Arylamine N-acetyltransferase activity of the human placenta.
The fetus is exposed to almost all of the substances found in the maternal circulation whether nutrients or foreign chemicals ("xenobiotics"). The main route of exposure is the placenta. The placenta is metabolically active toward xenobiotics and the nature of the compounds reaching the fetal circulation will, in part, depend on placental biotransformation reactions. Arylamine N-acetyltransferase (NAT) catalyzes the acetyl CoA-dependent N-acetylation of primary arylamine and hydrazine substrates such as sulfamethazine, isoniazid, p-aminobenzoic acid as well as arylamine carcinogens such as 2-aminofluorene and benzidine. NAT activity is multigenically determined and can be attributed to two independently expressed proteins: NAT1 and NAT2. The acetylation capacity of the human placenta has not been investigated extensively. In the current study we identified and characterized the NAT activity of human term placenta. The kinetic data show that the activity of NAT in human placenta predominantly reflects the NAT1 enzyme. The apparent affinity (19.1 +/- 0.97 microM; mean +/- S.E.M., n = 22) and maximal velocity (3.84 +/- 0.32 nmol/min/mg; mean +/- S.E.M., n = 22) of p-aminobenzoic acid N-acetylation are similar to those measured in other tissues such as liver, blood lymphocytes, neutrophils and monocytes. In addition, there is evidence of NAT2 activity in some of the placental samples assayed, although the contribution of a small amount of NAT2 activity to the overall acetylation capacity of the placenta is likely to be small.


Inhibition of tracheal smooth muscle contraction and myosin phosphorylation by ryanodine.
Previous studies have shown that muscarinic activation of airway smooth muscle in low Ca++ solutions increases myosin phosphorylation without increasing tension. Blocking Ca++ influx reduced phosphorylation, but not to basal levels. It was proposed that release of intracellular Ca++ contributed to dissociation of phosphorylation and contraction. To test this hypothesis the effects of ryanodine were studied under similar conditions. Ryanodine (10(-7) to 10(-5) M) antagonized caffeine-induced contraction of canine tracheal smooth muscle. Ryanodine also reduced carbachol-induced contractions and carbachol-induced myosin phosphorylation. The effect of ryanodine on potassium and serotonin-induced contractions was also investigated to test for a nonspecific inhibitory effect. In contrast to the effect on carbachol responses, ryanodine (10(-5) M) potentiated the contractile response to low concentrations of serotonin and potassium, but had no effect on the maximum response to either stimulant. Carbachol (10(-6) M) and ryanodine (10(-5) M) both significantly decreased 45Ca++ content of tracheal muscle. The effect of ryanodine and carbachol together on 45Ca++ content was not greater than either drug alone suggesting that ryanodine reduces the caffeine and carbachol responses by depleting releaseable Ca++ stores. Ryanodine significantly reduced Ca++-induced contraction and myosin phosphorylation in carbachol-stimulated muscle, suggesting that some of the Ca++ responsible for elevated phosphorylation is released from the sarcoplasmic reticulum.


An assessment of mumps vaccine effectiveness by dose during an outbreak in Canada.
This investigation was done to assess vaccine effectiveness of one and two doses of the measles, mumps and rubella (MMR) vaccine during an outbreak of mumps in Ontario. The level of coverage required to reach herd immunity and interrupt community transmission of mumps was also estimated. Information on confirmed cases of mumps was retrieved from Ontario's integrated Public Health Information System. Cases that occurred between Sept. 1, 2009, and June 10, 2010, were included. Selected health units supplied coverage data from the Ontario Immunization Record Information System. Vaccine effectiveness by dose was calculated using the screening method. The basic reproductive number (R(0)) represents the average number of new infections per case in a fully susceptible population, and R(0) values of between 4 and 10 were considered for varying levels of vaccine effectiveness. A total of 134 confirmed cases of mumps were identified. Information on receipt of MMR vaccine was available for 114 (85.1%) cases, of whom 63 (55.3%) reported having received only one dose of vaccine; 32 (28.1%) reported having received two doses. Vaccine effectiveness of one dose of the MMR vaccine ranged from 49.2% to 81.6%, whereas vaccine effectiveness of two doses ranged from 66.3% to 88.0%. If we assume vaccine effectiveness of 85% for two doses of the vaccine, vaccine coverage of 88.2% and 98.0% would be needed to interrupt community transmission of mumps if the corresponding reproductive values were four and six. Our estimates of vaccine effectiveness of one and two doses of mumps-containing vaccine were consistent with the estimates that have been reported in other outbreaks. Outbreaks occurring in Ontario and elsewhere serve as a warning against complacency over vaccination programs.


Timing of Antihypertensive Drug Therapy: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.
The timing of antihypertensive drugs administration is controversial. The aim was to compare the efficacy of dosing of antihypertensive drugs in the morning versus evening. A PubMed, EMBASE, and clinicaltrials.gov databases search for randomized clinical trials of antihypertensive therapies where patients were randomized to morning versus evening dosing. The outcomes were ambulatory blood pressure (BP) parameters (day-time, night-time, and 24/48-hour systolic blood pressure [SBP] and diastolic blood pressure [DBP]) and cardiovascular outcomes. Of 72 randomized controlled trials included, evening dosing significantly reduced ambulatory BP parameters: 24/48-hour SBP (mean difference [MD]=1.41 mm Hg; [95% CI, 0.48-2.34]), DBP (MD=0.60 mm Hg [95% CI, 0.12-1.08]), night-time SBP (MD=4.09 mm Hg [95% CI, 3.01-5.16]), DBP (MD, 2.57 mm Hg [95% CI, 1.92-3.22]), with a smaller reduction in day-time SBP (MD=0.94 mm Hg [95% CI, 0.01-1.87]), and DBP (MD=0.87 mm Hg [95% CI, 0.10-1.63]), and numerically lower cardiovascular events compared with morning dosing. However, when controversial data by Hermida (23 trials, 25 734 patients) were omitted (Pheterogeneity<0.05 for most outcomes), the above effect of evening dosing attenuated with no significant effect on 24/48-hour ambulatory blood pressure, day-time BP, and major adverse cardiac event and smaller reduction in night-time ambulatory SBP and DBP. Evening dosing of antihypertensive drugs significantly reduced ambulatory BP parameters and lowered cardiovascular events but the effect was mainly driven by trials by Hermida group. Unless the intention is to specifically lower night-time BP, antihypertensive drugs should be taken at a time of day that is convenient, optimizes adherence, and minimizes undesirable effects.


Intraparenchymal injection of bone marrow mesenchymal stem cells reduces kidney fibrosis after ischemia-reperfusion in cyclosporine-immunosuppressed rats.
Ischemia-reperfusion and immunosuppressive therapy are a major cause of progressive renal failure after kidney transplantation. Recent studies have shown that administration of bone marrow mesenchymal stem cells (MSCs) improves kidney functional recovery in the acute phase of post ischemia-reperfusion injury. In the present study, we used an original model of renal ischemia-reperfusion in immunosuppressed rats (NIRC) to investigate the effects of bone marrow MSCs on progression of chronic renal failure and the mechanisms potentially involved. Left renal ischemia-reperfusion (IR) was induced in unilateral nephrectomized Lewis rats. After IR, rats were treated daily with cyclosporine (10 mg/kg SC) for 28 days. MSCs were injected into the kidney at day 7 after IR. At day 28 after IR, kidneys were removed for histomorphological, biochemical, and gene expression analysis. The effect of conditioned media from MSCs on epithelial-mesenchymal transition was studied in vitro on HK2 cells. Our results show that, as compared to untreated NIRC rats, rats treated by intrarenal injection of MSCs 7 days after IR displayed improvement in renal function, reduction of interstitial fibrosis, and decrease in chronic tubule injury. These effects were associated with a decrease in interstitial α-SMA accumulation and MMP2 activity, markers of fibroblast/fibroblast-like cell activation, and renal remodeling, respectively. Finally, experiments in vitro showed that MSC-conditioned medium prevented epithelial-mesenchymal transition induced by TGF-β in HK2 cells. In conclusion, our results show that, in immunosuppressed animals, a single intrarenal administration of MSCs reduced renal fibrosis and promoted the recovery of renal function.


Subsets of CD4+ T cells and their roles in autoimmunity.
The CD4 molecule has a very restricted tissue distribution being found at high levels only on subpopulations of thymocytes and peripheral T cells. This finding implicated the molecule in the specialized actions of these cells and provided the impetus for studies directed at determining the function of the CD4 molecule itself and of those T cells that expressed it. The first part of this paper reviews briefly some of the earlier work in this field in which Alan Williams played such a major role. The paper concludes with an account of more recent findings which reveal that CD4+ T cells are themselves phenotypically heterogeneous and that the different subsets that can be identified mediate markedly different immunological functions. In particular studies with laboratory rats have shown that one subset plays an essential role in the prevention of autoimmunity. This finding indicates that self tolerance cannot be accounted for entirely in terms of the deletion or irreversible inactivation of autoreactive T cells and raises a number of questions about how the immune response to self antigens is actively regulated and how possible deficiencies in this regulation may give rise to autoimmune disease.


