Mass spectrometric method for distinguishing isomers of dexamethasone via fragment mass ratio: An HRMS approach.
The major challenge in identifying dexamethasone, betamethasone, and paramethasone from a mixture of these corticosteroids is difficulty in achieving an efficient separation. In this study, we aimed to develop an efficient technique to identify these co-eluting isomers based on the mass spectral patterns of them and their corresponding phase II metabolites after electrospray ionization. Fragmentation pathways in tandem mass spectrometry revealed acceptable specificity within the groups of conjugates. The method was validated using individual isomers and mixtures at various compositions. The effects of concentration and collision energies on fragmentation patterns were also studied extensively. Matrix-fortified equine urine and plasma samples were also included so that matrix effects and interferences on fragmentation ratios could be elucidated. Preliminary results using biological samples demonstrated the suitability of this analytical strategy for direct measurement from their fragmentation patterns. Possible fragmentation pathways for each isomer were proposed.


Phase II trial of combination chemotherapy with cisplatin, carboplatin and etoposide in stage IIIB and IV small-cell lung cancer. Fukuoka Lung Cancer Study Group.
A phase II trial combining cisplatin, carboplatin and etoposide was conducted in previously untreated patients with stage IIIB and IV small-cell lung cancer, in an attempt to increase response rates and prolong survival. Previously untreated patients with small-cell lung cancer, with measurable disease, aged < or = 72 years, performance status < or = 2, and adequate hematologic, hepatic and renal function were enrolled in the study. They were treated with 80 mg/m2 cisplatin on day 1, 100 mg/m2 carboplatin on days 2, 3 and 8, and 50 mg/m2 etoposide on days 1, 2, 3 and 8. A total of 46 patients (20 with stage IIIB and 26 with stage IV disease) were enrolled in the study. A total of 186 courses of chemotherapy were given, and the dose was reduced in 27 courses (15%). The chemotherapy was repeated for four or more courses in 30 patients. There were 10 complete responses and 32 partial responses, for a total response rate of 91% (95% confidence interval, 79% to 98%). The median survival time and 2-year survival rates were 18 months and 22% for stage IIIB disease, and 14 months and 15% for stage IV disease. Major side effects were hematologic: leukopenia, anemia, and thrombocytopenia of grade 3 or more occurred in 48%, 46%, and 43% of patients, respectively. The three-drug regimen of cisplatin, carboplatin and etoposide is feasible and active against small-cell lung cancer.


RP-HPLC method for the quantitative analysis of naturally occurring flavonoids in leaves of Blumea balsamifera DC.
A selective and sensitive reversed-phase (RP) high-performance liquid chromatographic method is developed for the quantitative analysis of five naturally occurring flavonoids of Blumea balsamifera DC, namely dihydroquercetin-7,4'-dimethyl ether (DQDE), blumeatin (BL), quercetin (QN), 5,7,3',5'-tetrahydroxyflavanone (THFE), and dihydroquercetin-4'-methyl ether (DQME). These compounds have been isolated using various chromatographic methods. The five compounds are completely separated within 35 min using an RP C18, Nucleosil column and with an isocratic methanol-0.5% phosphoric acid (50:50, v/v) mobile phase at the flow rate of 0.9 mL/min. The separation of the compounds is monitored at 285 nm using UV detection. Identifications of specific flavonoids are made by comparing their retention times with those of the standards. Reproducibility of the method is good, with coefficients of variation of 1.48% for DQME, 2.25% for THFE, 2.31% for QN, 2.23% for DQDE, and 1.51% for BL. The average recoveries of pure flavonoids upon addition to lyophilized powder and subsequent extraction are 99.8% for DQME, 99.9% for THFE, 100.0% for BL, 100.6% for DQDE, and 97.4% for QN.


Platelet aggregation as a sign of septicemia in thermal injury. A prospective study.
Serial measurements of coagulation activity, platelet counts, and platelet aggregation were done in patients with full-thickness burns involving 25% or more of body surface area to detect specific changes that might correlate with the onset of septicemia. Mean and maximal values for prothrombin time, partial thromboplastin time, thrombin time, activities of factor V and factor VIII, and concentrations of fibrinogen and fibrinogen-related antigens observed in the presence of bacterial septicemia did not differ significantly from those observed in the absence of septicemia. Mean platelet counts were significantly less with sepsis, but values in individual subjects were not indicative of the presence of septicemia. By contrast, platelet aggregation in response to adenosine diphosphate, epinephrine, and collagen always became severely abnormal with the onset of septicemia but not in the absence of sepsis.


Severe thoracic kyphosis in the older patient in the absence of vertebral fracture: association of extreme curve with age.
Limited data exist on the natural history of thoracic kyphosis in elderly patients. The purpose of this study was to determine the statistical distribution of the thoracic kyphotic angle (TKA) measurement in older patients without vertebral body abnormalities when compared with a young population. The TKA was measured by Cobb angle on digital lateral chest radiographs in 90 patients >65 years of age, 60 patients 51-65 years of age, 67 patients 36-50 years of age, and 63 patients 18-35 years of age. Patients with vertebral compression, vertebral body angulation, congenital anomaly, or significant scoliosis were excluded. In patients >65 years of age, average TKA was 41.9 degrees , but the distribution was unexpectedly bimodal, with a low mode at 28.3 degrees and an upper mode at 51.5 degrees (P < .001). Elderly women and men independently demonstrated a bimodal TKA distribution. Two-thirds of elderly women and half of elderly men had a TKA >40 degrees (upper mode). In young patients, average TKA was 26.8 degrees . In middle-aged patients, TKA was intermediate and nonbimodal. The TKA distribution in elderly patients (>65 years) without vertebral body abnormality is unexpectedly bimodal (non-normal distribution) with a subpopulation of patients significantly more affected by extreme kyphosis. Extreme thoracic kyphosis therefore occurs independently in a large subset of people, in the absence of vertebral wedge compression. The development of extreme thoracic kyphosis might contribute to excess biomechanical stress in the spine and may identify a population at risk for future vertebral compression fracture in particular at the thoracolumbar junction.


Service users' expectations of treatment and support at the Community Mental Health Centre in their recovery.
Focus on service users' needs, coping and empowerment, user involvement, and comprehensiveness are supposed to be key elements of the Community Mental Health Centres in Norway. Taking a user-oriented approach means acknowledging the individual's own expectations, aims and hopes. However, studies that have investigated service users' expectations of treatment and support at Community Mental Health Centres are hard to find. The aim of the study was therefore to explore service users' expectations at the start of treatment at a Community Mental Health Centre. Within a collaborative framework, taking a hermeneutic-phenomenological approach, ten service users participated in in-depth interviews about their expectations, hopes and aims for treatment and recovery. The participants sought help due to various mental health issues that had interfered with their lives and created disability and suffering. A data-driven stepwise approach in line with thematic analysis was used. The study was approved by the Norwegian Social Science Data Services. The following four main themes representing participants' expectations at the start of treatment were elicited: hope for recovery, developing understanding, finding tools for coping and receiving counselling and practical assistance. Participants' expectations about treatment were tightly interwoven with their personal aims and hopes for their future life, and expectations were often related to practical and financial problems, the solution of which being deemed necessary to gain a safe basis for recovery in the long run. The transferability of the results may be limited by the small number of participants. The study emphasises how important it is that service users' personal aims and expectations guide the collaborative treatment process. In addition to providing treatment aimed at improving symptoms, Community Mental Health Centres should take a more comprehensive approach than today by providing more support with family issues, social life, education, work and financial issues.


MDMA elicits behavioral and neurochemical sensitization in rats.
Rats were treated with repeated injections of saline or one of two doses of (+/-)3,4-methylenedioxymethamphetamine (MDMA; 5 or 20 mg/kg, s.c.). Rats pretreated with either of the two repeated MDMA treatment regimens demonstrated an augmented increase in motor activity to an injection of MDMA made 12 days after the last repeated injection compared with either the first MDMA injection or MDMA given to animals pretreated with repeated saline. Furthermore, animals pretreated with the highest dose of repeated MDMA revealed a greater behavioral response to cocaine (15 mg/kg, i.p.). Microdialysis was conducted in the nucleus accumbens and the capacity of MDMA (5 mg/kg, s.c.) to elevate extracellular dopamine content was augmented in rats pretreated with repeated MDMA compared with the animals pretreated with repeated saline. These data reveal repeated MDMA administration produces behavioral sensitization and enhanced dopamine transmission in the nucleus accumbens of rats.


The reduced local lymph node assay: the impact of group size.
The local lymph node assay (LLNA) is a skin sensitization test that provides animal welfare benefits. To reduce animal usage further, a modified version (rLLNA) was proposed. Conducting the rLLNA as a screening test with a single high dose group and vehicle control differentiated accurately between skin sensitizers and non-sensitizers. This study examined whether a reduction in animal number/group is feasible. Historical data were utilized to examine the impact of conducting the rLLNA with two mice/group. To assess the effect on the stimulation index (SI) 41 datasets with individual animal data derived using five mice/group were analysed. SIs were calculated on all possible combinations of two control and two high dose group disintegrations per minute (dpm) values. For 25 of 33 sensitizer datasets, > 96% of possible dpm combinations resulted in a calculated SI > 3. The lowest percentages of positive SIs were observed with weak allergens when, in the standard LLNA, the mean SIs would have been nearer to the threshold value of 3. The results indicate that moderate, strong and extreme allergens are more likely than weak allergens to be identified as sensitizers when group sizes of two mice are used within the rLLNA. It is concluded that a rLLNA with two mice/group would display decreased sensitivity and is inappropriate for use in hazard identification.


Isolation and structural characterization of insulin from the holocephalan fish, Chimaera monstrosa (rabbit fish).
Insulin has been isolated from the pancreas of the holocephalan fish, Chimaera monstrosa (rabbit fish), and characterized by automated Edman degradation and fast atom bombardment mass spectrometry. The primary structure of rabbit fish insulin was identical to that of insulin from the holocephalan fish, Hydrolagus colliei (Pacific ratfish), and contained 21 residues in the A-chain and 38 residues in the B-chain. The amino acid compositions of both rabbit fish and ratfish insulins demonstrated a value consistently lower than that expected for the leucine content of the peptides. It is suggested, therefore, that the insulins were probably isolated as a mixture of the intact peptides and components lacking the C-terminal leucine residue in the B-chain.


