated unilateral ventriculomegaly is likely to be low. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.


[Gunshot injury of the spinal cord].
108 pigs were shot at the level of lumbar 1 to investigate the changes of spinal cord in relation to the speed of shooting and the trajectory through which the bullet passed. The cord lesions of the specimens could be divided, according to its severity, into 4 grades: (1) transection in 41; (2) complete destruction in 43; both lesion 1&2 resulted in permanent paraplegia; (3) incomplete destruction in 13, those resulted in incomplete paraplegia eventually recovered; (4) mild damage, that was concussion in 11, resumed perfectly. Through a transducer sealed into the spinal canal, the intracanal pressure was recorded: (1) Shooting through spinal canal with a pressure over 5 kg caused cord transection. (2) shooting through canal wall with a pressure of 2.5 to 5; 0 kg caused complete cord destruction. (3) shooting nearby the outer margin of vertebra with a pressure less than 1.0 kg caused mild cord damage. It was found that the speed of bullet, the trajectory with relation to cord and the grade of cord lesion are in agreement with each other. The mutual effects among them would make one think it reasonable to classify cord injury as follows: 1. Injury from bullet through spinal canal or vertebral body usually causes cord transaction; 2. Injury from bullet through canal wall at high speed would make a chance of complete destruction in 94%; at low speed, a chance of either complete or incomplete lesion in 50% each. 3. Injury nearby vertebra, high speed bullet would cause a chance of complete cord lesion in 86%; low speed one would make a chance of incomplete lesion in 1/3 and mild lesion in 2/3.


Effect of oil extraction methods on walnut oil quality characteristics and the functional properties of walnut protein isolate.
Walnut oils were obtained by supercritical carbon dioxide extraction (SCB), cold-pressing (CP), hexane extraction (HE), and subcritical butane extraction (SBE), and walnut protein isolates (WPI) from the walnut cakes were performed. The results indicate that SCB has the highest oil yield for walnut oil, which was 62.72%, and the total content of trace nutrients (total tocopherols, total phytosterols, and total phenolic compounds) in SCB-walnut oil was also the highest at 2186.75 mg/kg, approximately 1.05 times higher than CP-walnut oil and 1.21 times higher than SBE-walnut oil. Meanwhile, the treatment of WPI with SCB results in a decrease in β-Sheet and α-Helix structures and an increase in β-Turn and Random coil structures. Thereby increasing its oil-holding capacity (OHC) and solubility by approximately 1.16 times and 1.27 times compared to CP, respectively. Interestingly, SCB as a green oil production technology, also has good prospects for retaining WPI functionality characteristics.


Us helping us: The evolution of a peer support group for formerly incarcerated people.
Physical, psychological, and emotional trauma experienced while incarcerated influences subsequent mental health outcomes. Upon release, there is a fragmented landscape of mental health services and many of the existing services do not account for the root causes of challenges faced by formerly incarcerated people (FIP). To address the unmet social, psychological, behavioral, and emotional needs of FIP in Louisiana, the Formerly Incarcerated Peer Support (FIPS) Group developed a twelve-unit curriculum in 2019. We detail the evolution, development, and evaluation of the FIPS Group program. Additionally, we describe the community-driven process for developing the curriculum. The FIPS Group has grown from informal meetings of a handful of FIP in New Orleans, Louisiana, into a multi-state, interdisciplinary network of more than 150 stakeholders. FIPS Group has developed the only peer support curriculum we are aware of that is designed by FIP, for FIP, and uses the shared experience of incarceration and reentry as its organizing principle. Limitations of the model include the lack of pending evaluation data and challenges with technological proficiency among FIP. The FIPS Group model may be generalized in a number of settings. Similar approaches may benefit the mental health of the millions of Americans involved in the criminal-legal system.


Culturally competent social robots target inclusion in Africa.
Embedding culturally sensitive body, hand, and facial gestures in social robots will make them more acceptable in Africa.