Reducing cultural and psychological barriers to Latino enrollment in HIV-prevention counseling: initial data on an enrollment meta-intervention.
Aspects of Latino culture (e.g., machismo, marianism) can act as barriers to enrollment in HIV-prevention programs. To lift these barriers, a culturally appropriate meta-intervention was designed to increase intentions to enroll in HIV-prevention counseling by Latinos. Latino participants (N=41) were recruited from the community and randomly assigned to either an experimental or control meta-intervention condition that varied the introduction to a HIV-prevention counseling program. Following the meta-intervention, participants were issued an invitation to take part in HIV-prevention counseling. The outcome measure was the intention to enroll in a HIV-prevention counseling session. Findings indicated that enrollment intentions were higher in the experimental meta-intervention condition (96%) than in the control meta-intervention condition (53%). In addition, the effects of the meta-intervention were comparable across genders and participant ages. Findings suggest that the use of a culturally appropriate meta-intervention may be an effective strategy for increasing Latino enrollment in HIV-prevention programs. These promising findings warrant further investigation into the efficacy and effectiveness of this meta-intervention.


Rebamipide induces dendritic cell recruitment to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-exposed rat gastric mucosa based on IL-1β upregulation.
Rebamipide is usually used for mucosal protection, healing of gastric ulcers, treatment of gastritis, etc., but its effects on gastric malignancy have not been elucidated. Using Lewis and Buffalo rat strains treated with peroral administration of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), we evaluated the effect of rebamipide on the induction of tumor-suppressive dendritic cells, which are known to be heterogeneous antigen-presenting cells of bone marrow origin and are critical for the initiation of primary T-cell responses. Using CD68 as a marker for dendritic cells, the stomach pyloric mucosae of Lewis and Buffalo rats were immunohistochemically analyzed in the presence or absence of rebamipide and MNNG. After a 14-day treatment of rebamipide alone, no significant change in number of CD68-expressing cells was detected in either rat strain. However, after concurrent exposure to MNNG for 14 days, treatment with rebamipide slightly increased CD68-positive cells in the Lewis strain, and significantly increased them in the Buffalo strain. Analysis of two chemotactic factors of dendritic cells, IL-1β and TNF-α, in the gastric cancer cells showed that expression of IL-1β, but not TNF-α, was induced by rebamipide in a dose-dependent manner. A luciferase promoter assay using gastric SH-10-TC cells demonstrated that an element mediating rebamipide action exists in the IL-1β gene promoter region. In conclusion, rebamipide has potential tumor-suppressive effects on gastric tumorigenesis via the recruitment of dendritic cells, based on the upregulation of the IL-1β gene in gastric epithelial cells.


Microelectromechanical reprogrammable logic device.
In modern computing, the Boolean logic operations are set by interconnect schemes between the transistors. As the miniaturization in the component level to enhance the computational power is rapidly approaching physical limits, alternative computing methods are vigorously pursued. One of the desired aspects in the future computing approaches is the provision for hardware reconfigurability at run time to allow enhanced functionality. Here we demonstrate a reprogrammable logic device based on the electrothermal frequency modulation scheme of a single microelectromechanical resonator, capable of performing all the fundamental 2-bit logic functions as well as n-bit logic operations. Logic functions are performed by actively tuning the linear resonance frequency of the resonator operated at room temperature and under modest vacuum conditions, reprogrammable by the a.c.-driving frequency. The device is fabricated using complementary metal oxide semiconductor compatible mass fabrication process, suitable for on-chip integration, and promises an alternative electromechanical computing scheme.


2D QSAR and Virtual Screening based on Pyridopyrimidine Analogs of Epidermal Growth Factor Receptor Tyrosine Kinase.
Epidermal Growth Factor Receptor tyrosine kinase (EGFR) is an important anticancer drug target. Series of pyridopyrimidine analogs have been reported as EGFR inhibitors and they inhibit by binding to the ATP binding pocket of the tyrosine kinase domain. To identify key properties of pyridopyrimidine analogs involved in the inhibition of the EGFR protein tyrosine kinase by developing 2D QSAR model. Variable selection was performed by least absolute shrinkage and selection operator (LASSO) method and multiple linear regression (MLR) method was applied by using Build QSAR software to develop QSAR model. Model validation was done by Leave One Out method (LOO). Further, based on the bioactive and structural similarity, virtual screening was performed using Pubchem database. Using the developed QSAR model and Molinspiration server, PIC50 values and kinase inhibition activity were predicted for all the virtually screened compounds respectively. The best QSAR model consists of two descriptors namely Basak and MOE type descriptors, and has R2 = 0.8205, F= 57.129 & S = 0.308 and the validation results show significant statistics of R2/cv = 0.655, Average standard deviation = 0.416. 140 compounds were obtained from virtual screening and the predicted PIC50 of all these compounds are in the range of 4.73 - 6.78. All the compounds produce positive scores which suggest that the compounds may have good kinase inhibitory profile. This developed model may be useful to predict EGFR inhibition activity (PIC50) for the newly synthesized pyridopyrimidines analogs.


Myofibroblasts in murine cutaneous fibrosis originate from adiponectin-positive intradermal progenitors.
Accumulation of myofibroblasts in fibrotic skin is a hallmark of systemic sclerosis (SSc; scleroderma), but the origins of these cells remain unknown. Because loss of intradermal adipose tissue is a consistent feature of cutaneous fibrosis, we sought to examine the hypothesis that myofibroblasts populating fibrotic dermis derive from adipocytic progenitors. We performed genetic fate mapping studies to investigate the loss of intradermal adipose tissue and its potential role in fibrosis in mice with bleomycin-induced scleroderma. Modulation of adipocytic phenotypes ex vivo was investigated in adipose tissue-derived cells in culture. A striking loss of intradermal adipose tissue and its replacement with fibrous tissue were consistently observed in mice with bleomycin-induced fibrosis. Loss of adipose tissue and a decline in the expression of canonical adipogenic markers in lesional skin preceded the onset of dermal fibrosis and expression of fibrogenic markers. Ex vivo, subcutaneous adipocytes were driven by transforming growth factor β to preferentially undergo fibrogenic differentiation. Cell fate mapping studies in mice with the adiponectin promoter-driven Cre recombinase transgenic construct indicated that adiponectin-positive progenitors that are normally confined to the intradermal adipose tissue compartment were distributed throughout the lesional dermis over time, lost their adipocytic markers, and expressed myofibroblast markers in bleomycin-treated mice. These observations establish a novel link between intradermal adipose tissue loss and dermal fibrosis and demonstrate that adiponectin-positive intradermal progenitors give rise to dermal myofibroblasts. Adipose tissue loss and adipocyte-myofibroblast transition might be primary events in the pathogenesis of cutaneous fibrosis that represent novel potential targets for therapeutic intervention.


Magnesium sulfate prevents maternal inflammation-induced impairment of learning ability and memory in rat offspring.
Maternal chorioamnionitis is associated with newborn neurologic injury. Recent evidence suggests that maternal administration of magnesium sulphate (MG) may protect fetuses from white matter injury. Previously we demonstrated evidence by magnetic resonance imaging that MG may prevent maternal inflammation-induced gray matter injury of offspring. Thus, we sought to determine the potential of maternal inflammation to induce fetal neurological/behavioral deficits and assess whether maternal MG attenuates these effects. Pregnant rats at day 18 received injections of intraperitoneal lipopolysaccharide (LPS) or saline. Dams were treated with subcutaneous saline/MG (270 mg/kg followed by 27 mg/kg every 20 minutes) for 2 hours before and following LPS/saline injections. Pups were delivered spontaneously. At 1 and 3 months of age, 11-12 offspring of each group (saline, LPS, MG, LPS-MG) underwent a 2-way shuttle box avoidance testing. The shuttle box is divided in half and the animal moves between compartments to avoid an electric shock in response to an auditory stimulus. Control offspring demonstrated significantly improved learning and memory abilities from age 1 to 3 months. At 1 month, LPS-treated dams' offspring were similar to controls with no improvement in learning abilities at 3 months. MG treatment of LPS dams significantly improved offspring learning at 3 months, to equal or better than that of controls. LPS-stimulated inflammation during pregnancy impairs offspring learning ability and memory, which is ameliorated by maternal MG treatment. These results suggest that maternal MG therapy may prevent white and gray matter injuries associated with maternal infection/inflammation.


Clinical response to pandemic H1N1 influenza virus from a fatal and mild case in ferrets.
The majority of pandemic 2009 H1N1 (A(H1N1)pdm09) influenza virus (IV) caused mild symptoms in most infected patients, however, a greater rate of severe disease was observed in healthy young adults and children without co-morbid conditions. The purpose of this work was to study in ferrets the dynamics of infection of two contemporary strains of human A(H1N1)pdm09 IV, one isolated from a patient showing mild disease and the other one from a fatal case. Viral strains isolated from a patient showing mild disease-M (A/CastillaLaMancha/RR5661/2009) or from a fatal case-F (A/CastillaLaMancha/RR5911/2009), both without known comorbid conditions, were inoculated in two groups of ferrets and clinical and pathological conditions were analysed. Mild to severe clinical symptoms were observed in animals from both groups. A clinical score distribution was applied in which ferrets with mild clinical signs were distributed on a non-severe group (NS) and ferrets with severe clinical signs on a severe group (S), regardless of the virus used in the infection. Animals on S showed a significant decrease in body weight compared to animals on NS at 4 to 7 days post-infection (dpi). Clinical progress correlated with histopathological findings. Concentrations of haptoglobin (Hp) and serum amyloid A (SAA) increased on both groups after 2 dpi. Clinically severe infected ferrets showed a stronger antibody response and higher viral titres after infection (p = 0.001). The severity in the progress of infection was independent from the virus used for infection suggesting that the host immune response was determinant in the outcome of the infection. The diversity observed in ferrets mimicked the variability found in the human population.