[Prognosis in multiple sclerosis].
Prognosis of the natural course of multiple sclerosis is most often measured on Kurtzke's "expanded disability status scale" (EDSS), a non-linear scale over 20 steps, heavily weighted on mobility. Optic neuritis and sensory disturbances as initial symptoms, lower age at onset of the disease, female sex and a longer interval between relapses are indicators of a more favorable prognosis. As a rule, disability as measured on this scale 5 years after onset corresponds to 3/4 of the disability status after 15 years. The number of relapses diminishes naturally over the course of the disease. Presence and extent of lesions on the initial MRI of the brain in clinically isolated syndromes are valuable predictors of dissemination of the disease process over the following 5-10 years. New therapies (e.g. interferon beta 1b and 1a, copolymer 1) reduce relapse frequency by 1/3 and diminish the extent of pathological lesions in brain MRI, but fail to show (as yet) significant influence on disability.


[Therapeutic communication of blood: elements for a phenomenologic social psychology of the living].
Blood is the most available and admissible of substitutive human products. However, neither an attitude favourable to its therapeutic transfusion nor a positive representation of blood is sufficient to predict an effective gift or an absence of fear to its reception. In this article, we synthesize various research of social psychology aiming at understanding what are these different bloods that the subjects accept or refuse to communicate. In order to give a new interpretation of the problems of the social communication of substitutive human product, we will evoke practice, attitudes and representations of blood starting from a model including seven factors of representation of biological materials - this model reflecting dimensions on which is based the intersubjective social network in which is carried out the therapeutic communication of blood.


Applications of the Premack Principle: A Review of the Literature.
The Premack principle states that any Response A can reinforce any other Response B if the independent rate of A is greater than the independent rate of B. This theory demonstrates reinforcer relativity, where the relative probabilities of responses can be more impactful than preference. Applying the Premack principle involves arranging the environment to restrict access to certain responses based on relative probabilities of a set of given responses. Though the Premack principle is described in modern behavior analytic texts, Konarski et al. identified a lack of empirical evidence to support its application. The purpose of the current paper is to systematically review the extant literature using the Premack principle and evaluate how and if researchers have applied reinforcer relativity as described by Premack and the subsequent effectiveness of these procedures. Additionally, we make recommendations for practitioners and future researchers based on our findings.


Computer-tomographic characteristics of root length incisors and canines of the upper and lower jaws in boys and girls with different craniotypes and physiological bite.
In recent years, in world literature appeared research, which focuses on the study of relationships craniotypes with odonto-metric indicators, size, shape of the dental arches and occlusion. However, most of the experts focus on the study of individual features of the structure of the teeth-jaw system in people with different types of faces and aspects of sexual dimorphism and ethnic characteristics. Studies containing information about cranio-typological variability of the roots of teeth we did not encounter. The aim is to reveal features length of roots of incisors and canines of the upper and lower jaw, according to the CT scan in boys and girls of different craniotypes with physiological bite, residents Podilskiy region of Ukraine. The study involved young men with orthognathic bite and their cephalometric performance taken from database from Scientific and Research Center Vinnitsa National Medical University named after Pirogov. To make CT used dental cone beam CT scan - Veraviewepocs 3D, Morita. In the upper and lower incisors and canines were measured vestibular-oral and mesio-distal projection length of the root. The height (length) of the root was measured in the medial (or distal) norm, focusing on border basics crowns (root) and the apex of the tooth root. Established the following distribution craniotype: mesocephalic boys - 16, boys brachycephalic - 19, mesocephalic girls - 16, brachycephalic girls- 26. Statistical analysis of the results was performed using the statistical software package licensed "Statistica 6,0" using non-parametric estimation methods. The peculiarities computed tomographic characteristics of root length incisors and canines of the upper and lower jaws in boys and girls Podilskiy region of Ukraine with different craniotypes and physiological bite have been set. In boys or girls mesocephals majority values of vestibular-oral and mesio-distal projection length of the teeth root, medial and lateral incisors in the upper and lower jaws significantly higher compared to studied similar gender brachycephals. Most values vestibular-oral and mesiodistal projection length of the teeth root, medial and lateral incisors in the upper and lower jaws in boys of total group and brachycephals significantly higher compared with girls of similar comparison groups. In boys mesocephals only value of vestibular-oral projection length of teeth root on the lower jaw was significantly higher compared with girls of the same craniotype. In mesocephalic boys or girls majority values of vestibular-oral and mesio-distal length projection of the root teeth, medial and lateral incisors on the upper and lower jaws significantly higher compared to similar brachycephalic genders studied.


A pulse of insulin and dexamethasone stimulates serum leptin in fasting human subjects.
We have previously shown that dexamethasone increases serum leptin in fed but not in fasted human subjects. We hypothesized that insulin and/or glucose mediated the effect of food intake. The primary aim of this study was to determine whether the administration of a pulse of insulin with dexamethasone was sufficient to increase serum leptin in vivo in fasted human subjects. Whether the presence of transient hyperglycemia and the dose of insulin were important was tested as a secondary aim. Twenty-nine normal subjects were studied. In experiment 1 (meal-like), a pulse of insulin (0.03 U/kg s.c.) and of dexamethasone (2 mg i.v.) was given, and the blood glucose transiently elevated to 50 mg/dl above baseline for the first 2 h. In experiments 2 and 3 (dose-response), the effect of two doses of insulin (0.03 U/kg in experiment 2 and 0.06 U/kg in experiment 3) was tested in combination with dexamethasone, this time without transient hyperglycemia. Nine subjects were studied under fasting conditions, with or without dexamethasone, as a control experiment. A meal-like transient hyperinsulinemia and hyperglycemia, with a pulse of dexamethasone, increased serum leptin levels from baseline by 54+/-21% at 9 h (P=0.038). In the absence of transient hyperglycemia, leptin increased significantly after doses of both insulin and dexamethasone. The effect of insulin was dose-dependent, with a larger increment of serum leptin at 9 h after the highest dose of insulin (75.2+/-15.7% vs 21.3+/-8.5%, P=0.013). Fasting, with or without dexamethasone, resulted in a significant 20% decrease in leptin from morning basal levels. Conversely, the administration of a pulse of insulin and glucose, in the absence of dexamethasone, prevented the drop in serum leptin observed during fasting, regardless of the insulin dose or the serum glucose elevation. With the permissive effect of dexamethasone, a single pulse of insulin triggered a rise in serum leptin in humans, even in the absence of transient hyperglycemia. A single pulse of insulin with glucose can prevent the drop in serum leptin normally observed during fasting.


Hormone replacement therapy (oestradiol-only preparations): can the laboratory recommend a concentration of plasma oestradiol to protect against osteoporosis?
Target concentrations of plasma oestradiol to protect against osteoporosis have now been published in at least one textbook and are increasingly discussed by clinicians. A survey of the literature revealed that many reports do not give details of oestradiol assay methods, despite the fact that there is a wide range of biases. Plasma oestradiol measurements made after ingestion of equine oestrogen preparations are not valid, and for oral oestradiol and oestradiol valerate preparations a single untimed sample does not give a reliable estimate of the average exposure over 24 h. Oestradiol measurements in plasma from women using patch, gel or implant preparations could be useful provided that consideration is given to the time of sampling and to the assay method used, although target levels have not been established. Further studies are required in this area.


Estimating the budget impact of new technologies added to the National List of Health Services in Israel: stakeholders' incentives for adopting a financial risk-sharing mechanism.
The Israeli National List of Health Services (NLHS) is updated annually according to a government allocated budget. The estimated annual cost of each new technology added to this list is based on budget-impact estimations provided by the HMOs and the manufacturers. The HMOs argue that once a new technology is reimbursed, extensive marketing efforts by industry expands demand and renders the allocated budget insufficient. Industry claims that HMOs, in order to secure a sufficient budget, tend to over-estimate the number of target patients. We provide a framework for a financial risk-sharing mechanism between HMOs and the industry, which may be able to balance these incentives and result in more accurate early budget-impact estimates. To explore the current stakeholders' incentives and behaviors under the existing process of updating the NLHS, and to examine the possible incentives for adopting a financial risk-sharing mechanism on early budget-impact estimations. According to the financial risk-sharing mechanism, HMOs will be partially compensated by the industry if actual use of a technology is substantially higher than what was projected. HMOs will partially refund the government for a budget that was not fully used. To maintain profits, we assume that the industry will present a more realistic budget-impact analysis. HMOs will be less apprehensive of technology promotion, as they would be compensated in case of budget under-estimation. In case of over-estimation of technology use, the budget re-allocated will be used to enlarge the NLHS which is in the best interest of the health technology industry. Our proposed risk-sharing mechanism is expected to counter balance incentives and disincentives that currently exist in adopting new health technologies in the Israeli healthcare system.


Ultrafast excited state dynamics of allopurinol, a modified DNA base.
The decay of electronically excited allopurinol riboside was studied through the fluorescence up-conversion technique and high level ab initio calculations. For the allopurinol system with a pyrazolic five-membered ring, we observed an ultrafast decay of the fluorescence signal in water (τ < 0.2 ps), similar to what has been observed for hypoxanthine and inosine (with an imidazolic five-membered ring). These results show that the S(1) dynamics in this type of heterocyclic systems are general and dominated by the distortion in the pyrimidinic six-membered ring with a negligible influence of the rest of the heterocycle. The measurements are consistent with the presence of a highly accessible conical intersection between the S(1) (π-π*) excited state and S(0), as calculated by MR-CIS/CASSCF computations. Our calculations show that the loss of planarity of the six-membered ring is responsible for direct access to the S(1)-S(0) degeneracy region without requiring distortions in the rest of the molecule.


Human BRE1 is an E3 ubiquitin ligase for Ebp1 tumor suppressor.
Human Bre1, an E3 ligase for H2B monoubiquitination, binds p53 and enhances activator-dependent transcription. Ebp1, an ErbB3 receptor-binding protein, inhibits cell proliferation and acts as a tumor suppressor. Here, we show that hBre1 acts as an E3 ubiquitin ligase for Ebp1 tumor suppressor and promotes its polyubiquitination and degradation. Ebp1 is polyubiquitinated in cancer cells, which is regulated by its phosphorylation. We identified hBre1 acting as an E3 ligase for Ebp1 and increasing its polyubiquitination. Depletion of hBre1 blocks Ebp1's polyubiquitination and elevates its protein level, preventing cancer proliferation. hBre1 binds Ebp1 and suppresses its repressive effect on E2F-1. Moreover, Ebp1 protein level is substantially diminished in human cancers. It is robustly phosphorylated and localized in the nucleus of primary gliomas, correlating with hBre1 subcellular residency. Thus, hBre1 inhibits Ebp1's tumor suppressive activity through mediating its polyubiquitination and degradation.