[Vestibular nystagmus as a result of the interactions between semicircular canals and the otolithic membrane subsystems of the vestibular system].
Untreated and treated (unilateral section of utricular and saccular branches of the vestibular nerve) pigeons Columba livia were rotated in the dark in the horizontal plane, the head being in a different position relative to the axis of rotation. The range of angular acceleration was 7-19 deg/c2 and the peak value of centrifugal acceleration was 0.5 g. The neck and eye nystagmus was recorded. It was found that: 1) the result of canal-otolith interaction was not directly related to the pattern of changes of otolith afferentation but was determined by the ratio of otolith afferent signals in the right and left labyrinths and, consequently, by the ratio of patterns of activities in the CNS paired structures that receive otolith afferentation; 2) the same result of interaction (enhancement or attenuation of vestibular responses) can be achieved through both increase or decrease of otolith afferentation; 3) if joint stimulation of semicircular canals and otolith organs induces asymmetry of neuronal activities of paired brain structures that perceive otolith afferentation, then, irrespective of the mechanism of origin of this asymmetry, it is followed by changes of oppositely directed nystagmus of different sign (increase for one nystagmus and decrease for the other). It is concluded that the symmetry of reactions recorded in response to isolated stimulation of semicircular canals (otolith organs) cannot be considered as a reliable criterion of functional symmetry of semicircular canals (otolith organs).


Heterogeneity among enhancer RNAs: origins, consequences and perspectives.
Enhancer RNAs (eRNAs) are non-coding RNAs transcribed from distal cis-regulatory elements (i.e. enhancers), which are stereotyped as short, rarely spliced and unstable. In fact, a non-negligible fraction of eRNAs seems to be longer, spliced and more stable, and their cognate enhancers are epigenomically and functionally distinguishable from typical enhancers. In this review, we first summarized the genomic and molecular origins underlying the observed heterogeneity among eRNAs. Then, we discussed how their heterogeneous properties (e.g. stability) affect the modes of interaction with their regulatory partners, from promiscuous cis-interactions to specific trans-interactions. Finally, we highlighted the existence of a seemingly continuous spectrum of eRNA properties and its implications in the genomic origins of non-coding RNA genes from an evolutionary perspective.


A multicenter case-control study on postoperative intestinal fistula in Chinese patients with Crohn disease.
The aim of this study was to (1) assess the independent factors affecting patients with postoperative intestinal fistula from Crohn disease (CD) by analyzing preoperative clinical data, (2) establish a nomogram prediction model for this condition based on these factors, and (3) validate this model and evaluate its accuracy. In this retrospective multicenter case-control study, the clinical data of 240 patients with CD admitted for surgical treatment between September 2019 and September 2021 at 3 centers were collected. Patients were randomly divided into a training set (168 patients) and a validation set (72 patients). Univariate analysis was performed for relevant factors, and statistically significant factors were then analyzed using multivariate logistic regression to determine the independent influencing factors. A nomogram model for predicting postoperative intestinal fistula in patients with CD was constructed and the accuracy of the model was evaluated using calibration curves. Univariate analysis showed that disease behavior, abdominal abscess, intestinal perforation, neutrophil-to-lymphocyte ratio, systemic immunoinflammatory index, and prognostic nutrition index were factors affecting postoperative intestinal fistula in patients with CD. Multivariate logistic regression analysis showed that neutrophil-to-lymphocyte ratio, prognostic nutrition index, disease behavior, and Crohn disease activity index score were independent influencing factors. After assessing the validation set, the area under the curve was 0.899, indicating good predictive accuracy of the nomogram model. The prediction model developed in this study can effectively predict the risk of postoperative intestinal fistula.


Evidence that gonadotropin-releasing hormone (GnRH) functions as a prolactin-releasing factor in a teleost fish (Oreochromis mossambicus) and primary structures for three native GnRH molecules.
Three forms of gonadotropin-releasing hormone (GnRH) are isolated and identified here by chemical sequence analysis for one species of tilapia, Oreochromis niloticus, and by HPLC elution position for a second species of tilapia, O. mossambicus. Of the three GnRH forms in O. mossambicus, chicken GnRH-II (cGnRH-II) and sea bream GnRH (sbGnRH) are present in greater abundance in the brain and pituitary than salmon GnRH (sGnRH). These three native forms of GnRH are shown to stimulate the release of prolactin (PRL) from the rostral pars distalis (RPD) of the pituitary of O. mossambicus in vitro with the following order of potency: cGnRH-II > sGnRH > sbGnRH. In addition, a mammalian GnRH analog stimulated the release of PRL from the pituitary RPD incubated in either iso-osmotic (320 mosmol/l) or hyperosmotic (355 mosmol/l) medium, the latter normally inhibiting PRL release. The response of the pituitary RPD to GnRH was augmented by co-incubation with testosterone or 17 beta-estradiol. The effects of GnRH on PRL release appear to be direct effects on PRL cells because the RPD of tilapia contains a nearly homogeneous mass of PRL cells without intermixing of gonadotrophs. Our data suggest that GnRH plays a broad role in fish, depending on the species, by affecting not only gonadotropins and growth hormone, but also PRL.