Antibodies against erythrocyte Ca2+-transport ATPase specifically inhibit the calmodulin-dependent fraction of the enzyme's activity.
Antibodies against purified Ca2+-transport ATPase from human erythrocytes were raised in rabbits. Immunodiffusion experiments revealed that precipitating antibodies had been developed. The immunoglobulin fraction inhibited solely the calmodulin-dependent fraction of erythrocyte Ca2+-transport ATPase activity, whereas the basal (in the absence of added calmodulin) activity of the enzyme was not significantly affected by the antibodies. The antibodies produced similar doseresponse curves for the calmodulin- and the oleic acid-stimulated enzyme. However, the immunoglobulin fraction was considerably less effective in inhibiting Ca2+-transport ATPase activated by limited proteolysis. The results obtained with our antibodies are compatible with the interpretation that at least one subpopulation of the antibodies attacks the enzyme at or close to the calmodulin-binding site of the ATPase. The antibodies also inhibited the calmodulin-regulated Ca2+-transport ATPase from pig smooth-muscle plasma membrane, though with lower potency. However, the immunoglobulin fraction failed to suppress pig cardiac sarcoplasmicreticulum Ca2+-transport ATPase activity in the concentration range investigated. In addition, the activity of phosphodiesterase from rat brain, another enzyme modulated by calmodulin, was not at all affected by the immunoglobulin fraction.


Postharvest Treatments with Sulfur-Containing Food Additives to Control Major Fungal Pathogens of Stone Fruits.
The sulfur-containing salts, classified as food additives, sodium metabisulfite (SMBS), potassium metabisulfite (PMBS), aluminum sulfate (AlS), and aluminum potassium sulfate (AlPS), were evaluated for their activity against Monilinia fructicola, Rhizopus stolonifer, and Geotrichum candidum, the most economically important fungal pathogens causing postharvest disease of stone fruit. In in vitro tests with potato dextrose agar (PDA) Petri dishes amended with different concentrations of the salts (0, 10, 20, 30, 50, and 100 mM), SMBS and PMBS at all concentrations, AlS above 20 mM, and AlPS above 30 mM, completely inhibited the mycelial growth of the three fungi after incubation at 25 °C for up to 10 days. In in vivo primary screenings with artificially inoculated nectarines, aqueous solutions of the four salts reduced the incidence and severity of brown rot (BR) at concentrations of 10 and 50 mM, whereas only AlS and AlPS reduced Rhizopus rot (RR), and none of the salts was effective against sour rot (SR). Solutions at 100 mM were phytotoxic and injured the fruit peel. In small-scale trials, 1 min dip treatments at 20 °C in SMBS or PMBS at 10 mM significantly reduced the incidence and severity of BR after incubation at 20 °C for up to 8 days. Conversely, dips in AlS and AlPS reduced neither BR nor RR. Results highlight the potential of SMBS and PMBS as new nonpolluting tools for the integrated control of BR, but not RR and SR, on stone fruit.


Medical volume segmentation by overfitting sparsely annotated data.
Semantic segmentation is one of the most significant tasks in medical image computing, whereby deep neural networks have shown great success. Unfortunately, supervised approaches are very data-intensive, and obtaining reliable annotations is time-consuming and expensive. Sparsely labeled approaches, such as bounding boxes, have shown some success in reducing the annotation time. However, in 3D volume data, each slice must still be manually labeled. We evaluate approaches that reduce the annotation effort by reducing the number of slices that need to be labeled in a 3D volume. In a two-step process, a similarity metric is used to select slices that should be annotated by a trained radiologist. In the second step, a predictor is used to predict the segmentation mask for the rest of the slices. We evaluate different combinations of selectors and predictors on medical CT and MRI volumes. Thus we can determine that combination works best, and how far slice annotations can be reduced. Our results show that for instance for the Medical Segmentation Decathlon-heart dataset, some selector, and predictor combinations allow for a Dice score 0.969 when only annotating 20% of slices per volume. Experiments on other datasets show a similarly positive trend. We evaluate a method that supports experts during the labeling of 3D medical volumes. Our approach makes it possible to drastically reduce the number of slices that need to be manually labeled. We present a recommendation in which selector predictor combination to use for different tasks and goals.


Predictors of Outcome Following Cerebral Aqueductoplasty: An Individual Participant Data Meta-analysis.
The evidence supporting the efficacy and safety of cerebral aqueductoplasty (CA) is limited to small surgical series. To perform an individual participant data meta-analysis to determine the efficacy and safety of CA and to determine the effect of patient's age, etiology, surgical approach, and use of stent on success. Electronic databases (MEDLINE, EMBASE, and CINAHL) were searched with no language or date restrictions to identify cohort studies of consecutive participants undergoing CA (without concomitant endoscopic third ventriculostomy or cerebrospinal fluid [CSF] shunt) that reported outcome. Outcome was defined as the time elapsed from the index operation until a second procedure was performed for CSF diversion. Of 146 citations, 14 articles reporting on 137 participants were eligible. One hundred three participants (75%) did not require a second CSF diversion procedure. The mean duration until repeat CSF diversion procedure was 121.6 months (95% confidence interval [CI], 102.2-141.0). In multivariate analysis, older age at surgery (hazard ratio [HR], 0.43; 95% CI, 0.21-0.88; P = .020), congenital etiology (HR, 0.18; 95% CI, 0.04-0.85; P = .030), and use of stent (HR, 0.30; 95% CI, 0.13-0.70; P = .006) were independent predictors of good outcome. Morbidity, mainly ophthalmoparesis and hemorrhage, was experienced in 22% of participants. Small retrospective cohort studies are inherently prone to biases, some of which are overcome through the use of individual participant data. The best available evidence suggests that CA is an effective procedure with a moderate morbidity profile. Older age at surgery, congenital etiology, and use of stent predict a good outcome with respect to delaying the requirement for a second CSF diversion procedure.


The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial.
To examine the efficacy and safety of different rituximab doses plus methotrexate (MTX), with or without glucocorticoids, in patients with active rheumatoid arthritis (RA) resistant to disease-modifying antirheumatic drugs (DMARDs), including biologic agents. A total of 465 patients were randomized into 9 treatment groups: 3 rituximab groups (placebo [n = 149], 500 mg [n = 124], or 1,000 mg [n = 192] on days 1 and 15) each also taking either placebo glucocorticoids, intravenous methylprednisolone premedication, or intravenous methylprednisolone premedication plus oral prednisone for 2 weeks. All patients received MTX (10-25 mg/week); no other DMARDs were permitted. Significantly more patients who received 2 500-mg or 2 1,000-mg infusions of rituximab met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 24 (55% and 54%, respectively) compared with placebo (28%; P < 0.0001). ACR50 responses were achieved by 33%, 34%, and 13% of patients, respectively (P < 0.001), and ACR70 responses were achieved by 13%, 20%, and 5% of patients (P < 0.05). Changes in the Disease Activity Score in 28 joints (-1.79, -2.05, -0.67; P < 0.0001) and moderate to good responses on the European League Against Rheumatism criteria (P < 0.0001) reflected the ACR criteria responses. Glucocorticoids did not contribute significantly to the primary efficacy end point, ACR20 response at 24 weeks. Intravenous glucocorticoid premedication reduced the frequency and intensity of first infusion-associated events; oral glucocorticoids conferred no additional safety benefit. Rituximab was well tolerated; the type and severity of infections was similar to those for placebo. Both rituximab doses were effective and well tolerated when added to MTX therapy in patients with active RA. The primary end point (ACR20 response) was independent of glucocorticoids, although intravenous glucocorticoid premedication improved tolerability during the first rituximab infusion.


Role of lectins in plant--microorganism interactions. IV. Ultrastructural localization of soybean lectin binding sites of Rhizobium japonicum.
The binding of purified, ferritin-labeled soybean seed lectin to the cell surfaces of Rhizobium japonicum 31 lb 138 has been examined by whole mount, thin section, and freeze-etch electron microscopy. The ferritin-labeled lectin binds in a biochemically specific manner to the capsular material of this bacterium. The lectin does not bind to the outer membranes of the cells or to flagella. Labeled lectin binds to sites throughout the capsular structure, although the density of labeling is somewhat greater on the outer surface of the capsule. Some cells appear to be partially encapsulated. Preservation of the capsular material proved difficult, and methods for retaining most of the capsular material were developed.


Protocol for phase I study of pembrolizumab in combination with Bacillus Calmette-Guérin for patients with high-risk non-muscle invasive bladder cancer.
The initial treatment for high-risk non-muscle invasive bladder cancer (NMIBC) is endoscopic resection of the tumour followed by BCG therapy. In those who develop recurrence, the standard treatment is radical cystectomy. Despite the advancement in surgical technique and postoperative care, the degree of morbidity associated with radical cystectomy remains high, therefore less invasive treatment modalities are desirable. Therapies targeting the programmed death (PD) pathway have shown promise in urothelial carcinoma. We undertook the current study to determine the safety and efficacy of administering pembrolizumab (a monoclonal antibody targeting the interaction between PD-1 and its ligand) in combination with BCG in high-risk NMIBC. This is a single-centre phase I safety and efficacy study of pembrolizumab used in combination with intravesicular BCG treatment for subjects with pathologically documented high-risk NMIBC despite having received two courses of induction therapy or BCG treatment followed by maintenance BCG. Fifteen subjects will be enrolled, patients will receive treatment with 200 mg of pembrolizumab every 21 days, starting 2 weeks from the initial endoscopic resection and continuing for 6 weeks after the final dose of BCG. The primary objective is to determine the safety of administering pembrolizumab at a fixed dose of 200 mg every 3 weeks in conjunction with intravesicular BCG treatment in patients with high-risk NMIBC who have failed previous treatment. Secondary objectives are to determine the 19 weeks and the 3, 12 and 24 months post-treatment completion complete response rate with combined pembrolizumab and intravesicular BCG therapy in the aforementioned patients. The study has been approved by the Institutional Review Board of the Henry Ford Hospital. The results of this study will be published in a peer-reviewed journal and presented at a scientific conference. NCT02324582.