HIV seroprevalence among participants at a Supervised Injection Facility in Vancouver, Canada: implications for prevention, care and treatment.
North America's first government sanctioned medically supervised injection facility (SIF) was opened during September 2003 in Vancouver, Canada. This was in response to a large open public drug scene, high rates of HIV and hepatitis C transmission, fatal drug overdoses, and poor health outcomes among the city's injection drug users. Between December 2003 and April 2005, a representative sample of 1,035 SIF participants were enrolled in a prospective cohort that required completing an interviewer-administered questionnaire and providing a blood sample for HIV testing. HIV infection was detected in 170/1007 (17%) participants and was associated with Aboriginal ethnicity (adjusted Odds Ratio [aOR], 2.70, 95% Confidence Interval [95% CI], 1.84-3.97), a history of borrowing used needles/syringes (aOR, 2.0, 95% CI, 1.37-2.93), previous incarceration (aOR, 1.87, 95% CI, 1.11-3.14), and daily injection cocaine use (aOR, 1.42, 95% CI, 1.00-2.03). The SIF has attracted a large number of marginalized injection drug users and presents an excellent opportunity to enhance HIV prevention through education, the provision of sterile injecting equipment, and a supervised environment to self-inject. In addition, the SIF is an important point of contact for HIV positive individuals who may not be participating in HIV care and treatment.


Increased levels of Gab1 and Gab2 adaptor proteins skew interleukin-4 (IL-4) signaling toward M2 macrophage-driven pulmonary fibrosis in mice.
M2-polarized macrophages, also known as alternatively activated macrophages, have long been associated with pulmonary fibrosis; however, the mechanism has not been fully defined. Gab1 and Gab2 proteins belong to the Gab family of adaptors and are integral components of the signal specificity in response to various extracellular stimuli. In this report, we found that levels of both Gab1 and Gab2 were elevated in M2-polarized macrophages isolated from bleomycin-induced fibrotic lungs. In vitro Gab1/2 deficiency in bone marrow-derived macrophages abrogated IL-4-mediated M2 polarization. Furthermore, in vivo conditional removal of Gab1 (Gab1MyKO) and germ line knock-out of Gab2 (Gab2-/-) in macrophages prevented a bias toward the M2 phenotype and attenuated bleomycin-induced fibrotic lung remodeling. In support of these observations, Gab1/2 were involved in responses predominated by IL-4 signaling, an essential determinant for macrophage M2 polarization. Further investigation revealed that both Gab1 and -2 are recruited to the IL-4 receptor, synergistically enhancing downstream signal amplification but conferring IL-4 signal preference. Mechanistically, the loss of Gab1 attenuated AKT activation, whereas the absence of Gab2 suppressed STAT6 activation in response to IL-4 stimulation, both of which are commonly attributed to M2-driven pulmonary fibrosis in mice. Taken together, these observations define a non-redundant role of Gab docking proteins in M2 polarization, adding critical insights into the pathogenesis of idiopathic pulmonary fibrosis.


Validation of MELD 3.0 scoring system in East Asian patients with cirrhosis awaiting liver transplantation.
Recently, a new predictive model that jointly considers the Model of End-stage Liver Disease (MELD) 3.0 and albumin has been proposed. This study investigated the performance of the MELD 3.0 score in predicting the 3-month survival of East Asian patients with cirrhosis compared with the other MELD-based scores. Validation was performed with the retrospective data of 2153 patients in South Korea who were listed for liver transplantation (LT). Discrimination and calibration analyses were performed using the MELD-based scores as an independent variable. On average, patients had the original MELD score of 18.70 ± 9.65. Alcohol (39.99%) and chronic HBV (38.55%) were the 2 main etiologies. The MELD 3.0 with albumin showed slightly better discrimination [c-index = 0.738, incremental AUC (iAUC) = 0.719] compared with the MELD 3.0 without albumin (c-index = 0.737, iAUC = 0.715), MELD-Na (c-index = 0.730, iAUC = 0.707), or the original MELD (c-index = 0.718, iAUC = 0.687) for predicting 3-month survival but not significantly different compared with prior models. Likewise, in the stratified analysis according to the strata of MELD, although the performance of MELD 3.0 was better throughout all the MELD strata than MELD original, there was no statistical difference in performance. The MELD 3.0 with albumin reclassified 22.61% of cases classified by the original MELD to higher MELD score categories, and there was no significant difference in the reclassification rate between males and females. The predictive power of the MELD-based system is lower in Asian populations than in western countries. Nonetheless, the MELD 3.0 score with albumin was significantly better in predicting the short-term prognosis of East Asian patients on the LT waitlist than the current allocation system, original MELD.


Canine malignant hyperthermia susceptibility: erythrocytic defects--osmotic fragility, glucose-6-phosphate dehydrogenase deficiency and abnormal Ca2+ homeostasis.
Two dogs were diagnosed as malignant hyperthermia susceptible based on increased susceptibility (P less than 0.001) of biopsied muscle to caffeine-induced contracture. Erythrocytes from malignant hyperthermia and normal dogs were then examined for an antioxidant system deficiency. Values for serum muscle enzymes, reticulocytes and corpuscular hemoglobin were mildly elevated. Osmotic fragility was increased: hemolysis occurred at a NaCl concentration 10 mM higher than for normal dogs (P less than 0.001). A 35% glucose-6-phosphate dehydrogenase deficiency (P less than 0.001) with a 40% compensatory increase (P less than 0.01) in 6-phosphogluconate dehydrogenase activity was found. The membrane Ca2+-activated ATPase activity was abnormal: 100% increased with a 40% decreased Arrhenius activation energy (P less than 0.005) and increased thermostability. A 40% increased intracellular accumulation of total Ca2+ occurred in response to in vitro energy depletion in erythrocytes from one malignant hyperthermia dog (P less than 0.01). The multifactorial pattern of inheritance and the broad spectrum of malignant hyperthermia susceptibility are proposed to result from an antioxidant system deficit unmasking or aggravating an intrinsic muscle membrane anomaly. An individual from a family with a history of malignant hyperthermia or unexplained anesthetic death should be considered malignant hyperthermia susceptible if erythrocyte osmotic fragility is abnormal and there is a mild, unexplained elevation in serum creatine kinase.


Effect of a novel nicotinic receptor antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide, on nicotine self-administration and hyperactivity in rats.
Recent work has shown that the novel compound N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) may selectively block nicotinic acetylcholine receptors involved in regulating dopamine release. The current experiments examined the acute effect of bPiDDB on nicotine self-administration, sucrose-maintained responding, and nicotine-induced changes in acute and sensitized locomotor activity. Rats were first trained to respond for either nicotine (i.v.) or sucrose pellets using a standard two-lever operant conditioning procedure using a fixed ratio 5 schedule of reinforcement and were then pretreated with bPiDDB (0, 0.3, 1, or 3 mg kg(-1)) 15 min prior to the session. In separate experiments, rats were assessed for nicotine-induced changes in locomotor activity following pretreatment with bPiDDB (1 or 3 mg kg(-1)) or mecamylamine (1 mg kg(-1)); pretreatments were assessed with both acute and repeated nicotine (0.4 mg kg(-1)) treatment. Results showed that bPiDDB dose-dependently decreased nicotine self-administration, but not sucrose-maintained responding. In the locomotor experiments, bPiDDB attenuated the hyperactivity produced by acute and repeated nicotine; however, this effect was not robust compared to mecamylamine. In contrast to mecamylamine, bPiDDB did not block the initial hypoactivity produced by acute nicotine. Since bPiDDB decreased nicotine self-administration specifically, this novel nicotinic receptor antagonist may constitute a lead for the development of a clinically useful treatment for tobacco dependence.


Assessment of the utilization of a state AIDS/STD hotline by persons with and without HIV infection and their information needs.
A large number of AIDS/sexually transmitted disease (STD) helplines provide support to people seeking information how to avoid infection with HIV or how to deal with the infection if they have already contracted it. Nevertheless, limited knowledge is available about how such helplines are being utilized by different segments of the population and what the main concerns of the people calling the helplines are. The goal of this study was to evaluate the use of the State AIDS/STD Hotline in New Jersey and describe the information needs of its callers. Callers were categorized as either having HIV or being free of the virus based on their self-reported HIV status. A cross-sectional design was then used combining caller information from the New Jersey AIDS/STD Hotline with data from the state health department on the number of people living with HIV in each county in New Jersey. The utilization rate of the New Jersey AIDS/STD Hotline was significantly higher among persons with HIV infection compared to the utilization rate among persons who were either free of the virus or unaware of their HIV status. The callers infected with HIV differed significantly from the rest of the callers in terms of the type of information they requested. While callers who had the infection were most likely to ask about treatment options, financial assistance, and support groups, the rest of the callers were more likely to inquire about testing site location and prevention information.


[Clinical and biochemical aspects of flixotide administration in patients with moderate bronchial asthma].
To compare clinical, device and biochemical aspects of monotherapy with flixotide vs combination of flixotide with serevent in patients with moderate bronchial asthma (MBA). 18 patients with MBA received flixotide and 18 MBA patients flixotide plus serevent for two weeks of lead-in and eight weeks of basic treatment. A special study was made of neutrophils which were examined for activity of LPO-antioxidants and phospholipid spectrum of membranes. There were similar changes in function of the system LPO-antioxidants and lipid structure in neutrophilic membranes of moderate BA patients of both the groups. Clinicobiochemical efficacy of mean doses of a new topic inhalation glucocorticoid flixotide alone or in combination with prolonged beta 2-adrenostimulator serevent is demonstrated. There were positive trends in metabolic processes in neurophilic membrane. Use of flixotide in combination with serevent is clinically preferable.