Microbial community of anammox bacteria immobilized in polyethylene glycol gel carrier.
Anaerobic ammonium oxidation (anammox) is a recently discovered microbial pathway in the biological nitrogen cycle and a new cost-effective way to remove ammonium from wastewater. We have so far developed new immobilization technique that anammox bacteria entrapped in polyethylene glycol (PEG) gel carrier. However, fate and behavior of anammox bacteria in a gel carrier is not well understood. In the present study, we focused on the population changes of anammox bacteria in a gel carrier. Three specific primer sets were designed for real-time PCR. For quantification of anammox bacteria in a gel carrier, real-time PCR was performed. The anammox bacteria related to HPT-WU-N03 clone were increased the rate in anammox population, and found to be a major population of anammox bacteria in a gel carrier. Furthermore, from the results of nitrogen removal performance and quantification of anammox bacteria, the correlation coefficient between copy numbers of anammox bacteria and nitrogen conversion rate was calculated as 0.947 in total anammox population. This is the first report that population changes of anammox bacteria immobilized in a gel carrier were evaluated.


Responses of thalamic and hypothalamic neurons to scrotal warming in rats: non-specific responses?
Activities of thalamic and hypothalamic neurons in response to scrotal temperature change were investigated in urethanized (1.2-1.5 g/kg) rats with special attention to changes in cortical electroencephalogram (EEG). Somatosensory relay neurons were identified electrophysiologically in the ventrobasal complex (VB) of the thalamus. These neurons had tactile receptive fields in areas outside the scrotum. Forty out of 44 of these neurons responded to scrotal warming by increase in firing rate. The responses occurred abruptly at threshold temperatures ranging from 31 to 40 degrees C (switching response) with simultaneous changes in EEG from high to low voltages (desynchronization). In both the thalamus and the hypothalamus, neurons excited or inhibited by scrotal warming were also excited or inhibited, respectively, by noxious stimulation that produced EEG desynchronization. Neurons showing no response to scrotal warming were not affected by noxious stimulation. In deeply anesthetized (2.5 g/kg urethane) rats, VB relay neurons responded to tactile stimulation of their receptive fields, but scrotal warming produced no change in either EEG or activities of thalamic and hypothalamic neurons. These facts suggest that the responses of thalamic and hypothalamic neurons to scrotal warming may be 'non-specific'. Most thalamic and hypothalamic neurons showing switching responses did not appear to mediate specific information concerning scrotal skin temperature.


Drivers of the growth in global greenhouse gas emissions.
Greenhouse gas emissions increased by 8.9 Gigatons CO2 equivalent (Gt) in the period 1995-2008. A phenomenon that has received due attention is the upsurge of emission transfers via international trade. A question that has remained unanswered is whether trade changes have affected global emissions. For each of five factors (one of which is trade changes) in 40 countries we quantify its contribution to the growth in global emissions. We find that the changes in the levels of consumption per capita have led to an enormous growth in emissions (+14.0 Gt). This effect was partly offset by the changes in technology (-8.4 Gt). Smaller effects are found for population growth (+4.2 Gt) and changes in the composition of the consumption (-1.5 Gt). Changes in the trade structure had a very moderate effect on global emissions (+0.6 Gt). Looking at the geographical distribution, changes in the emerging economies (Brazil, Russia, India, Indonesia and China) have caused 44% of emission growth whereas the increase in their national emissions accounted for 59% of emission growth. This means that 15% (1.4 Gt) of all extra GHG emissions between 1995 and 2008 have been emitted in emerging countries but were caused by changes in other countries.