[Antibiotic activity of marine gram-negative bacteria].
An antimicrobial substance was isolated from the culture fluid of Vibrio fischeri belonging to ++gram-negative sea bacteria. The substance was shown to be highly active against ++gram-positive cocci and less active against some other ++gram-positive bacteria and fungi. The active substance was defined as a low molecular weight compound which appeared to be thermostable and had positive ninhydrin reaction. The antibiotic formed when the culture was grown in the media containing sea water and protein hydrolysates or yeast extract during the exponential phase. The maximum antibiotic activity was observed during the stationary phase of culture development.


Understanding the magnetic interaction between intrinsic defects and impurity ions in room-temperature ferromagnetic Mg1-xFexO thin films.
Understanding the nature and characteristics of the intrinsic defects and impurities in the dielectric barrier separating the ferromagnetic electrodes in a magnetic tunneling junction is of great importance for understanding the often observed 'barrier-breakdown' therein. In this connection, we present herein systematic experimental (SQUID and synchrotron-radiation-based x-ray absorption spectroscopy) and computational studies on the electronic and magnetic properties of Mg1-xFexO thin films. Our studies reveal: (i) defect aggregates comprised of basic and trimer units (Fe impurity coupled to 1 or 2 Mg vacancies) and (ii) existence of two competing magnetic orders, defect- and dopant-induced, with spin densities aligning anti-parallel if the trimer is present in the oxide matrix. These findings open up new avenues for designing tunneling barriers with high endurance and tunneling effect upon tuning the concentration/distribution of the two magnetic orders.


Identification of Paraproteins via Serum Immunofixation or Serum Immunosubtraction and Immunoturbidimetric Quantitation of Serum Immunoglobulins in the Laboratory Testing for Monoclonal Gammopathies.
In laboratory testing for monoclonal gammopathies, paraproteins are identified via serum immunofixation or serum immunosubtraction, and immunoturbidimetric quantitation of serum immunoglobulins is often used. To evaluate methodologic differences between serum immunofixation and serum immunosubtraction, as well as in the quantitation of serum immunoglobulins on different clinical chemical platforms. Three hundred twenty-two unique routine patient samples were blinded and used for comparison between serum immunofixation on Sebia's HYDRASIS 2 and serum immunosubtraction on Sebia's CAPILLARYS 2, as well as between quantitation results of immunoglobulin A, G, and M on Abbott's ARCHITECT c16000PLUS and Roche's Cobas c 502 module. Microsoft Excel 2019 with the add-on Abacus 2.0 and MedCalc were used for statistical analysis and graphic depiction via bubble diagram, Passing-Bablok regressions, and Bland-Altman plots. The median age of patients was 75 years, and samples with paraproteinemia were nearly evenly split between sexes. Paraprotein identification differed remarkably between immunofixation and immunosubtraction. Quantitation of serum immunoglobulins showed higher values on Abbott's ARCHITECT c16000PLUS when compared with Roche's Cobas c 502 module. Identification of paraproteins via serum immunosubtraction is inferior to serum immunofixation, which can have implications on the diagnosis and monitoring of patients with monoclonal gammopathy. If immunoturbidimetric quantitation of immunoglobulins is used for follow-up, the same clinical-chemical platform should be used consistently.


Benefit of interferon-alpha2b in a patient with unresectable hepatoma and chronic infection with hepatitis C virus.
Only in a small proportion of patients is advanced hepatocellular carcinoma (HCC) resectable, so the need for effective non-surgical treatments is obvious. We present details of a 72-year-old woman with inoperable HCC and chronic infection with hepatitis C virus, proved by the presence of antibodies directed against hepatitis C virus and positive polymerase chain reaction. The patient was treated with subcutaneous recombinant human interferon-alpha-2b. Within a few weeks, a partial tumour remission, paralleled by a decrease in serum levels of tumour markers and liver enzymes, was observed. In addition, polymerase chain reaction became negative. This observation facilitates the hypothesis that the anti-viral effects of interferon might have been jointly responsible for the anti-tumour activity observed. Interferon-alpha might serve as a treatment option in patients with unresectable hepatoma and chronic active viral hepatitis, but prospective studies are warranted.


Models to Study NK Cell Biology and Possible Clinical Application.
Natural killer (NK) cells are large granular lymphocytes of the innate immune system, responsible for direct targeting and killing of both virally infected and transformed cells. NK cells rapidly recognize and respond to abnormal cells in the absence of prior sensitization due to their wide array of germline-encoded inhibitory and activating receptors, which differs from the receptor diversity found in B and T lymphocytes that is due to the use of recombination-activation gene (RAG) enzymes. Although NK cells have traditionally been described as natural killers that provide a first line of defense prior to the induction of adaptive immunity, a more complex view of NK cells is beginning to emerge, indicating they may also function in various immunoregulatory roles and have the capacity to shape adaptive immune responses. With the growing appreciation for the diverse functions of NK cells, and recent technological advancements that allow for a more in-depth understanding of NK cell biology, we can now begin to explore new ways to manipulate NK cells to increase their clinical utility. In this overview unit, we introduce the reader to various aspects of NK cell biology by reviewing topics ranging from NK cell diversity and function, mouse models, and the roles of NK cells in health and disease, to potential clinical applications. © 2015 by John Wiley & Sons, Inc.


Olfactory Dysfunction in Incidental Lewy Body Disease and Parkinson's Disease: An Update.
Measuring olfactory dysfunction shows promise as one of a number of nonmotor biomarkers that can be used to detect clinically manifest and prodromal Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and to differentiate these from nonsynucleinopathies. Using a larger sample size than in our previous study, we evaluated the relationship between olfactory dysfunction based on the University of Pennsylvania Smell Identification Test (UPSIT) to the clinicopathological findings in patients with PD (n=41), patients with incidental Lewy body disease (ILBD) (n=47), and controls with no neurodegenerative disease (n=137). This study was conducted through the Arizona Study of Aging and Neurodegenerative Disease (AZSAND). We selected individuals who had an UPSIT score completed antemortem and were clinicopathologically diagnosed with PD, ILBD, or control. Various measures included density of Lewy type synucleinopathy (aSyn) in the olfactory bulb and tract, as well as connected mesial temporal lobe structures. Cases and controls were analyzed using one-way analysis of variance (ANOVA) with pairwise contrasts. Compared to controls (mean: 27.8, standard deviation [SD]: 6.0), the mean UPSIT scores were lower for PD (15.8, SD: 6.0, p<0.001) and ILBD (24.1, SD: 8.6, p<0.001). The sensitivity for detecting ILBD from controls, based on a cutoff score of less than 23 (23/47), was 48.9 percent. The specificity for detecting a control was 79.6 percent with a cutoff greater than 23 (109/137). These findings replicate, with a larger sample size, our previously published findings that individuals with autopsy-confirmed PD and ILBD have significantly lower UPSIT scores compared to controls. These data add to the growing body of evidence supporting early olfactory dysfunction as a prodromal biomarker for the risk of developing PD and ILBD as a prodromal Lewy body disorder.


Survey of sterile technique used by dermatologic surgeons.
A survey was made of the sterile technique practices of dermatologists interested in dermatologic surgery. The steam autoclave is the most popular method for sterilizing surgical instruments. Dry heat sterilization is often used, as is cold, chemical sterilization. The most popular agent for chemical sterilization continues to be quaternary ammonium compounds despite warnings to the contrary. Gas sterilization is rarely used. Alcohol is the most popular agent for prepping the skin and iodophors are also quite popular. Dermatologists are now wearing gloves for most procedures. Prophylactic antibiotics are used minimally in surgical cases, as is recommended by established standards.


Clinicians' Perceptions of Screening for Food Insecurity in Suburban Pediatric Practice.
National organizations recommend pediatricians screen for food insecurity (FI). Although there has been growing research in urban practices, little research has addressed FI screening in suburban practices. We evaluated the feasibility, acceptability, and impact of screening in suburban practices. We conducted a mixed methods study that implemented FI screening in 6 suburban pediatric primary care practices. We included all children presenting for either a 2-, 15-, or 36-month well-child visit (N = 5645). Families who screened positive were eligible to be referred to our community partner that worked to connect families to the Supplemental Nutrition Assistance Program. We conducted focus groups with clinicians to determine their perceptions of screening and suggestions for improvement. Of the 5645 children eligible, 4371 (77.4%) were screened, of which 122 (2.8%) screened positive for FI (range: 0.9%-5.9% across practices). Of the 122 food-insecure families, only 1 received new Supplemental Nutrition Assistance Program benefits. In focus groups, 3 themes emerged: (1) Time and workflow were not barriers to screening, but concerns about embarrassing families and being unable to provide adequate resources were; (2) Clinicians reported that parents felt the screening showed caring, which reinforced clinicians' continued screening; (3) Clinicians suggested implementing screening before the visit. We found it is feasible and acceptable for clinicians to screen for FI in suburban practices, but the referral method used in this study was ineffective in assisting families in obtaining benefits. Better approaches to connect families to local resources may be needed to maximize the effectiveness of screening in suburban settings.