Synthesis and anticonvulsant properties of new mannich bases derived from 3,3-disubstituted pyrrolidine-2,5-diones. Part IV.
A library of 21 new N-Mannich bases of 3,3-diphenyl- (5a-g), 3-methyl-3-phenyl- (6a-g), and 3-ethyl-3-methylpyrrolidine-2,5-diones (7a-g) were synthesized and evaluated for their anticonvulsant activity in the maximum electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure tests after intraperitoneal injection into mice. The acute neurological toxicity was determined applying the rotarod screen. The results in mice showed that 13 compounds were effective in the MES or/and scPTZ screen. From these, seven molecules were tested in the MES seizures after oral administration in rats. The quantitative studies showed that N-[{4-(2-hydroxyethyl)-piperazin-1-yl}-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6c) and N-[(4-benzylpiperidin-1-yl)-methyl]-3-methyl-3-phenylpyrrolidine-2,5-dione (6f) revealed higher protection in the MES and scPTZ tests than valproic acid or ethosuximide which were used as reference antiepileptic drugs. Four compounds (5c, 6c, 6e, 6f) showed high effectiveness in the 6-Hz psychomotor seizure model of partial and therapy resistant epilepsy.


Nonlinear association structures in flexible Bayesian additive joint models.
Joint models of longitudinal and survival data have become an important tool for modeling associations between longitudinal biomarkers and event processes. The association between marker and log hazard is assumed to be linear in existing shared random effects models, with this assumption usually remaining unchecked. We present an extended framework of flexible additive joint models that allows the estimation of nonlinear covariate specific associations by making use of Bayesian P-splines. Our joint models are estimated in a Bayesian framework using structured additive predictors for all model components, allowing for great flexibility in the specification of smooth nonlinear, time-varying, and random effects terms for longitudinal submodel, survival submodel, and their association. The ability to capture truly linear and nonlinear associations is assessed in simulations and illustrated on the widely studied biomedical data on the rare fatal liver disease primary biliary cirrhosis. All methods are implemented in the R package bamlss to facilitate the application of this flexible joint model in practice.


[Two historical changes in the vicissitudes of Hungarian psychoanalysts in the forties].
Between 1940 and 1950, Hungarian history struck two blows at psychoanalysts--as a movement and in their personal lives. The paper relates several episodes from this period and briefly traces the birth and development of the "Budapest School". Between the two world wars, the small group of Hungarian analysts played a relatively important role in the international movement. During the years of Fascism it was in Hungary that psychoanalysis was able to survive the longest. But in 1944, a quarter of all the Hungarian analysts perished. After the war the analysts' activity was notable chiefly for its extensive nature but after a few years the Association was dissolved. The paper describes the analysts' problems and fluctuating fortunes and also their incessant efforts, inspired by the hope of a theoretical and practical renewal of Hungarian psycho-analysis.


[Study on pyrogen in natural and cultivated edible mushrooms].
We examined endotoxin and pyrogen contents in several kinds of natural and cultivated edible mushrooms, as well as some cultivated vegetables. According to the Japanese Pharmacopoeia, 14th Ed., two types of endotoxin (gel-clot Limulus amebocyte lysate) test and the pyrogen test were performed using natural edible mushrooms collected in Aichi Prefecture and cultivated mushrooms and vegetables purchased at a market. The endotoxin contents of natural mushrooms were apparently higher than those of cultivated mushrooms or vegetables. The endotoxin contents in the cultivated mushrooms were slightly higher than those in the vegetables. Similar results were obtained in the pyrogen test.


Independent control of haze and total transmittance with a dye-doped liquid crystal phase-grating device.
This paper presents a dye-doped liquid crystal (LC) phase-grating cell that is switchable between transparent, dark, and opaque states. The device can control haze and transmittance independently. Initially, LC and dye molecules are twist-aligned to make the cell opaque but haze-free due to the absorption of incident light without scattering. Switching to the transparent state could be achieved by applying a vertical electric field, whereas switching to the opaque state could be achieved by applying an in-plane electric field. It exhibited several advantages, such as a low switching voltage (<18 V) and fast response time (<30 ms).


Multi-frequency band pyroelectric sensors.
A methodology is proposed for designing a multi-frequency band pyroelectric sensor which can detect subjects with various frequencies or velocities. A structure with dual pyroelectric layers, consisting of a thinner sputtered ZnO layer and a thicker aerosol ZnO layer, proved helpful in the development of the proposed sensor. The thinner sputtered ZnO layer with a small thermal capacity and a rapid response accomplishes a high-frequency sensing task, while the thicker aerosol ZnO layer with a large thermal capacity and a tardy response is responsible for low-frequency sensing tasks. A multi-frequency band pyroelectric sensor is successfully designed, analyzed and fabricated in the present study. The range of the multi-frequency sensing can be estimated by means of the proposed design and analysis to match the thicknesses of the sputtered and the aerosol ZnO layers. The fabricated multi-frequency band pyroelectric sensor with a 1 μm thick sputtered ZnO layer and a 20 μm thick aerosol ZnO layer can sense a frequency band from 4000 to 40,000 Hz without tardy response and low voltage responsivity.


[Soluble PD-1 can augment anti-tumor immunity induced by HSP70-peptide complex in tumor-bearing mice].
To explore the effect of soluble PD-1 (sPD-1) on the anti-tumor immunity induced by HSP70-peptide. BALB/c mice were immunized with HSP70-peptide, then the cytotoxic activity of splenocytes was detected by MTT colorimetry. Expression of PD-1 and its ligand on splenocytes was determined by semi-quantitative RT-PCR. For some mice, sPD-1 plasmid was injected alone or in combination with HSP70-peptide and then the tumor weight and cytotoxic activity of splenocytes were measured. sPD-1 alone had anti-tumor effect. HSP70-peptide complex not only induced tumor-specific cytotoxic T lymphocytes(CTLs), but also promoted expression of PD-1 and its ligand. The combination of sPD-1 with HSP70-peptide complex induced much more stronger anti-tumor effect as compared with sPD-1 or HSP70-peptide alone. sPD-1 transfection in mice could enhance the cytotoxic activity of splenocytes from immunized mice. sPD-1 enhanced the anti-tumor efficacy of HSP70-peptide.


Metabolic responses to the acute ingestion of two commercially available carbonated beverages: A pilot study.
The purpose of this placebo-controlled, double-blind cross-over study was to compare the effects of two commercially available soft drinks on metabolic rate. After giving informed consent, twenty healthy men and women were randomly assigned to ingest 12 ounces of Celsiustrade mark and, on a separate day, 12 ounces of Diet Coke(R). All subjects completed both trials using a randomized, counterbalanced design. Metabolic rate (via indirect calorimetry) and substrate oxidation (via respiratory exchange ratio) were measured at baseline (pre-ingestion) and at the end of each hour for 3 hours post-ingestion. Two-way ANOVA revealed a significant interaction (p < 0.001) between trials in metabolic rate. Scheffe post-hoc testing indicated that metabolic rate increased by 13.8% (+ 0.6 L/min, p < 0.001) 1 hr post, 14.4% (+0.63 L/min, p < 0.001) 2 hr post, and 8.5% (+0.37 L/min, p < 0.004) 3 hr post Celsiustrade mark ingestion. In contrast, small (~4-6%) but statistically insignificant increases in metabolic rate were noted following Diet Coke(R) ingestion. No differences in respiratory exchange ratio were noted between trials. These preliminary findings indicate Celsiustrade mark has thermogenic properties when ingested acutely. The effects of repeated, chronic ingestion of Celsiustrade mark on body composition are unknown at this time.


Operative treatment of pediatric pelvic fractures--our experience.
Treatment of unstable pelvic fractures in children is a serious surgical problem. Despite similarities between the epidemiology, diagnosis and treatment of pelvic fractures in children and adults, this article attempts to demonstrate age-specific differences in patient management. In a group of 46 children with pelvic fractures hospitalized in the years 2001-2009, 18 patients required surgical treatment. The fractures were classified according to Tile as type B1 fractures (11% of the patients operated on), type B2 (28%), B3 (22%), and C (39%). Surgical treatment was based on Gordon's classification. Patients were evaluated at 3, 6, and 12 months after surgery. All patients achieved radiological bone union by 3 months after surgery. The length of the lower limbs assessed at 12 months after surgery was the same in all patients. No patients demonstrated an oblique pelvic position. None of the patients had resting pain, but in one case there was slight pain in the sacro-iliac joint region due to incomplete reduction of sacro-iliac subluxation, but repeat surgery was not necessary. In one patient, there was a difference of approximately 15˚ in internal rotation of the hip joints caused by asymmetrical reduction of the pelvic fracture. One patient developed inflammation, which resolved after antibiotic therapy. Operative treatment of pelvic fractures in children over 8 years of age should be based on the principles of stable fixation and early rehabilitation, as it is in adults. Surgical treatment of unstable pelvic fractures with osteosynthesis in children is a challenge and needs expertise and a well-prepared multi-specialty team.


Bayesian Parameter Identification for Turing Systems on Stationary and Evolving Domains.
In this study, we apply the Bayesian paradigm for parameter identification to a well-studied semi-linear reaction-diffusion system with activator-depleted reaction kinetics, posed on stationary as well as evolving domains. We provide a mathematically rigorous framework to study the inverse problem of finding the parameters of a reaction-diffusion system given a final spatial pattern. On the stationary domain the parameters are finite-dimensional, but on the evolving domain we consider the problem of identifying the evolution of the domain, i.e. a time-dependent function. Whilst others have considered these inverse problems using optimisation techniques, the Bayesian approach provides a rigorous mathematical framework for incorporating the prior knowledge on uncertainty in the observation and in the parameters themselves, resulting in an approximation of the full probability distribution for the parameters, given the data. Furthermore, using previously established results, we can prove well-posedness results for the inverse problem, using the well-posedness of the forward problem. Although the numerical approximation of the full probability is computationally expensive, parallelised algorithms make the problem solvable using high-performance computing.


[Undifferentiated sarcoma of the ulna in a patient with Paget's disease].
The development of bone sarcoma in a patient with Paget disease is a classic but rare event. The authors describe the XR, CT and MR features of an undifferentiated Paget sarcoma arising in the proximal ulna, a very rare location of this tumoral complication. Clinical symptoms, radiological pattern and epidemiology are discussed. In every Paget patient presenting with a new or different pain, with or without mass effect, the radiologist has to search for signs of sarcomatous transformation, i.e. cortical osteolysis, soft tissue mass and sometimes an associated fracture.