Development and Temporal Validation of a Machine Learning Model to Predict Clinical Deterioration.
Early warning scores detecting clinical deterioration in pediatric inpatients have wide-ranging performance and use a limited number of clinical features. This study developed a machine learning model leveraging multiple static and dynamic clinical features from the electronic health record to predict the composite outcome of unplanned transfer to the ICU within 24 hours and inpatient mortality within 48 hours in hospitalized children. Using a retrospective development cohort of 17 630 encounters across 10 388 patients, 2 machine learning models (light gradient boosting machine [LGBM] and random forest) were trained on 542 features and compared with our institutional Pediatric Early Warning Score (I-PEWS). The LGBM model significantly outperformed I-PEWS based on receiver operating characteristic curve (AUROC) for the composite outcome of ICU transfer or mortality for both internal validation and temporal validation cohorts (AUROC 0.785 95% confidence interval [0.780-0.791] vs 0.708 [0.701-0.715] for temporal validation) as well as lead-time before deterioration events (median 11 hours vs 3 hours; P = .004). However, LGBM performance as evaluated by precision recall curve was lesser in the temporal validation cohort with associated decreased positive predictive value (6% vs 29%) and increased number needed to evaluate (17 vs 3) compared with I-PEWS. Our electronic health record based machine learning model demonstrated improved AUROC and lead-time in predicting clinical deterioration in pediatric inpatients 24 to 48 hours in advance compared with I-PEWS. Further work is needed to optimize model positive predictive value to allow for integration into clinical practice.


IFN-gamma induces apoptosis in ovarian cancer cells in vivo and in vitro.
The purpose of this study was to compare in vitro and in vivo responses of primary human tumor cells to IFN-gamma. IFN-gamma may have therapeutic activity in patients with ovarian cancer. We showed previously that this cytokine had direct antiproliferative activity against human ovarian cancer cell lines and xenografts in nude mice. To further understand the role of IFN-gamma in ovarian cancer, we compared its action on 8 ovarian cancer cell lines with the response of 14 primary cultures of ovarian tumor cells isolated from patients with ascitic disease. A pilot clinical study was then conducted to see whether IFN-gamma would also induce apoptosis in human tumor cells in vivo. Six patients with ascites and advanced disease were given IFN-gamma by i.p. injection, and sequential samples of ascites were analyzed. IFN-gamma had antiproliferative activity in 8 of 8 ovarian cancer cell lines and 11 of 14 primary cultures. This activity was dose related, and cleaved poly(ADP-ribose) polymerase in protein isolates provided evidence of apoptosis. In the clinical study, there was a 3 log(10) pharmacokinetic advantage in peritoneal compared with plasma levels of IFN-gamma. In two of six patients, there was a 90% reduction in tumor cells in ascites after IFN-gamma treatment, and this was related to clinical benefit as assessed by intervals between paracentesis. In all six patients, there were increased amounts of cleaved poly(ADP-ribose) polymerase in protein extracts of ascitic cells sampled during IFN-gamma treatment. IFN-gamma induces apoptosis in vitro and in vivo in human epithelial ovarian cancer.


Proteinaceous microspheres for targeted RNA delivery prepared by an ultrasonic emulsification method.
In the present work we used sonochemically prepared proteinaceous BSA spheres as a novel RNA-delivery system. The preparation of RNA-loaded BSA spheres was accomplished using an environmental friendly method termed the "ultrasonic emulsification method". It was demonstrated that ultrasonic waves do not cause the RNA chains to degrade and the RNA molecules remain untouched. The BSA-RNA complex was successfully introduced into mammalian (human) U2OS osteosarcoma cells and Trypanosoma brucei parasites. Using PVA coating of the RNA-BSA spheres we have achieved a significant increase in the number of microspheres penetrating mammalian cells. The mechanism of RNA encapsulation and the structure of the RNA-BSA complex are reported.