Epidural injections for spinal pain: a systematic review and meta-analysis evaluating the "control" injections in randomized controlled trials.
Epidural steroid injection is the most frequently performed pain procedure. This study of epidural steroid "control" injections aimed to determine whether epidural nonsteroid injections constitute a treatment or true placebo in comparison with nonepidural injections for back and neck pain treatment. This systematic review with direct and indirect meta-analyses used PubMed and EMBASE searches from inception through October 2012 without language restrictions. Study selection included randomized controlled trials with a treatment group receiving epidural injections of corticosteroids or another analgesic and study control groups receiving either an epidural injection devoid of treatment drug or a nonepidural injection. Two reviewers independently extracted data including short-term (up to 12 weeks) pain scores and pain outcomes. All reviewers evaluated studies for eligibility and quality. A total of 3,641 patients from 43 studies were included in this systematic review and meta-analysis. Indirect comparisons suggested epidural nonsteroid were more likely than nonepidural injections to achieve positive outcomes (risk ratio, 2.17; 95% CI, 1.87-2.53) and provide greater pain score reduction (mean difference, -0.15; 95% CI, -0.55 to 0.25). In the very limited direct comparisons, no significant differences were noted between epidural nonsteroid and nonepidural injections for either outcome (risk ratio [95% CI], 1.05 [0.88-1.25]; mean difference [95% CI], 0.22 [-0.50 to 0.94]). Epidural nonsteroid injections may provide improved benefit compared with nonepidural injections on some measures, though few, low-quality studies directly compared controlled treatments, and only short-term outcomes (≤12 weeks) were examined.


Influence of agents that affect intracellular calcium regulation on progesterone secretion in small and large luteal cells of the sheep.
Enriched fractions of small and large luteal cells were incubated for 2 h with 1 or 10 microM calcium ionophore, A23187: unstimulated secretion of progesterone and viability in small cells were not affected but these measures were decreased (P less than 0.01) for unstimulated large cells and were significantly correlated (P less than 0.05). This effect in large cells was independent of extracellular calcium. Therefore, incubations of the two cell types were made in the presence of increasing concentrations of a protein kinase C activator, phorbol 12-myristate 13-acetate (TPA). Secretion of progesterone and viability were not augmented in unstimulated small cells, but TPA prevented (P less than 0.05) the full stimulation of secretion of progesterone by LH. Secretion of progesterone in unstimulated large cells was inhibited (P less than 0.01) by TPA (100 nM and 10 microM), although viability was unaffected. The non-tumour promoting phorbol ester, 4 alpha-phorbol didecanoate, had no effect on large cells. Extracellular calcium was not required for the observed effect of TPA. Sphingosine, an agent inhibitory to protein kinase C activity, inhibited (P less than 0.01) secretion of progesterone in small and large cells, and also reduced (P less than 0.01) cell viability. These values were significantly correlated (P less than 0.05) in both cell types. The above observations suggest that protein kinase C may invoke negative regulation on progesterone production in unstimulated large and hormone-stimulated small luteal cells of sheep. Since sphingosine significantly reduced viability in small and large cells and ionophore selectively inhibited viability in large cells, the ability of these agents to influence calcium-mediated intracellular regulation of steroidogenesis is still uncertain.


Comparison of culture media for the laboratory diagnosis of chancroid.
Seven different agar-based media were compared to determine the optimal set of culture media for primary isolation of Haemophilus ducreyi. Also, a new method for sampling genital ulcers -- with a disposable sterile plastic loop -- and processing specimens that provides a standardised inoculum for culture of H. ducreyi on various media is described. A total of 202 patients with genital ulcer disease was enrolled in this study. A sterile swab or plastic loop was used to sample the base of the ulcers and ulcer material was suspended in sterile phosphate-buffered saline. A 100-microl sample of this suspension was mixed with an equal volume of tryptic soy broth containing IsoVitaleX and centrifuged for 1 min. This suspension was used to inoculate the different media. Plates were incubated at 33 degrees C in micro-aerophilic conditions and examined for growth of H. ducreyi after 48 h. Of the 202 specimens, 77 (38.1%) were culture positive for H. ducreyi. None of the agar bases supported the growth of all H. ducreyi strains. Based on this observation, we recommend the universal use of Mueller-Hinton agar base supplemented with chocolate horse blood and IsovitaleX (MH-HBC) and Columbia agar base supplemented with bovine haemoglobin, activated charcoal, fetal calf serum and IsovitaleX (C-HgCh) to enable comparison of prevalence figures for chancroid. In addition, the novel sampling technique described in this study eliminates sampling bias normally associated with genital ulcer specimens.


Implant success in sinus-lifted maxillae and native bone: a 3-year clinical and computerized tomographic follow-up.
The present study was a 3-year follow-up evaluation of implant clinical success and radiographic bone remodeling in sinus floors elevated with different autogenous bone-grafting procedures and in similar native bone regions. This retrospective chart review examined consecutive edentulous patients with severe jaw atrophy treated between 2000 and 2002 via sinus lift, when needed, and implant insertion. Implants in sinus lift areas were divided into four groups by graft source (iliac crest, chin area) and technique (bone block, particulate). Implants positioned in native areas beneath the sinus floor served as controls. The cumulative success rate (CSR) and success rate (SR) were calculated, and linear measurements of bone remodeling around implants were assessed on computerized tomographic scans. Results were statistically compared with the Wilcoxon signed rank test. Twenty-eight patients were treated in the posterior maxilla via insertion of 70 screw-type, root-form, rough implants in 39 sinus-lifted areas. All surgical procedures were uneventful. Twenty-four implants were positioned in native areas beneath the sinus floor. The implant CSR was 95.8% in native areas (one failure/24 implants), 85% in sinuses lifted with particulate chin bone (three failures/20 implants), and 100% in the other three groups (eight in particulate iliac crest, 20 in chin block, and 22 in iliac crest block). Computerized tomographic scans revealed that bone remodeling around apices caused implants to bulge into the sinuses in both particulate bone graft groups. Crestal remodeling around implant necks was similar for all groups. The use of particulate chin bone grafts in sinus lift procedures does not seem to yield optimal outcomes. Milled iliac crest and chin bone tends to remodel around the implant apices, leading to bulging within the sinuses. Grafting sinuses with either chin or.iliac crest bone blocks yields the highest implant success rates and stable sinus floors.


Selective targeting of gene products with the megakaryocyte platelet factor 4 promoter.
We have used the 1.1 kilobases of the 5' upstream region of the platelet factor four (PF4) gene coupled to the prokaryotic beta-galactosidase gene to generate two lines of transgenic mice that express this construct. Studies of blood, bone marrow, spleen, and thymus reveal that platelets are the only circulating blood cells and megakaryocytes are the only hematopoietic precursor cells that possess the prokaryotic enzyme. The lack of transgene expression in brain, heart, intestine, kidney, liver, lung, and skeletal muscle was established by in situ staining of tissue sections as well as kinetic assay of tissue homogenates. These data suggest that this domain of the PF4 promoter contains most, if not all, of the tissue-specific region of the gene. Unexpectedly, the adrenal gland exhibits approximately 2% of the levels of beta-galactosidase possessed by megakaryocytes and the distribution of the prokaryotic enzyme corresponds to the location of mineralocorticoid-secreting cells. This result implies that either the PF4 gene is transcribed at low levels in specialized adrenal cells or that these specialized endocrine cells possess trans-acting factors similar to those that control the megakaryocyte promoter. The selective high-level expression of transgenes linked to the PF4 promoter should allow us to augment or suppress the in vivo levels of critical components in megakaryocytes and platelets and subsequently ascertain the effects of these modifications.


Idiotypic protein-pulsed adherent peripheral blood mononuclear cell-derived dendritic cells prime immune system in multiple myeloma.
Adherent peripheral blood mononuclear cell-derived dendritic cells pulsed with autologous idiotypic protein (Id) were given to a patient with advanced-stage refractory myeloma. Potentially beneficial antimyeloma Id-specific immune responses were produced, characterized by MHC-dependent T-cell-proliferative responses with cytokine release and the production of anti-Id antibodies. A T-cell line generated after vaccination was also able to lyse autologous Id-pulsed targets and recognize fresh autologous myeloma cells. The immune responses were associated with a transient minor fall in the serum Id level and were not ablated by high-dose myeloablative chemotherapy. This report therefore demonstrates the clinical use of adherent peripheral blood mononuclear cell-derived dendritic cells for vaccination in cancer and the persistence of immune responses after high-dose chemotherapy. Such a therapeutic approach may be useful in reducing the relapse rate in patients who have minimal residual disease after chemotherapy.