Factors Associated With Hearing Outcomes After Stapedotomy in Taiwanese Patients With Clinical Otosclerosis.
To examine the clinical factors associated with the effectiveness of stapedotomy in improving hearing sensitivity in Taiwanese patients with otosclerosis. In this retrospective study, we reviewed the medical records of 31 patients (36 ears) with otosclerosis undergoing stapedotomy performed by a single surgeon. Preoperative and postoperative hearing results were analyzed to identify factors associated with hearing outcomes after stapedotomy in the Taiwanese population with clinical otosclerosis. Compared with preoperative pure tone averages (PTAs), stapedotomy significantly improved postoperative air conduction (AC) thresholds (P < .0001), bone conduction (BC) thresholds (P = .025), and air-bone gaps (ABGs; P < .0001). Postoperative closure of ABGs less than 10 or 20 dB was achieved in 16 (44.4%) and 33 (91.7%) of 36 surgical ears. Improvement in postoperative AC thresholds and ABGs and the size of preoperative ABGs were significantly correlated (r = .650, P < .001 and r = .745, P < .001, respectively). Gender-stratified analysis indicated a stronger correlation between improvement in postoperative AC thresholds and preoperative ABGs in male patients than in female patients (r = .893, P < .001 and r = .476, P = .014, respectively), and in postoperative and preoperative ABGs (r = .933, P < .001 and r = .626, P < .001, respectively). With the more stringent criteria for surgical success, factors including age (≤50 years), type (conductive, BC ≤25 dB), and degree (PTA ≤55 dB) of preoperative hearing loss led to more favorable outcomes. We reported evidence supporting a potential gender difference on hearing outcomes after stapedotomy in Taiwanese patients with otosclerosis. Age, type, and degree of preoperative hearing loss may affect the surgical success rate.


[Modification of surgical treatment of ingrowing toenail].
The authors present their own modification of Emmert's operation used by treatment of ingrowing toenail. The modification itself consists in special technique of the suture of operation wound which prevents further nail incarnation. In second part the results of treatment of 51 patients are presented and discussed in context of other treatment modes. Patients treated by modified technique were treated approximately 14.06 +/- 5.44 days and needed approximately 3.79 +/- 1.04 checkups, others, treated by standard methods it was approximately 19.54 +/- 1.98 days and 4.73 +/- 0.62 checkups. The disposal of modified suture technique may reduce needed post-operation care. The question is if it is able to reduce the recurrence rate as well.


Predicting a Molecular Fingerprint from an Electron Ionization Mass Spectrum with Deep Neural Networks.
Electron ionization-mass spectrometry (EI-MS) hyphenated to gas chromatography (GC) is the workhorse for analyzing volatile compounds in complex samples. The spectral matching method can only identify compounds within the spectral database. In response, we present a deep-learning-based approach (DeepEI) for structure elucidation of an unknown compound with its EI-MS spectrum. DeepEI employs deep neural networks to predict molecular fingerprints from an EI-MS spectrum and searches the molecular structure database with the predicted fingerprints. We evaluated DeepEI with MassBank spectra, and the results indicate DeepEI is an effective identification method. In addition, DeepEI can work cooperatively with database spectral matching and NEIMS (fingerprint to spectrum method) to improve identification accuracy.


Molecular characterization of Macrophomina phaseolina and Fusarium species by a single primer RAPD technique.
Charcoal root rot and wilt, are two economically important diseases of many crop plants in North and South America, Asia and Africa and some parts of Europe. Genetic variation in 43 isolates of Macrophomina phaseolina and 22 isolates of Fusarium species, collected from geographically distinct regions over a range of hosts, was studied using random amplified polymorphic DNA (RAPD) markers. Initially, 210 arbitrary nucleotide (10-mer) primers were tested for amplification of genomic DNA of one M. phaseolina isolate, 70 primers amplified the genomic DNA of M. phaseolina. One primer OPA-13 (5'-CAGCACCCAC-3') produced fingerprint profiles, which clearly distinguished between the different isolates of M. phaseolina. UPGMA analysis classified these isolates into five major groups. By primer OPA-13, 22 isolates of pathogenic and non-pathogenic Fusarium species of different formae-speciales and races, were also distinguished from M. phaseolina. This marker is useful for distinguishing between these two important plant pathogens irrespective of hosts, virulence spectrum and races. This is the first report of reliable diagnosis of two soilborne pathogens (root/collar rot and wilt causing pathogens) at the level of isolates, formae-speciales and races by a single primer RAPD procedure with uniform PCR conditions.


Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes.
The use of tobacco products is associated with an increased incidence of periodontal disease, poor response to periodontal therapy, and a high risk for developing head and neck cancer. Nicotine and tobacco-derived nitrosamines have been shown to exhibit their pathobiologic effects due in part to activation of the nicotinic acetylcholine (ACh) receptors (nAChRs), mainly alpha7 nAChR, expressed by oral keratinocytes (KCs). This study was designed to gain mechanistic insight into alpha7-mediated morbidity of tobacco products in the oral cavity. We investigated the signaling pathways downstream of alpha7 nAChR in monolayers of oral KCs exposed for 24 h to aged and diluted sidestream cigarette smoke (ADSS) or an equivalent concentration of pure nicotine. By both real-time polymerase chain reaction (PCR) and In-cell Western, the KCs stimulated with ADSS or nicotine showed multifold increases of STAT-3. These effects could be completely blocked or significantly (P<0.05) diminished if the cells were pretreated with the alpha7 antagonist alpha-bungarotoxin (alphaBTX) or transfected with anti-alpha7 small interfering RNA (siRNA-alpha7). The use of pathway inhibitors revealed that signaling through the Ras/Raf-1/MEK1/ERK steps mediated alpha7-dependent up-regulation of STAT-3. Targeted mutation of the alpha7 gene prevented ERK1/2 activation by nicotine. Using the gel mobility shift assay, we demonstrated that an increased protein binding activity of STAT-3 caused by ADSS or pure nicotine was mediated by janus-activated kinase (JAK)-2. Activation of JAK-2/STAT-3 pathway could be prevented by alphaBTX or siRNA-alpha7. Thus, nuclear transactivation of STAT-3 in KCs exposed to tobacco products is mediated via intracellular signaling downstream from alpha7, which proceeds via two complementary pathways. The Ras/Raf-1/MEK1/ERK cascade culminates in up-regulated expression of the gene encoding STAT-3, whereas recruitment and activation of tyrosine kinase JAK-2 phosphorylates it. Elucidation of this novel mechanism of nicotine-dependent nuclear transactivation of STAT-3 identifies oral alpha7 nAChR as a promising molecular target to prevent, reverse, or retard tobacco-related periodontal disease and progression of head and neck cancer by receptor inhibitors.


Endoscopic management of pediatric posterior glottic stenosis.
Open laryngofissure with posterior cartilage grafting is advocated by some as the main treatment for posterior glottic stenosis in children. Endoscopic arytenoidectomy has been tried and recommended for bilateral vocal cord paralysis in children, but little published experience exists in its use for the treatment of pediatric posterior glottic stenosis. We describe our experience with this technique in 11 children ages 2 to 12 years, 6 of whom were under the age of 5 years. Nine of 11 patients at the initial surgery were tracheotomy-dependent; 2 others had previous laryngofissure with cartilage grafting, but continued to suffer from severe airway limitations. Modified carbon dioxide laser arytenoidectomies resulted in decannulation in 5 of 9 children and marked improvements in the 2 children without tracheotomies, as documented by flow volume loops and symptoms. Endoscopic arytenoidectomy, in our experience, is not as successful as open techniques described in previously published series of children, and requires multiple procedures due to the regrowth of granulation tissue. However, endoscopic repair is a viable option for low-grade stenosis and does not preclude an open repair in the future. It is also useful as an adjunctive procedure to augment the repair from an open approach.


Rh alloimmunization and term delivery.
Nowadays management of severe Rh alloimmunization consists of serial determination of middle cerebral artery peak systolic velocity, amniocentesis, cordocentesis, and in many instances intrauterine transfusion. We present a case of severe Rh alloimmunization who, for the first time in Iran, was delivered at term after several intrauterine transfusions.


Topologically protected plasmon mode with ultrastrong field localization in a graphene-based metasurface.
Graphene plasmons, the electromagnetic waves coupled to charge excitations in a graphene sheet, have attracted great interest because of their intriguing properties, such as electrical tunability, long plasmon lifetime, and high degree of spatial confinement. They may enable the manufacture of novel optical devices with extremely high speed, low driving voltage, low power consumption and compact sizes. In this paper, we propose a graphene-based metasurface which can support a topologically protected graphene plasmon mode with the ability of ultrastrong field localization. We show that such a plasmonic metasurface, constructed by depositing a graphene sheet on a periodic silicon substrate, would exhibit different bandgap topological characteristics as the filling factor of the periodic substrate changes. By setting suitable Fermi levels of graphene at two different areas of the metasurface, topological interface plasmon modes can be excited, resulting in over 8 orders of magnitude enhancement of the plasmon intensity. The topologically protected plasmon mode is robust against the perturbation of the structural parameters, and its frequency can be tuned by adjusting the gate-voltage on the graphene sheet. This highly integrated platform could provide a pathway for low-power and actively controllable nonlinear optics.


[Psychiatric morbidity among adults in The Netherlands: the NEMESIS-Study. I. Objectives, design and methods. Netherlands Mental Health Survey and Incidence Study].
To determine prevalence, incidence and course of psychiatric disorders in non-institutionalised Dutch adults. Prospective and cross-sectional. Trimbos Institute, Utrecht, the Netherlands. A multistage, stratified random sampling procedure was used to obtain a sample of 7076 adults (18-64 years). Respondents were interviewed throughout 1996 in their homes. The main diagnostic instrument was the 'Composite international diagnostic interview' (CIDI), designed to assess lifetime prevalence of mental disorders according to Diagnostic and statistical manual of mental disorders, 3rd revised edition (DSM-III-R). The diagnostic categories were: affective disorders, anxiety disorders, eating disorders, schizophrenia and other non-affective psychoses, and substance use disorders (dependence and abuse). The sample was weighted towards national census data on sex, age, marital status and urbanicity. The results of the first measurement (1996) will be described in the next article (1997:2353-60). The response rate was 64.2%. There were no indications that the psychiatric morbidity of non-respondents differed from respondents. The same respondents will be interviewed again after 12 (1997) and after 36 months (1999).


miRNA-146a-5p is upregulated in serum and cartilage samples of patients with osteoarthritis.
Osteoarthritis (OA) is a widely prevalent joint disease leading to motor disability and pain. Appropriate indicators for identifying patients at risk for this progressive disease, identifying molecular events for detecting early phases of the disease, or biomarkers to screen for treatment responses, however, are lacking. Micro RNAs (miRNAs), which play crucial roles in OA, could be potential biomarkers of OA. Because circulating miRNA levels reflect the disease state, they may be useful for OA screening and as diagnostic tools, reducing the need for invasive procedures and minimizing the cost of current diagnostic methods. The expression levels of 18 microRNAs (let-7e-5p, miR-21-5p, miR-93-5p, miR-101-3p, miR-103a-3p, miR-130a-3p miR-146a-5p, miR-16-5p, miR-193b-3p miR-199a-3p, miR-210-3p, miR-222-3p, miR-22-3p, miR-27a-3p, miR-27b-3p, miR-335-5p, miR-454-3p, and miR-98-5p) were analyzed by quantitative real-time polymerase chain reaction in the cartilage tissues and serum samples of 28 OA patients and were compared to those of 2 healthy controls. Expression of microRNA-146a-5p was significantly upregulated in the cartilage (p=0.006) and serum (p=0.002) of OA patients. The expression levels of miR-146a-5p in the serum were positively correlated with those in the cartilage (Pearson correlation coefficient R=0.32; p=0.002). miR-146a-5p was significantly overexpressed in patients with OA, both in the articular cartilage tissue and serum, with a positive correlation between the levels in both types of samples. Therefore, the miR-146a-5p serum level could reflect the molecular processes in the cartilage, suggesting its clinical utility as a biomarker for OA management. Implementing noninvasive biomarker using serum miRNAs involves the analysis of the misregulated miRNAs linked to the cartilage pathology.