[Actin cytoskeleton organization and spreading of bone marrow stromal cells and cartilage cells during their combined and independent cultivation on different extracellular matrix proteins].
To clarify the mutual influence of bone marrow stromal cells (BMSCs) and cartilage cells we studied the organization of their actin cytoskeleton and cell spreading on different extracellular matrix proteins--laminin 2/4, collagen type I or fibronectin. It has been shown that the most pronounced difference in morphological characteristics of the cells such as their form, size and actin cytoskeleton organization occur in the case of interaction with fibronectin. So, after separate brief incubation of both cell types on fibronectin, the average area of BMSCs spreading was about 4 times greater than the area of the cartilage cell spreading. However, in the co-culture of these cells in a ratio of 1:1, the average jointed spreading area on fibronctin was nearly 1.5 times less than the theoretically calculated. To determine the nature of exposure of the cells to each other we have studied spreading of these cells in the media conditioned by another cell type. We have found that the area of BMSC's spreading in the medium conditioned by cartilage cells is markedly smaller than the area of spreading of the same cells in the control medium. These data suggest that the cartilage cells secrete factors that reduce BMSC's spreading.


Effects of localized and general fatigue on static and dynamic postural control in male team handball athletes.
In team sports, sensorimotor impairments resulting from previous injuries or muscular fatigue have been suggested to be factors contributing to an increased injury risk. Although it has been widely shown that physical fatigue affects static postural sway, it is still questionable as to what extent these adaptations are relevant for dynamic, sports-related situations. The objective of this study was to determine the effects of whole-body and localized fatigue on postural control in stable and unstable conditions. Nineteen male team handball players were assessed in 2 sessions separated by 1 week. Treadmill running and single-leg step-up exercises were used to induce physical fatigue. The main outcome measures were center of pressure (COP) sway velocity during a single-leg stance on a force plate and maximum reach distances of the star excursion balance test (SEBT). The COP sway velocity increased significantly (p < 0.05) after general (+47%) and localized fatigue (+10%). No fatigue effects were found for the SEBT. There were no significant correlations between COP sway velocity and SEBT mean reach in any condition. The results showed that although fatigue affects static postural control, sensorimotor mechanisms responsible for regaining dynamic balance in healthy athletes seem to remain predominantly intact. Thus, our data indicate that the exclusive use of static postural sway measures might not be sufficient to allow conclusive statements regarding sensorimotor control in the noninjured athlete population.


Estimation of body fat from skinfold thicknesses in middle-aged and older men and women: A multiple component approach.
The relationship of skinfold thicknesses and body density to body fatness was assessed, and skinfold prediction equations were developed for the estimation of body fatness determined from measures of body density, total body water, and bone mineral in a sample of 91 males and 116 females aged 34-84 years. For a given skinfold thickness, adjustment for individual deviations in the water and bone mineral fractions of the fat-free body assumed constant by traditional body composition models resulted in absolute reductions in overstimates of body fatness from 4.5 to 1.9% in females and from 2.8 to 1.7% in males for every 15 year increase in age. Percentage fat from density, water, and bone was estimated from skinfold thicknesses with SEEs of 2.9% in males and 3.8% in females. When compared to percentage fat from our multicomponent-derived criterion, percentage fat from body density and a two-component model resulted in individual errors ranging from underestimates of 5.6% fat to overestimates of 14.0% fat. The multicomponent prediction equations presented herein should produce more valid estimates of body composition in middle-aged and older men and women than equations based on two-component models. © 1992 Wiley-Liss, Inc.


SIMPLE TESTS OF RENAL FUNCTION USING CREATININE, PHENOLSULPHONPHTHALEIN, AND PITRESSIN.
The reciprocals of the blood urea nitrogen and plasma creatinine levels, the maximum specific gravity of the urine after vasopressin, and three modified forms of the phenolsulphonphthalein (P.S.P.) excretion test were found to be directly related to the glomerular filtration rate (G.F.R.) in hospital patients. From 34 to 75 patients were studied for each test, and in 21 patients all tests were performed concurrently. The plasma creatinine level and the 15-minute urinary excretion of P.S.P. were found to be the most useful simple tests of renal function and gave sufficiently accurate estimates of total function (G.F.R.) to justify their more extensive use. The G.F.R. (ml./min./1.73 sq. m. of body surface area) could be calculated from each test, using the following equations:- [Formula: see text] G.F.R. = 3.15 x P.S.P.% + 19, where P.S.P.% is the 15-minute urinary excretion of P.S.P., expressed as a percentage of the administered dose. Satisfactory estimates of G.F.R. were also given by the simplified relationships [Formula: see text]. In the presence of impaired renal function more accurate estimates of G.F.R. were obtained from the plasma creatinine and P.S.P. excretion tests (S.D. of estimate 8 and 13 ml./min. respectively). It was thought that these tests could well replace the commonly used blood urea nitrogen estimation as simple tests of renal function.