Hydroxyethyl starch as a priming solution for cardiopulmonary bypass impairs hemostasis after cardiac surgery.
We investigated the influence of hydroxyethyl starch (HES) as a priming solution for the cardiopulmonary bypass (CPB) circuit on postoperative hemostasis in 45 patients undergoing elective coronary artery bypass grafting. In a randomized sequence, 20 mL/kg of low-molecular-weight HES (HES 120; molecular weight 120,000 daltons), high-molecular-weight HES (HES 400; molecular weight 400,000 daltons), or 4% human albumin (ALB) was used as the main component of the CPB priming solution. The thromboelastographic values indicating the speed of solid clot formation (alpha-angle) and the strength of the fibrin clot (maximum amplitude and shear elastic modulus) were decreased up to 2 h after CPB in both HES groups. Four hours after the operation, blood loss through the chest tubes had increased in the HES groups: HES 120, mean 804 mL (range, 330-1390 mL); HES 400, mean 1008 mL (range, 505-1955 mL); and ALB, mean 681 mL (range, 295-1500 mL) (P < 0.05 between the HES 400 and ALB groups). We conclude that HES solutions, when given in doses of 20 mL/kg in connection with the CPB prime, compromise hemostasis after cardiac surgery. This effect appears related to formation of a less stable thrombus compared with that formed in the presence of ALB. The influence of hydroxyethyl starch (HES) on postoperative hemostasis was investigated in cardiac surgery. The thromboelastographic values indicated that HES solutions, when given in connection with the cardiopulmonary bypass prime, compromise hemostasis after cardiac surgery. This effect seems to occur through the formation of a less stable clot.


Abdominal sacrocolpopexy with Burch colposuspension to reduce urinary stress incontinence.
We designed this trial to assess whether the addition of standardized Burch colposuspension to abdominal sacrocolpopexy for the treatment of pelvic-organ prolapse decreases postoperative stress urinary incontinence in women without preoperative symptoms of stress incontinence. Women who did not report symptoms of stress incontinence and who chose to undergo sacrocolpopexy to treat prolapse were randomly assigned to concomitant Burch colposuspension or to no Burch colposuspension (control) and were evaluated in a blinded fashion three months after the surgery. The primary outcomes included measures of stress incontinence (symptoms, stress testing, or treatment) and measures of urge symptoms. Enrollment was stopped after the first interim analysis because of a significantly lower frequency of stress incontinence in the group that underwent the Burch colposuspension. Of 322 women who underwent randomization, 157 were assigned to Burch colposuspension and 165 to the control group. Three months after surgery, 33.6 percent of the women in the Burch group and 57.4 percent of the controls met one or more of the criteria for stress incontinence (P<0.001) [Corrected]. There was no significant difference between the Burch group and the control group in the frequency of urge incontinence (32.7 percent vs. 38.4 percent, P=0.48). After surgery, women in the control group were more likely to report bothersome symptoms of stress incontinence than those in the Burch group who had stress incontinence (24.5 percent vs. 6.1 percent, P<0.001). In women without stress incontinence who are undergoing abdominal sacrocolpopexy for prolapse, Burch colposuspension significantly reduced postoperative symptoms of stress incontinence without increasing other lower urinary tract symptoms.


Two slow conduction systems co-ordinate shell-climbing behaviour in the sea anemone Calliactis parasitica.
1. Pulses in two slow conducting systems, the ectodermal SS 1 and the endodermal SS 2, were recorded during shell-climbing behaviour. The mean pulse interval of SS 1 pulses was 7-4 s and that of SS 2 pulses was 6-4 s. Activity in both systems may arise as a sensory response of tentacles to shell contact, but the SS 1 and SS 2 may not share the same receptors. 2. Electrical stimulation of the SS 1 and SS 2 together, at a frequency of 1 shock every 5 s, elicits shell-climbing behaviour in the absence of a shell. 3. Low-frequency nerve-net activity (about 1 pulse every 15 s) accompanies column bending during both normal and electrically elicited responses. This activity probably arises as a result of column bending and is not due to a sensory response to the shell.


Child Witnesses to Intimate Partner Violence: Their Descriptions of Talking to People About the Violence.
Witnessing intimate partner violence (IPV) may have damaging effects on children's well-being and development. How children understand IPV affects the risk of their developing negative outcomes. Talking with children about the violent episodes they have experienced can change their beliefs regarding their parents' IPV, and therefore may also be a way to help them deal with these adverse experiences. The purpose of the current study was to use the children's narratives to explore the relationship between how IPV was perceived by the children and their experience of talking about it. Interviews with 31 children between 9 and 13 years of age were analyzed using a thematic method. Two main groups of children were identified: children who described the violence as a horrifying experience and children who preferred not to think about the violence. The findings showed that children who described the violence as a horrifying experience perceived talking about the violence as a positive, yet sometimes distressing, experience that made a real difference in their lives; whereas, children who preferred not to think about the violence did not see much need to talk about it and benefit from talking about it. The study confirms previous research indicating that talking about IPV experiences sometimes leads to feelings of relief in children. Thereby, professionals play an important role by providing an appropriate setting to help children reduce their distressing feelings.


Adjustment problems among Soviet immigrants at risk, Part 2: Emotional distress among elderly Soviet immigrants during the Gulf War.
The nature and components of emotional distress under the threefold stress--old age, immigration and war--were studied in a group of 170 elderly Soviet immigrants in two settings--a mental health hotline for Soviet immigrants and an outreach project to immigrants deemed at risk. Most of the subjects reported distress during and following the war. Outreach subjects reported lower levels of distress determined by emotional factors and were much more concerned with objective problems related to immigration. In contrast, the predominant determinants of the hotline subjects' distress were emotional reactions related to the war. Among the emotional reactions, anxiety reactions were the most common symptom among women, while depressive reactions were more characteristic of men. Identified risk factors for emotional distress in men included prior experience with acute stress (Chernobyl accident) and living within an extended family. Academic education was identified as a resilience factor for women. No factors were identified that related to emotional distress combined with active help seeking behavior. This finding is particularly important in the context of primary and secondary prevention with Soviet immigrants.


T-cell receptor γ chain variable and joining region genes of subgroup 1 are clonally rearranged in feline B- and T-cell lymphoma.
Lymphoma is one of the most common tumours of domestic cats. Microscopically, it can be challenging to distinguish lymphoma (monoclonal lymphoid proliferation) from reactive lymphoid hyperplasia (polyclonal lymphoid proliferation). Molecular methods that characterize cellular clonality can overcome this diagnostic challenge; however, it is essential to know which variable and joining region variants are utilized by neoplastic lymphocytes before a sensitive and specific assay can be developed. The present study describes a polymerase chain reaction assay that allows for complete sequencing of clonally recombined T-cell receptor (TCR) γ chain genes from formalin-fixed and paraffin wax-embedded samples of feline lymphoma. The variable (V) and joining (J) region variants of the TCR γ chain were characterized in 50 feline lymphomas. Amplification and sequencing with primers directed against conserved framework regions 1, 2 and 4 of the TCR γ chain identified clonal rearrangement in 68% of T-cell lymphomas and 22% of B-cell lymphomas. The distribution of TCR variants present in B- and T-cell lymphomas was similar and included V region variants 1 and 3, and J region variants 1.2, 1.3 and 1.5. V region variants 2 and 4 were not identified in either tumour type. Some feline B-cell lymphomas had a clonally rearranged TCR, a finding reported in human, but not canine, B-cell lymphoma.


Medical students' palliative care education in a Latin American university: a three-year experience at Austral University in Buenos Aires, Argentina.
The School of Medicine of Austral University incorporated palliative care as an elective in undergraduate medicine curriculum during 2010. We analyzed the experience and results after 3 years of teaching palliative care. We compared students who chose palliative care as an elective subject (PC Group) with students who did not (Non-PC Group). We focused on the experience of contact with palliative care patients and self-perceived attitudes. Additionally, the impact produced by palliative care education in knowledge, self-perceived attitudes, and comfort was evaluated. All the students tested completed a questionnaire on their attitude when exposed to dying patients. Students in the PC Group completed an additional questionnaire to assess their level of knowledge and their self-perceived comfort when interacting with patients. We tested 146 students. All students in the PC Group and 95.2% in the Non-PC Group considered that specific death issues ought to be part of the curriculum. Some students indicated that they could be present in a mandatory course. Before taking their elective, students in the PC Group confirmed a lack of technical training to understand palliative care patients, as did those students in the Non-PC Group. After taking a palliative care elective students expressed an improvement in self-perceived attitudes toward suffering and there was a significant increase (p<0.0001-0.0045) in knowledge. They also expressed an improvement in comfort levels in evaluation and treatment of pain. More than 95% of the students in the PC Group rated the experience as valuable and perceived the content as not available elsewhere in their training. Our results show that palliative care education provides opportunities to improve attitudes not specific to this discipline: interprofessional collaboration, holistic care, patient-centered care, self-awareness, and humanism. We conclude that an exposure to palliative care improved student's perception about the complexities of dying patients and their care.


Evidence for glomerular actions of ADH and dibutyryl cyclic AMP in the rat.
Experiments were performed on 54 chronically water diuretic Munich-Wistar rats to investigate the effects of various antidiuretic peptides on the determinants of glomerular ultrafiltration. Transition from water diuresis to antidiuresis, induced either by intravenous infusion of 1) exogenous peptides (Pitressin, synthetic arginine vasopressin, or synthetic [1-deamino,4-valine]-8-D-arginine vasopressin) or 2) dibutyryl cyclic AMP, or by stimulation of endogenous ADH release by acute, mild arterial hemorrhage, was associated with near-constant or decreased values for single nephron (SN) and total kidney GFR. Nevertheless, the glomerular transcapillary hydraulic pressure difference (deltaP) uniformly increased with antidiuresis, due to consistent reductions in Bowman's space hydraulic pressure rather than to increases in glomerular capillary hydraulic pressure, the former a consequence of the fall in urine flow rate. In all antidiuretic states, the rats were uniformly observed to be at filtration pressure disequilibrium, permitting calculation of unique values of the glomerular ultrafiltration coefficient (Kf). These values of Kf in antidiuresis were invariably lower than the values obtained during water diuresis. Whether these effects of ADH and DBcAMP on deltaP and Kf represent physiological influences in the control of GFR remains uncertain; their offsetting effects in the present studies usually failed to alter GFR appreciably.