Trabecular bone response to injectable calcium phosphate (Ca-P) cement.
The aim of this study was to investigate the physicochemical, biological, and handling properties of a new developed calcium phosphate (Ca-P) cement when implanted in trabecular bone. Ca-P cement consisting of a powder and a liquid phase was implanted as a paste into femoral trabecular bone of goats for 3 days and 2, 8, 16, and 24 weeks. The cement was tested using three clinically relevant liquid-to-powder ratios. Polymethylmethacrylate bone cement, routinely used in orthopedics, was used as a control. The Ca-P cement was easy to handle and was fast setting with good cohesion when in contact with body fluids. X-ray diffraction at the different implantation periods showed that the cement had set as an apatite and remained stable over time. Histological evaluation after 2 weeks, performed on 10 microm un-decalcified sections, showed abundant bone apposition on the cement surface without any inflammatory reaction or fibrous encapsulation. At later time points, the Ca-P cement implants were totally covered by a thin layer of bone. Osteoclast-like cells, as present at the interface, had resorbed parts of the cement mass. At locations where Ca-P cement was resorbed, new bone was formed without loss of integrity between the bone bed and the cement. This demonstrated the osteotransductive property of the cement, i.e., resorption of the material by osteoclast-like cells, directly followed by the formation of new bone. Histological and histomorphometrical evaluation did not show any significant differences between the Ca-P cement implanted at the three different liquid/powder ratios. The results indicate that the investigated Ca-P cement is biocompatible, osteoconductive, as well as osteotransductive and is a candidate material for use as a bone substitute.


On the sensitisation of skin radionecrosis in mice by misonidazole at low doses.
The sensitisation by misonidazole of tail radionecrosis in mice has been assessed using single doses from 0.01 to 1 mg g-1 body weight, for tails in three different states of oxygenation affecting sensitivity. The levels of sensitisation after different injected doses of misonidazole could be described reasonably well by the Alper -Howard-Flanders relationship, originally applied to the sensitisation of cells by oxygen, and hence the relationship could be used for interpolation. With clamped tails gassed with nitrogen at room temperature, 21-25 degrees C, the injected dose giving half the maximum sensitisation (defined as K inj ) was about 0.12-0.17 mg g-1 (0.6-0.8 mM). Unclamped tails in air demonstrated a value for K inj of about 0.14 mg g-1, indicating that the background level of oxygen and the injected misonidazole were not additive regarding sensitisation. With clamped tails gassed with nitrogen warmed to 37 degrees C (near body-core temperature) the sensitivity was slightly increased compared with clamped tails at 21-25 degrees C, and the additional increase in sensitivity following injections of misonidazole ( K inj of about 0.22 mg g-1) was less than at 21-25 degrees. With tails in air at 37 degrees C the increase in sensitivity following misonidazole was much more marked ( K inj of about 0.05 mg g-1) than expected. When eight "daily" fractions were given using 0.67 mg g-1 misonidazole and with the target cells well oxygenated at 37 degrees C (effective OER of about 2.0), the amount of sensitisation was less than for single doses, but it was similar (i.e. dose-modifying) for radiation doses per fraction between 2.6 and 6.3 Gy. At a dose of 0.1 mg g-1, giving a serum level corresponding to about the maximum tolerable in humans, the dose reduction factor would be only about 1.03 which corresponds roughly to a doubling in the tail necrosis rate from 5% to 10%. With future less neurotoxic drugs, higher serum levels may be expected to be tolerated and hence the dose reduction factor could be greater. This aspect, applicable to some but not all tissues tested in mice, should not be neglected in the design of future clinical trials with hypoxic-cell radiosensitisers .


Should measurement of cognition be part of recovery programs for patients with Psychotic Illness?
The recovery model of schizophrenia is central to the devlopment of community services for patients with schizophrenia. However often when applying the recovery model of psychosis, often formal identification of cognitive imparements is not carried out, nor are interventions to improve cognitive functioning offered in a targeted way. Here we discuss how these issues relate to each other and argue for the use of cognitive testing in order to elp recovery in schizophrenia.


Comparing the efficacy and neuroinflammatory potential of three anti-abeta antibodies.
Immunotherapy is a promising strategy for the treatment of Alzheimer's disease (AD). Antibodies directed against Amyloid Beta (Aβ) are able to successfully clear plaques and reverse cognitive deficits in mouse models. Excitement towards this approach has been tempered by high profile failures in the clinic, one key issue has been the development of inflammatory side effects in the brain (ARIAs). New antibodies are entering the clinic for Alzheimer's disease; therefore, it is important to learn all we can from the current generation. In this study, we directly compared 3 clinical candidates in the same pre-clinical model, with the same effector function, for their ability to clear plaques and induce inflammation in the brain. We produced murine versions of the antibodies: Bapineuzumab (3D6), Crenezumab (mC2) and Gantenerumab (chGantenerumab) with an IgG2a constant region. 18-month transgenic APP mice (Tg2576) were injected bilaterally into the hippocampus with 2 µg of each antibody or control. After 7 days, the mice tissue was analysed for clearance of plaques and neuroinflammation by histology and biochemical analysis. 3D6 was the best binder to plaques and in vitro, whilst mC2 bound the least strongly. This translated into 3D6 effectively clearing plaques and reducing the levels of insoluble Aβ, whilst chGantenerumab and mC2 did not. 3D6 caused a significant increase in the levels of pro-inflammatory cytokines IL-1β and TNFα, and an associated increase in microglial expression of CD11B and CD68. chGantenerumab increased pro-inflammatory cytokines and microglial activation, but minimal changes in CD68, as an indicator of phagocytosis. Injection of mC2 did not cause any significant inflammatory changes. Our results demonstrate that the ability of an antibody to clear plaques and induce inflammation is dependent on the epitope and affinity of the antibody.


Fecal microbiota transplantation for recurrent Clostridioides difficile infection in frail and very old patients.
Older age is a well-known risk factor for recurrent and severe Clostridioides difficile infection (CDI). Fecal microbiota transplantation (FMT) is widely recognized as an effective and safe therapeutic option for the treatment of recurrent CDI (rCDI). However, the efficacy and safety of FMT for rCDI in very old patients are uncertain. This study evaluated the efficacy and safety of FMT in a group of very old subjects with rCDI, and the reliability of overall comorbidity and frailty assessment for identifying patients at higher risk of worse clinical outcomes. This is a retrospective single-center study including patients ≥85 years undergoing FMT for rCDI between 2014 and 2022. Primary outcomes included efficacy of FMT, defined as cure of CDI at 8 week-follow-up, and safety evaluation. At baseline, comorbidity was measured with the Charlson Comorbidity Index (CCI). Frailty was measured with the Clinical Frailty Scale (CFS). Overall, 43 patients with a median age of 88 years underwent FMT by colonoscopy in the study period. The rate of first FMT success was 77%. Five of the 10 patients who failed the first FMT infusion were cured after repeat FMT, with an overall efficacy of 88%. In patients with successful treatment, the CFS was significantly lower compared to those who failed the FMT or underwent repeat FMT (p < 0.01 for both). Mild adverse events occurred in 11 patients (25%). One death, not related to FMT or rCDI, occurred within 7 days from the first procedure. FMT is effective and safe in very old patients. Frailty and high comorbidity do not limit use of FMT in these patients. Frailty assessment has potential to better identify patients at higher risk of worse outcomes or for repeat treatment with FMT.


Loop-mediated isothermal amplification assay as a point-of-care diagnostic tool for Vibrio parahaemolyticus: recent developments and improvements.
A number of DNA-based diagnostic tools have been developed for the detection of Vibrio parahaemolyticus in seafood. However, the loop-mediated isothermal amplification (LAMP) has distinct advantages with regards to its simplicity, speed and the ease of performing without any need for sophisticated equipment. Over the last decade, LAMP has emerged as a potential tool for the detection of V. parahaemolyticus. Area covered: The literature search was restricted to LAMP assay and its variants for the detection of V. parahaemolyticus. The focus in this review is to enlist the various techniques that have been developed using the principle of the LAMP towards improved simplicity, sensitivity and specificity of the assay. Expert commentary: LAMP assay and its variants are significantly faster and require minimum accessories compared to other DNA based molecular techniques such as PCR and their types. Despite the availability of several versions, LAMP-based diagnostics is not the first choice for the detection of V. parahaemolyticus in the seafood sector. Our recommendation would be to explore the possibilities of developing cost-effective LAMP kits and implementing these kits as point-of-care diagnostic tools for rapid and sensitive detection of pathogenic V. parahaemolyticus.