The global problem of early deaths in acute promyelocytic leukemia: A strategy to decrease induction mortality in the most curable leukemia.
Acute promyelocytic leukemia (APL) is a hyper-acute illness and presents with profound cytopenias in most patients and disseminated intravascular coagulation (DIC). Excellent treatment options are now available with drugs such as all-trans retinoic acid (ATRA), arsenic trioxide (ATO), anthracyclines and cytarabine. The outcome in APL has improved tremendously in the last 50years due to better understanding of the disease, development of effective targeted agents and improvement in supportive care. Carefully selected groups of patients treated in large multi-center trials on a protocol and in experienced centers have shown survival rates in excess of 85%. However population data and other studies show that approximately 30% of patients die during induction. This is an Institutional, national and global problem and remains a pressing and frustrating challenge in APL. While most APL experts are aware of the high rate of early deaths (ED), such awareness is not typically present among general hematologists and oncologists. Our area of focus over the last 7years has been the reduction of ED in both academic and community centers; as a result we have acquired substantial experience in APL induction. Two centers have implemented population-wide prospective trials; Brazil and Georgia/South Carolina, USA with improvement in the ED rate. Both centers used standardized guidelines along with consultative support and sharing of expertise which proved effective and helped to decrease ED. Induction mortality in APL is 30% or greater. We believe ED is largely preventable and population-wide survival can be improved. An effective strategy is to utilize a set of simplified treatment guidelines coupled with support from a group of experts during induction. Treating oncologists in both academic and community hospitals should receive aggressive education about ED and be encouraged to seek advice from a core group of established APL experts. This model could be implemented nationally to improve population-wide survival in this most curable leukemia.


Racial and Ethnic Differences in Knowledge About One's Dementia Status.
To examine racial and ethnic differences in knowledge about one's dementia status. Prospective cohort study. The 2000 to 2014 Health and Retirement Study. Our sample included 8,686 person-wave observations representing 4,065 unique survey participants, aged 70 years or older, with dementia, as identified by a well-validated statistical prediction model based on individual demographic and clinical characteristics. Primary outcome measure was knowledge of one's dementia status, as reported in the survey. Patient characteristics included race/ethnicity, age, sex, survey year, cognition, function, comorbidity, and whether living in a nursing home. Among subjects identified as having dementia by the prediction model, 43.5% to 50.2%, depending on the survey year, reported that they were informed of the dementia status by their physician. This proportion was lower among Hispanics (25.9%-42.2%) and non-Hispanic blacks (31.4%-50.5%) than among non-Hispanic whites (47.7%-52.9%). Our fully adjusted regression model indicated lower dementia awareness among non-Hispanic blacks (odds ratio [OR] = 0.74; 95% confidence interval [CI] = 0.58-0.94) and Hispanics (OR = 0.60; 95% CI = 0.43-0.85), compared to non-Hispanic whites. Having more instrumental activity of daily living limitations (OR = 1.65; 95% CI = 1.56-1.75) and living in a nursing home (OR = 2.78; 95% CI = 2.32-3.32) were associated with increased odds of subjects reporting being told about dementia by a physician. Less than half of individuals with dementia reported being told by a physician about the condition. A higher proportion of non-Hispanic blacks and Hispanics with dementia may be unaware of their condition, despite higher dementia prevalence in these groups, compared to non-Hispanic whites. Dementia outreach programs should target diverse communities with disproportionately high disease prevalence and low awareness. J Am Geriatr Soc 68:1763-1770, 2020.