Exploring How Social Media Exposure and Interactions Are Associated With ENDS and Tobacco Use in Adolescents From the PATH Study.
Tobacco use is a current public health epidemic that puts individuals at risk for many health conditions and diseases, and adolescents are at high risk for the initiation and persistence of tobacco use behaviors partly due to engagement with social media content. The objective of this study is to examine the association between engaging in social media behaviors and patterns of electronic nicotine delivery systems (ENDS) and tobacco use at a 1-year follow-up among 11 279 adolescents from the PATH study. Five social media variables were questioned at Wave 2 and then compared to ENDS and tobacco status transitions (i.e., initiation, persistence, and escalation) at a 1-year follow-up, respectively. Survey-weighted multivariable logistic regression models were used to calculate adjusted odds ratios and 95% confidence interval. Passive behaviors on social media were related to higher likelihoods of starting to use ENDS and other tobacco products. Additionally, active behaviors on social media were related to higher likelihoods for the initiation and persistence of tobacco use. In particular, sending tobacco content to other users was further associated with a higher likelihood of escalation of tobacco product use. Both exposure to and interactions with social media tobacco content had a significant impact on the patterns of ENDS and tobacco use in adolescents. Due to the amount of time adolescents spend engaging with online content, social media may be a critical place in which to intervene, possibly with the use of antitobacco or tobacco prevention messages. The results of this study have implications for public health and the policies surrounding adolescents and their exposure to social media. Reducing the ENDS and tobacco content to which adolescents are exposed has the potential to decrease the instances of initiation and persistence of ENDS and tobacco use. Intervening on social media may prevent or slow the progression of ENDS and tobacco use, and increase motivation and actions toward the cessation of tobacco use in adolescents.


Silencing long noncoding RNA NEAT1 alleviates acute liver failure via the EZH2-mediated microRNA-139/PUMA axis.
This study aimed to investigate the role of long noncoding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) in the development of ALF. We collected blood samples from patients with acute liver failure (ALF) and established an ALF mouse model induced by D-galactosamine/Lipopolysaccharide (D-GalN/LPS) for in vivo studies. Peripheral blood mononuclear cells (PMBCs) induced with LPS were isolated for in vitro experiments. Survival tests, histological analysis, and biochemical indicator assays were conducted. Luciferase assay was performed to determine the binding affinity between microRNA-139 (miR-139) and p53-upregulated modulator of apoptosis (PUMA). Expression of lncRNA NEAT1, enhancer of zeste homolog 2 (EZH2), and PUMA was upregulated, while the expression of miR-139 was downregulated in clinical samples and D-GalN/LPS induced ALF mouse model. LncRNA NEAT1 promoted the enrichment of H3K27me3 on the promoter region of miR-139 via EZH2, which led to suppression of miR-139. The inhibition of miR-139 resulted in the upregulation of its downstream target PUMA. The NEAT1/miR-139/PUMA pathway upregulated the production of pro-inflammatory cytokines, tumor necrosis factor alpha, interleukin (IL)-6, and IL-1β, thereby mediating the progression of ALF. In conclusion, silencing lncRNA NEAT1 upregulated the expression of miR-139 through EZH2, leading to the downregulation of PUMA, which alleviated the development of ALF.


Transient supramolecular hydrogels formed by catalytic control over molecular self-assembly.
The present work shows how transient supramolecular hydrogels can be formed by catalytically controlled molecular self-assembly. Catalysis formation of molecular gelators leads the self-assembly along a kinetically favored pathway, resulting in transient hydrogels. This work demonstrates an effective approach towards pathway-dependent supramolecular materials.


Juxta-terminal Helix Unwinding as a Stabilizing Factor to Modulate the Dynamics of Transmembrane Helices.
Transmembrane helices of integral membrane proteins often are flanked by interfacial aromatic residues that can serve as anchors to aid the stabilization of a tilted transmembrane orientation. Yet, physical factors that govern the orientation or dynamic averaging of individual transmembrane helices are not well understood and have not been adequately explained. Using solid-state (2) H NMR spectroscopy to examine lipid bilayer-incorporated model peptides of the GWALP23 (acetyl-GGALW(LA)6 LWLAGA-amide) family, we observed substantial unwinding at the terminals of several tilted helices spanning the membranes of DLPC, DMPC, or DOPC lipid bilayers. The fraying of helix ends might be vital for defining the dynamics and orientations of transmembrane helices in lipid bilayer membranes.


Assessment of glaucoma referral letter for quality and accuracy among patients referred to a tertiary eye care center.
To assess the quality and accuracy of glaucoma referrals from ophthalmologist. Retrospective review of patients chart with referral letter to a tertiary glaucoma center between January and December 2017. Patients aged <16 years, lens-induced glaucoma, uveitic glaucoma, and glaucoma following retinal and corneal surgery were excluded. A total of 184 patients referred by 55 ophthalmologists were included. Mean patient age (SD) was 57.8 ± 14 years. Intraocular pressure was not documented in the referral letter in 113 (61%) patients, gonioscopy in 174 (95%) patients, disc findings in 149 (81%) patients, and visual fields in 175 (95%) patients. Thirteen (37%) of the 35 patients referred as open angle glaucoma were found to have angle closure glaucoma. Pseudoexfoliation glaucoma was diagnosed in 29 (16%) patients, of which 18 were missed by the referring ophthalmologist. In our study >90% of referral letter did not have the essential parameters. A standard template for glaucoma referral is suggested, which will help the patient to get better transfer of care.


A novel function for p21Cip1 and acetyltransferase p/CAF as critical transcriptional regulators of TGFβ-mediated breast cancer cell migration and invasion.
Tumor cell migration and invasion are critical initiation steps in the process of breast cancer metastasis, the primary cause of breast cancer morbidity and death. Here we investigated the role of p21Cip1 (p21), a member of the core cell cycle machinery, in transforming growth factor-beta (TGFβ)-mediated breast cancer cell migration and invasion. A mammary fat pad xenograft mouse model was used to assess the mammary tumor growth and local invasion. The triple negative human breast cancer cell lines MDA-MB231 and its sub-progenies SCP2 and SCP25, SUM159PT, SUM149PT, SUM229PE and SUM1315MO2 were treated with 5 ng/ml TGFβ and the protein expression levels were measured by Western blot. Cell migration and invasion were examined using the scratch/wound healing and Transwell assay. TGFβ transcriptional activity was measured by a TGFβ/Smad reporter construct (CAGA12-luc) using luciferase assay. q-PCR was used for assessing TGFβ downstream target genes. The interactions among p21, p/CAF and Smad3 were performed by co-immunoprecipitation. In addition, Smad3 on DNA binding ability was measured by DNA immunoprecipitation using biotinylated Smad binding element DNA probes. Finally, the association among active TGFβ/Smad signaling, p21 and p/CAF with lymph node metastasis was examined by immunohistochemistry in tissue microarray containing 50 invasive ductal breast tumors, 25 of which are lymph node positive. We found p21 expression to correlate with poor overall and distant metastasis free survival in breast cancer patients. Furthermore, using xenograft animal models and in vitro studies, we found p21 to be essential for tumor cell invasion. The invasive effects of p21 were found to correlate with Smad3, and p/CAF interaction downstream of TGFβ. p21 and p/CAF regulates TGFβ-mediated transcription of pro-metastatic genes by controlling Smad3 acetylation, DNA binding and transcriptional activity. In addition, we found that active TGFβ/Smad signaling correlates with high p21 and p/CAF expression levels and lymph node involvement using tissue microarrays from breast cancer patients. Together these results highlight an important role for p21 and p/CAF in promoting breast cancer cell migration and invasion at the transcriptional level and may open new avenues for breast cancer therapy.


Analysis of the attitudes and needs/demands of dental practitioners in the field of patient safety and risk management.
Patient safety is a relatively new discipline aimed at improving the quality of care, minimising treatment errors and improving the safety of patients. Although health professions always have a specific concern for patient safety, few practitioners have a clear understanding of the broad context and not all health-care providers practice it. This might well be because of limited availability of information and materials as well as a lack of national or international laws and regulations. Thus, through member National Dental Associations (NDAs) of FDI (World Dental Federation), the present study aimed at analysing the attitudes of dental practitioners to the issues of patient safety and risk management, and the availability of materials and laws and regulations. Determination of their specific needs and demands in these fields was also attempted. For this purpose, an online questionnaire was developed for the member NDAs to respond. Questions mainly focused on the awareness regarding patient safety, availability of materials and regulations and the particular topics for which dentists needed further knowledge and information. A total of 40 responses were received. While some countries lack any documents, patient safety documents and materials were available in some countries but they were mostly limited to infection control and radiation protection and did not address other important aspects of patient safety. The NDAs clearly demanded more information. A significant number of countries also lacked national laws and/or regulations regarding patient safety. Although dentistry always has a genuine concern for patient safety, the findings of the survey suggest that yet more efforts are needed to improve the knowledge, understanding and awareness of dental practitioners regarding its broad context and the relatively 'new' patient safety culture. NDAs, dental educators, national, regional and international dental organisations and health authorities all can play significant roles to achieve these goals.