Structural analysis of the HLA-DR, -DQ, and -DP alleles on the celiac disease-associated HLA-DR3 (DRw17) haplotype.
Celiac disease is strongly associated with the HLA class II D-region serologic markers DR3 (DRw17) and DQw2. Moreover, by restriction fragment length polymorphism analysis, greater than 90% of DR3 (DRw17), DQw2 celiac disease patients have a polymorphic 4.0-kilobase Rsa I DP B gene DNA fragment. The present study sought to determine if there is a unique HLA class II D-region A or B gene structural variant on the DR3 (DRw17) haplotype found in celiac disease. The polymorphic second exons of the coding DRB, DQA and DQB, and DPA and DPB genes in celiac disease patients with the DR3 (DRw17) haplotype were sequenced after amplification by the polymerase chain reaction. To define the DP B genes associated with celiac disease, the second exons of the coding DP B genes from 27 celiac disease patients were amplified similarly and probed by using a panel of sequence specific oligonucleotides. The HLA-DR, -DQ, and -DP A and B gene second exon sequences of celiac disease patients were noted to be identical to sequences that can be found also, although at a significantly lower frequency, in unaffected individuals. This is compatible with a disease model wherein the HLA class II genes on the DR3 (DRw17) haplotype are necessary, but not sufficient, for the phenotypic expression of celiac disease. Analysis of the DP B genes revealed a significant increase in the frequency of the alleles DPB1 and DPB3 in celiac disease. Furthermore, the increased frequency of the 4.0-kilobase Rsa I DP B gene restriction fragment length polymorphism in celiac disease can be accounted for by the overrepresentation in disease of the alleles DPB1 and DPB3. The HLA-associated susceptibility to celiac disease appears to be multigenic, with specific, but structurally normal, allelic variants in the DP and DQ/DR subregions contributing to disease susceptibility.


[Effect of progesterone on the expression of GLUT in the brain following hypoxic-ischemia in newborn rats].
To investigate the expression of GLUT1 and GLUT3 in the hippocampus after cerebral hypoxic-ischemia (HI) in newborn rats and the effect of progesterone (PROG) on them. Forty newborn SD rats were randomly divided into four groups: normal group, sham-operated group, hypoxic-ischemic group and progesterone group. Model of hypoxic-ischemia encephalopathy (HIE) was established in the 7-day-old newborn SD rats. Immunohistochemical method was applied to detect the expression of GLUT1 and GLUT3 in hippocampus. GLUT1 and GLUT3 were slightly seen in normal and sham operation group, there was no obviously difference between the two groups (P > 0.05). The expression of GLUT1 and GLUT3 in hypoxic-ischemia group were all higher than that in sham operated group (P < 0.05). Not only the expression of GLUT in progesterone group were significantly higher than that in sham operated group (P < 0.01), but also than that in hypoxic-ischemia group (P < 0.05). PROG could increase the tolerance of neuron to hypoxic-ischemia with maintaining the energy supply in the brain by up-regulating GLUT expression.


Male genotype influences female reproductive investment in Drosophila melanogaster.
In many species, males can influence the amount of resources their mates invest in reproduction. Two favoured hypotheses for this observation are that females assess male quality during courtship or copulation and alter their investment in offspring accordingly, or that males manipulate females to invest heavily in offspring produced soon after mating. Here, we examined whether there is genetic variation for males to influence female short-term reproductive investment in Drosophila melanogaster, a species with strong sexual selection and substantial sexual conflict. We measured the fecundity and egg size of females mated to males from multiple isofemale lines collected from populations around the globe. Although these traits were not strongly influenced by the male's population of origin, we found that 22 per cent of the variation in female short-term reproductive investment was attributable to the genotype of her mate. This is the first direct evidence that male D. melanogaster vary genetically in their proximate influence on female fecundity, egg size and overall reproductive investment.


Making the Most of Our Community Health Assessment by Developing a Framework for Evaluation.
The Health District of Northern Larimer County is a special district delivering community health programs and services in Northern Colorado. Since 1995, we have conducted a community health assessment (CHA) every 3 years. In 2015, we looked at our CHA process to see whether improvements could be made. We gathered information to understand recommended processes and potential impacts of CHA. We then developed a logic model to describe our CHA process and intended outcomes. The model outlined our CHA activities and impacts and informed our evaluation questions. We identified areas for process improvement, including our ability to analyze health inequities and effectively disseminate CHA data and findings. We recommend that others conducting a CHA evaluate their processes and impacts. Developing a logic model can be a first step toward creating an evaluation. While evaluation requires resources, we believe that the practice of CHA could greatly benefit from additional evaluation efforts.


Gaussian pulse gated InGaAs/InP avalanche photodiode for single photon detection.
The capacitive response noise has been problematic for high-speed single photon detection based on gated InGaAs/InP avalanche photodiodes. Traditionally, the noise must be suppressed by complex electronic circuit if low afterpulse probability is desired. In this Letter, we propose a compact and flexible method for noise cancellation, which gates the photodiode with a Gaussian pulse. Because of the differential effect of junction capacitor, the shape of the capacitive response output in our method is the first-order derivative of the Gaussian function that can be matched by the rising edge of a delayed and attenuated version of the gating pulse itself. With matching signal, the avalanche pulse is raised onto a flat platform that can be easily discriminated from the background. For 1550 nm optical signal, the detection efficiency could reach 10.2% with 9.7×10(-6) per gate dark count probability and 3.4% afterpulse probability at 80 MHz gating frequency. Experimental results have shown that the proposed method can decrease the afterpulse probability sharply while maintaining the detection efficiency and dark count performance.


The mechanism of beta-bungarotoxin action. I. Modification of transmitter release at the neuromuscular junction.
The protein, beta-bungarotoxin, a presynaptic neurotoxin isolated from the venom of the snake Bungarus multicinctus, is known to inhibit mitochondrial function. Within 30 min after adding the toxin to a rat diaphragmphrenic nerve preparation, the quantal content increased tenfold and the frequency of miniature endplate potentials increased fourfold. No increase in miniature endplate potential frequency was seen in the absence of extracellular calcium. Since mitochondria may be involved in regulating intracellular calcium levels, the rate at which the transmitter release is turned off was studied by measuring delayed release in the presence and absence of toxin. Delayed release is elevated about eightfold by the toxin. If delayed release is due to residual calcium, as has been hypothesized, these data may be explained if the toxin does not alter the amount of calcium which enters the terminal, but rather the rate at which that calcium is removed. Alternatively, a calcium-dependent modification of the release process itself might be produced. The eventual reduction in transmitter output did not appear to result from depletion of the terminal of releaseable packets of transmitter, but does require extracellular calcium.


Recent Development in Three and Four Dimension Fetal Echocardiography.
Since its introduction >15 years ago, the use of spatial and temporal image correlation (STIC) technology has contributed substantially to fetal echocardiography. Moreover, significant advances have occurred in 3- and 4-dimensional (3D/4D) echocardiography over the past several years including the matrix probe along with advances in gray scale and color Doppler post processing, resulting in improved display of ultrasound images. In this article, we provide examples to show these recent developments including the use of color Doppler with STIC in the glass-body mode and the matrix probe thus enabling the demonstration of cardiac anomalies of the 4-chamber-view and great arteries. The use of the matrix probe allows the examination of cardiac structures in 2 orthogonal planes simultaneously, which can help in display of anatomy side by side (Biplane mode). In addition, the rapid image reconstruction of the matrix probe allows for the display of live 4D and the rapid acquisition of a STIC volume. The display of multiplanar images of the heart in 3D/4D has also been used to automate the display of ultrasound images, resulting in standardization of the image display and thus minimizing the operation dependency of the ultrasound examination. Future addition of image recognition software can also provide assistance in image review.


A mathematical equation for quantifying control functionality in agricultural tractors.
The overall accessibility of controls is one of the most important issues to consider when designing a control layout. Well-arranged controls, whose operational characteristics are based on both design guidelines and on human factors considerations, allow the operator to efficiently interact with the system in question. The objective of this article is to introduce a numerical index, referred to as the "index of functionality", capable of comparing, on a mathematical basis, different control arrangements in agricultural tractors. The model is based on information that has been gleaned from the published literature, with input from both professional ergonomists and experienced agricultural tractor operators. The numerical index may take any value between 0 and +1, with +1 being defined as an optimum value in terms of the functionality of a workstation. Data were collected from six old (pre-1982) and six modern (post-2003) tractor workstations to determine whether the model would recognize improvements that have occurred in the ergonomic design of tractor control layouts over the past 20 years. An average score of 0.19 +/- 0.07 was calculated for the pre-1982 tractor workstations. By contrast, an average score of 0.63 +/- 0.10 was calculated for the post-2003 tractor workstations. A number of limitations have been identified with the current model; despite these limitations, the index of functionality clearly recognized the ergonomic improvements in tractor workstations that have occurred over the past 20 years.


IGF binding protein-4 is required for the growth effects of glucagon-like peptide-2 in murine intestine.
Glucagon-like peptide-2 (GLP-2) is an enteroendocrine hormone that stimulates the growth of the intestinal epithelium. We have previously demonstrated that GLP-2 exerts its intestinotropic effect through an indirect mechanism that requires both IGF-1 and the intestinal epithelial IGF-1 receptor. However, the biological activity of IGF-1 is modulated by IGF binding proteins (IGFBPs), including IGFBP-4, which is highly expressed in the intestine. To determine the role of IGFBP-4 in the tropic effects of GLP-2, IGFBP-4 knockout (KO) and control mice were treated with degradation-resistant GLP-2 or vehicle for 10 days. Comparable levels of IGFBP-1-3/5-7 mRNAs were observed in the intestinal mucosa of all animals. IGFBP-4 KO mice had greater small intestinal weight and length, and deeper crypts (P < .05) as compared with controls, suggesting that IGFBP-4 has an inhibitory role in basal intestinal growth. However, small intestinal weight, crypt-villus height and crypt cell proliferation increased in response to GLP-2 in control mice (P < .05), and these changes were abrogated with IGFBP-4 KO. In contrast, pregnancy-associated plasma protein-A KO mice, which have increased levels of circulating IGFBP-4, demonstrated a normal intestinotropic response to GLP-2. Finally, GLP-2 treatment of control mice significantly increased IGFBP-4 mRNA expression in the jejunal mucosa (P < .05), a finding that was recapitulated by GLP-2 treatment of fetal rat intestinal cells in culture (10(-8)M for 2 h; P < .05). Collectively, these results indicate that the IGF-I-modulating protein, IGFBP-4, exerts a negative effect on basal intestinal growth but plays a positive regulatory role in the intestinotropic actions of GLP-2.