Strategies to improve deep learning-based salivary gland segmentation.
Deep learning-based delineation of organs-at-risk for radiotherapy purposes has been investigated to reduce the time-intensiveness and inter-/intra-observer variability associated with manual delineation. We systematically evaluated ways to improve the performance and reliability of deep learning for organ-at-risk segmentation, with the salivary glands as the paradigm. Improving deep learning performance is clinically relevant with applications ranging from the initial contouring process, to on-line adaptive radiotherapy. Various experiments were designed: increasing the amount of training data (1) with original images, (2) with traditional data augmentation and (3) with domain-specific data augmentation; (4) the influence of data quality was tested by comparing training/testing on clinical versus curated contours, (5) the effect of using several custom cost functions was explored, and (6) patient-specific Hounsfield unit windowing was applied during inference; lastly, (7) the effect of model ensembles was analyzed. Model performance was measured with geometric parameters and model reliability with those parameters' variance. A positive effect was observed from increasing the (1) training set size, (2/3) data augmentation, (6) patient-specific Hounsfield unit windowing and (7) model ensembles. The effects of the strategies on performance diminished when the base model performance was already 'high'. The effect of combining all beneficial strategies was an increase in average Sørensen-Dice coefficient of about 4% and 3% and a decrease in standard deviation of about 1% and 1% for the submandibular and parotid gland, respectively. A subset of the strategies that were investigated provided a positive effect on model performance and reliability. The clinical impact of such strategies would be an expected reduction in post-segmentation editing, which facilitates the adoption of deep learning for autonomous automated salivary gland segmentation.


Gastrointestinal symptoms as an extended clinical feature of Pierson syndrome: a case report and review of the literature.
Pierson syndrome (PS) is a rare autosomal recessive disorder, characterized by congenital nephrotic syndrome and microcoria. Advances in renal replacement therapies have extended the lifespan of patients, whereas the full clinical spectrum of PS in infancy and beyond remains elusive. We present the case of a 12-month-old boy with PS, manifesting as the bilateral microcoria and congenital nephrotic syndrome. He was born without asphyxia, and was neurologically intact from birth through the neonatal period. Generalized muscle weakness and hypotonia were recognized from 3 months of age. The infant showed recurrent vomiting at age 5 months of age, and was diagnosed with gastroesophageal reflux and intestinal malrotation. Despite the successful surgical treatment, vomiting persisted and led to severely impaired growth. Tulobuterol treatment was effective in reducing the frequency of vomiting. Targeted sequencing confirmed that he had a compound heterozygous mutation in LAMB2 (NM_002292.3: p.Arg550X and p.Glu1507X). A search of the relevant literature identified 19 patients with severe neuro-muscular phenotypes. Among these, only 8 survived the first 12 months of life, and one had feeding difficulty with similar gastrointestinal problems. This report demonstrated that severe neurological deficits and gastrointestinal dysfunction may emerge in PS patients after the first few months of life.


Highly sensitive methods based on seminested real-time reverse transcription-PCR for quantitation of human immunodeficiency virus type 1 unspliced and multiply spliced RNA and proviral DNA.
The effectiveness of highly active antiretroviral therapy (HAART), the standard of care for the treatment of human immunodeficiency virus type 1 (HIV-1) infection, is assessed by measuring the viral RNA load in plasma. A patient is considered to be successfully treated when the HIV-1 load in plasma stays below the detection limit of commercial assays. However, virus replication and evolution do continue in patients under HAART, which may eventually result in the development of drug-resistant HIV-1 strains and therapy failure. To monitor this low-level virus replication in peripheral blood mononuclear cells (PBMC), sensitive methods are required to measure HIV-1 molecular markers. We report the development of highly sensitive methods for the quantitation of unspliced and multiply spliced HIV-1 RNA and proviral DNA in PBMC. The methods are based on innovative seminested real-time reverse transcription-PCR (RT-PCR) that combines the accuracy and precision of real-time PCR and the sensitivity of nested PCR. We show that the newly developed methods are superior to the conventional single-step real-time RT-PCR in their sensitivity, accuracy, dynamic range, and the power of quantitative detection of HIV-1 RNA and DNA in clinical samples. These easy-to-perform methods can be widely used in research, including clinical studies, to monitor intracellular processes of virus replication.