Dibutyryl-cAMP up-regulates nur77 expression via histone modification during neurite outgrowth in PC12 cells.
An elevated level of cyclic AMP (cAMP) within cells activates gene expression through the cAMP-PKA-CREB pathway. Among the CREB target genes, some immediate early genes exist that are responsive to cAMP including the nur77 and c-fos genes. Treatment with dibutyryl-cAMP (dbcAMP) as well as nerve growth factor (NGF) induces neurite outgrowth in PC12 cells. Here, we report that acetylation of histone H3 was gradually stimulated after treatment with dbcAMP in PC12 cells and peaked 1 h after treatment. As the result of reverse transcription-polymerase chain reaction (RT-PCR) and quantitative real-time PCR (qPCR) experiments, both nur77 and c-fos gene expression were found to have peak 1 h after treatment. Knock-down with siRNA against nur77 mRNA inhibited the neurite outgrowth induced by dbcAMP, whereas knock-down with siRNA against c-fos mRNA did not inhibit the dbcAMP-induced neurite outgrowth. A chromatin immunoprecipitation (ChIP) assay revealed that the nur77 gene was associated with the acetylated Lys14 of histone H3 after treatment with dbcAMP. However, the amount of c-fos gene associated with acetylated histone H3 was not changed after treatment with dbcAMP. These results suggest that the expression of nur77, which is essential for the neuronal differentiation induced by dbcAMP, is up-regulated via dbcAMP-induced acetylation of the Lys14 of histone H3 in PC12 cells.


Prevention of lower extremity stress fractures: a controlled trial of a shock absorbent insole.
A prospective controlled trial was carried out to determine the usefulness of a viscoelastic polymer insole in prevention of stress fractures and stress reactions of the lower extremities. The subjects were 3,025 US Marine recruits who were followed for 12 weeks of training at Parris Island, South Carolina. Polymer and standard mesh insoles were systematically distributed in boots that were issued to members of odd and even numbered platoons. The most important finding was that an elastic polymer insole with good shock absorbency properties did not prevent stress reactions of bone during a 12-week period of vigorous physical training. To control for the confounding effects of running in running shoes, which occurred for about one and one-half hours per week for the first five weeks, we also examined the association of age of shoes and cost of shoes with injury incidence. A slight trend of increasing stress injuries by increasing age of shoes was observed. However, this trend did not account for the similarity of rates in the two insole groups. In addition, we observed a strong trend of decreasing stress injury rate by history of increasing physical activity, as well as a higher stress injury rate in White compared to Black recruits. The results of the trial were not altered after controlling for these factors. This prospective study confirms previous clinical reports of the association of stress fractures with physical activity history. The clinical application of a shock absorbing insole as a preventive for lower extremity stress reactions is not supported in these uniformly trained recruits. The findings are relevant to civilian populations.


An Artifact in Intracellular Cytokine Staining for Studying T Cell Responses and Its Alleviation.
Intracellular cytokine staining (ICS) is a widely employed ex vivo method for quantitative determination of the activation status of immune cells, most often applied to T cells. ICS test samples are commonly prepared from animal or human tissues as unpurified cell mixtures, and cell-specific cytokine signals are subsequently discriminated by gating strategies using flow cytometry. Here, we show that when ICS samples contain Ly6G+ neutrophils, neutrophils are ex vivo activated by an ICS reagent - phorbol myristate acetate (PMA) - which leads to hydrogen peroxide (H2O2) release and death of cytokine-expressing T cells. This artifact is likely to result in overinterpretation of the degree of T cell suppression, misleading immunological research related to cancer, infection, and inflammation. We accordingly devised easily implementable improvements to the ICS method and propose alternative methods for assessing or confirming cellular cytokine expression.


Selective neuronal vulnerability to deficits in RNA processing.
Emerging evidence indicates that errors in RNA processing can causally drive neurodegeneration. Given that RNA produced from expressed genes of all cell types undergoes processing (splicing, polyadenylation, 5' capping, etc.), the particular vulnerability of neurons to deficits in RNA processing calls for careful consideration. The activity-dependent transcriptome remodeling associated with synaptic plasticity in neurons requires rapid, multilevel post-transcriptional RNA processing events that provide additional opportunities for dysregulation and consequent introduction or persistence of errors in RNA transcripts. Here we review the accumulating evidence that neurons have an enhanced propensity for errors in RNA processing alongside grossly insufficient defenses to clear misprocessed RNA compared to other cell types. Additionally, we explore how tau, a microtubule-associated protein implicated in Alzheimer's disease and related tauopathies, contributes to deficits in RNA processing and clearance.


The colon: an overlooked site for therapeutics in dialysis patients.
Morbidity and mortality related to chronic kidney disease remain unacceptably high, despite tremendous progress in its prevention and treatment. In an ongoing quest to improve outcome in chronic kidney disease patients, the colon might be an appealing, but largely underexplored, therapeutic target. A clear bi-directional functional relationship exists between the colon and kidney, also referred as to the colo-renal axis. Uremia has an important impact on the colonic microbiome. The microbiome, in turn, is an important source of uremic toxins, with p-cresyl sulfate and indoxyl sulfate as important prototypes. These co-metabolites accumulate in the face of a falling kidney function, and may accelerate the progression of renal and cardiovascular disease. Several therapeutic interventions, including prebiotics and adsorbants, specifically target these colon-derived uremic toxins originating from bacterial metabolism. As kidney function declines, the colon also gains importance in the homeostasis and disposal of potassium and oxalate. Their colonic secretion may be increased by drugs increasing the expression of cAMP and by probiotics (e.g., Oxalobacter formigenes).


Movement markers of schizophrenia: a detailed analysis of patients' gait patterns.
Motor abnormalities occur in the majority of persons with schizophrenia but are generally neglected in clinical care. Psychiatric diagnostics fail to include quantifiable motor variables and few assessment tools examine full-body movement. We assessed full-body movement during gait of 20 patients and 20 controls with motion capture technology, symptom load (PANSS, BPRS) and Neurological Soft Signs (NSS). In a data-driven analysis, participants' motion patterns were quantified and compared between groups. Resulting movement markers (MM) were correlated with the clinical assessment. We identified 16 quantifiable MM of schizophrenia. While walking, patients and controls display significant differences in movement patterns related to posture, velocity, regularity of gait as well as sway, flexibility and integration of body parts. Specifically, the adjustment of body sides, limbs and movement direction were affected. The MM remain significant when controlling for medication load. They are systematically related to NSS. Results add assessment tools, analysis methods as well as theory-independent MM to the growing body of research on motor abnormalities in schizophrenia.


Measurement of personal exposure to outdoor aeromycota in northern New South Wales, Australia.
Aerobiological sampling traditionally uses a volumetric spore trap located in a fixed position to estimate personal exposure to airborne fungi. In this study, the number and identity of fungi inhaled by human subjects (n=34), wearing Intra-nasal air samplers (INASs), was measured over 2-hour periods in an outdoor community setting, and compared to fungal counts made with a Burkard spore trap and Institute of Occupational Medicine personal filter air samplers (IOMs). All sampling devices were in close proximity and located in an outdoor environment in Casino, northern New South Wales, Australia. Using INASs, the most prevalent fungi inhaled belonged to soil or vegetation borne spores of Alternaria, Arthrinium, Bipolaris, Cladosporium, Curvularia, Epicoccum, Exserohilum, Fusarium, Pithomyces, Spegazzinia and Tetraploa species, Xylariaceae ascospores, in addition to hyphal fragments. These results showed that inhaled fungal exposure in most people varied in a 2-fold range with 10-fold outliers. In addition, the INASs and personal air filters agreed more with each other than with Burkard spore trap counts (r=0.74, p < 0.0001). These findings further support a new paradigm of personal fungal exposure, which implicates the inhalation of a spectrum of fungi more closely associated with soil or vegetation borne mycoflora and hyphal fragments than what is collected by stationary spore traps in the same geographic region.


The meaning of caring for patients with cancer among traditional medicine practitioners in Uganda: A grounded theory approach.
Traditional medicine practitioners (TMPs) are a critical part of healthcare systems in many sub-Saharan African countries and play vital roles in caring for patients with cancer. Despite some progress in describing TMPs' caring experiences in abstract terms, literature about practice models in Africa remains limited. This study aimed to develop a substantive theory to clarify the care provided by TMPs to patients with cancer in Uganda. This study adhered to the principal features of the modified Straussian grounded theory design. Participants were 18 TMPs caring for patients with cancer from 10 districts in Uganda, selected by purposive and theoretical sampling methods. Researcher-administered in-depth interviews were conducted, along with three focus group discussions. Data were analyzed using constant comparative analysis. The core category that represented TMPs' meaning of caring for patients with cancer was "Restoring patients' hope in life through individualizing care." TMPs restored patients' hope through five main processes: 1) ensuring continuity in the predecessors' role; 2) having full knowledge of a patient's cancer disease; 3) restoring hope in life; 4) customizing or individualizing care, and 5) improving the patient's condition/health. Despite practice challenges, the substantive theory suggests that TMPs restore hope for patients with cancer in a culturally sensitive manner, which may partly explain why patients with cancer continue to seek their services. The findings of this study may guide research, education, and public health policy to advance traditional medicine in sub-Saharan Africa.


A 12-week interdisciplinary rehabilitation trial in patients with gliomas - a feasibility study.
This report aims to assess the safety and feasibility of using an interdisciplinary rehabilitation intervention for a future randomized controlled trial in patients with gliomas in the initial treatment phase. We conducted an outpatient two-part rehabilitation intervention that involved six weeks of therapeutic supervised training (part one) and six weeks of unsupervised training in a local gym following a training protocol (part two). Predefined feasibility objectives of safety (100%), consent rate (>80%), drop-out (<20%), adherence (>80%) and patient satisfaction (>80%) was achieved at part one. However, the failure to meet predefined feasibility objectives of drop-out, adherence and patient satisfaction of the unsupervised intervention at part two have led to a protocol revision for a future randomized controlled trial. This study demonstrates that an intensive rehabilitation intervention of physical therapy and occupational therapy in the initial treatment phase of patients with gliomas whose Karnofsky performance status is ≥70 is safe and feasible, if relevant inclusion criteria and precautionary screening are made. With the revised protocol, we are confident that the foundation for conducting a successful randomized controlled trial among these vulnerable patients has been established. Implications for rehabilitation Brain tumors constitute some of the most challenging cancer diagnoses presenting for rehabilitation intervention. Patients with gliomas experiences limitations in physical functioning, cognition, and emotional wellbeing. In a relatively small sample this study shows that supervised physical- and occupational therapy in patients with gliomas is safe and feasible in the initial treatment phase. Patients with gliomas can potentially improve functioning through interdisciplinary rehabilitation.