A Quantitative Examination of Extreme Facial Pain Expression in Neonates: The Primal Face of Pain across Time.
Many pain assessment tools for preschool and school-aged children are based on facial expressions of pain. Despite broad use, their metrics are not rooted in the anatomic display of the facial pain expression. We aim to describe quantitatively the patterns of initiation and maintenance of the infant pain expression across an expressive cycle. We evaluated the trajectory of the pain expression of three newborns with the most intense facial display among 63 infants receiving a painful stimulus. A modified "point-pair" system was used to measure movement in key areas across the face by analyzing still pictures from video recording the procedure. Point-pairs were combined into "upper face" and "lower face" variables; duration and intensity of expression were standardized. Intensity and duration of expression varied among infants. Upper and lower face movement rose and overlapped in intensity about 30% into the expression. The expression reached plateau without major change for the duration of the expressive cycle. We conclude that there appears to be a shared pattern in the dynamic trajectory of the pain display among infants expressing extreme intensity. We speculate that these patterns are important in the communication of pain, and their incorporation in facial pain scales may improve current metrics.


H-ABC syndrome and DYT4: Variable expressivity or pleiotropy of TUBB4 mutations?
Recently, mutations in the TUBB4A gene have been found to underlie hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) syndrome, a rare neurodegenerative disorder of infancy and childhood. TUBB4A mutations also have been described as causative of DYT4 ("hereditary whispering dysphonia"). However, in DYT4, brain imaging has been reported to be normal and, therefore, H-ABC syndrome and DYT4 have been construed to be different disorders, despite some phenotypic overlap. Hence, the question of whether these disorders reflect variable expressivity or pleiotropy of TUBB4A mutations has been raised. We report four unrelated patients with imaging findings either partially or totally consistent with H-ABC syndrome, who were found to have TUBB4A mutations. All four subjects had a relatively homogenous phenotype characterized by severe generalized dystonia with superimposed pyramidal and cerebellar signs, and also bulbar involvement leading to complete aphonia and swallowing difficulties, even though one of the cases had an intermediate phenotype between H-ABC syndrome and DYT4. Genetic analysis of the TUBB4A gene showed one previously described and two novel mutations (c.941C>T; p.Ala314Val and c.900G>T; p.Met300Ile) in the exon 4 of the gene. While expanding the genetic spectrum of H-ABC syndrome, we confirm its radiological heterogeneity and demonstrate that phenotypic overlap with DYT4. Moreover, reappraisal of previously reported cases would also argue against pleiotropy of TUBB4A mutations. We therefore suggest that H-ABC and DYT4 belong to a continuous phenotypic spectrum associated with TUBB4A mutations.


Electrolyte-gated transistors based on phenyl-C61-butyric acid methyl ester (PCBM) films: bridging redox properties, charge carrier transport and device performance.
The n-type organic semiconductor phenyl-C61-butyric acid methyl ester (PCBM), a soluble fullerene derivative well investigated for organic solar cells and transistors, can undergo several successive reversible, diffusion-controlled, one-electron reduction processes. We exploited such processes to shed light on the correlation between electron transfer properties, ionic and electronic transport as well as device performance in ionic liquid (IL)-gated transistors. Two ILs were considered, based on bis(trifluoromethylsulfonyl)imide [TFSI] as the anion and 1-ethyl-3-methylimidazolium [EMIM] or 1-butyl-1-methylpyrrolidinium [PYR14] as the cation. The aromatic structure of [EMIM] and its lower steric hindrance with respect to [PYR14] favor a 3D (bulk) electrochemical doping. As opposed to this, for [PYR14] the doping seems to be 2D (surface-confined). If the n-doping of the PCBM is pursued beyond the first electrochemical process, the transistor current vs. gate-source voltage plots in [PYR14][TFSI] feature a maximum that points to the presence of finite windows of high conductivity in IL-gated PCBM transistors.


Familial optic atrophy with negative electroretinograms.
We describe optic atrophy and abnormal electroretinographic findings in affected members from two families. Central vision failed in the second to third decade of life. Examination findings included visual acuities of 20/20 (1.0) to 20/500 (0.4), defective color vision, mild to moderate myopia, pericentral or centrocecal scotomas, and, in four of five patients, optic atrophy. Dark adaptometry found elevated cone and rod psychophysical thresholds. Bright flash electroretinograms showed normal a-wave amplitude and markedly subnormal b-wave amplitude. Rod responses were low normal to moderately subnormal in amplitude with normal implicit times. Photopic electroretinographic b-wave amplitudes varied from normal to mildly subnormal. Cone implicit times were normal. Because negative electroretinograms are not seen with other familial optic atrophies, the association of optic atrophy with the abnormal negative electroretinogram configuration in these patients represents a newly appreciated genetic disorder.


Shell thickness dependent photostability studies of green-emitting "Giant" quantum dots.
Highly efficient green-emitting core/shell giant quantum dots have been synthesized through a facile "one-pot" gradient alloy approach. Furthermore, an additional ZnS shell was grown using the "Successive Ionic Layer Adsorption and Reaction" (SILAR) method. Due to the faster reactivity of Cd and Se compared to an analogue of Zn and S precursors it is presumed that CdSe nuclei are initially formed as the core and gradient alloy shells simultaneously encapsulate the core in an energy-gradient manner and eventually thick ZnS shells were formed. Using this gradient alloy approach, we have synthesized four different sized green-emitting giant core-shell quantum dots to study their shell thickness-dependent photostability under continuous UV irradiation, and temperature-dependent PL properties of nanocrystals. There was a minimum effect of the UV light exposure on the photostability beyond a certain thickness of the shell. The QDs with a diameter of ≥8.5 nm show substantial improvement in photostability compared to QDs with a diameter ≤ 7.12 nm when continuously irradiated under strong UV light (8 W cm-2, 365 nm) for 48 h. The effect of temperature on the photoluminescence intensities was studied with respect to the shell thickness. There were no apparent changes in PL intensities observed for the QDs ≥ 8.5 nm, on the contrary, for example, QDs with <8.5 nm in diameter (for ∼7.12 nm) show a decrease in PL intensity at higher temperatures ∼ 90 °C. The synthesized green-emitting gradient alloy QDs with superior optical properties can be used for highly efficient green-emitters and are potentially applicable for the fabrication of green LEDs.


Football training over 5 years is associated with preserved femoral bone mineral density in men with prostate cancer.
This study investigated the association between long-term adherence to football training and retaining bone mineralization and physical capacity in men with prostate cancer (PCa) managed with androgen deprivation therapy (ADT). Patients completing follow-up at 32 weeks in the FC Prostate Randomized Controlled Trial (RCT) in 2012 or 2013 were invited to 5-year follow-up assessments in May 2017 (n = 30). Changes in physiological outcomes over time between the football participants (FTG) and nonparticipants (CON) were examined. Twenty-two men accepted the invitation of which 11, aged 71.3 ± 3.8 years, had continued to play self-organized football 1.7 (SD 0.5) times per week for 4½ years (±8 months). At 5 years, right femoral neck bone mineral density (BMD) had improved significantly in the FTG compared to CON (P = .028). No other significant between-group differences were observed. In FTG, RHR decreased by 4.3 bpm (P = .009) with no changes in CON. Muscle mass, knee-extensor muscle strength, VO2 max, and postural balance decreased in both groups. In FTG, the fraction of training time with HR between 80%-90% or >90% of HRmax was 29.9% (SD 20.6) and 22.8% (SD 28.7), respectively. Average distance covered during 3 × 20 minutes of football training was 2524 m (SD 525). Football training over a 5-year period was associated with preserved femoral neck BMD in elderly men with PCa managed on ADT. Intensity during football training was >80% of HRmax for 51% of training time after 5 years. Body composition and physical capacity deteriorated over 5 years regardless of football participation.


Team approach to manage difficult-to-treat TB cases: Experiences in Europe and beyond.
As recommended by the World Health Organization (WHO), optimal management of MDR-TB cases can be ensured by a multi-speciality consultation body known as 'TB Consilium'. This body usually includes different medical specialities, competences and perspectives (e.g., clinical expertise both for adults and children; surgical, radiological and public health expertise; psychological background and nursing experience, among others), thus lowering the risk of making mistakes - or managing the patients inappropriately, in order to improve their clinical outcomes. At present, several high MDR-TB burden countries in the different WHO regions (and beyond) have introduced TB Consilium-like bodies at the national or subnational level to reach consensus on the best treatment approach for their patients affected by TB. In addition, in countries/settings where a formal system of consultation does not exist, specialized staff from MDR-TB reference centres or international organizations usually spend a considerable amount of their working time responding to phone or e-mail clinical queries on how to manage M/XDR-TB cases. The aim of this manuscript is to describe the different experiences with the TB Consilia both at the international level (European Respiratory Society - ERS/WHO TB Consilium) and in some of the countries where this experience operates successfully in Europe and beyond. The Consilium experiences are described around the following topics: (1) history, aims and focus; (2) management and funding; (3) technical functioning and structure; (4) results achieved. In addition a comparative analysis of the TB Consilia in the different countries has been performed.


[Two-stage excision of extensive cutaneous carcinoma of the face. A retrospective study of 80 patients].
Delayed reconstruction (two-step surgery) comprised of tumor resection and repair three or four days later, after paraffin tissue fixation and histopathological examination, is one of the techniques used for complete excision of spreading cutaneous carcinomas. In order to evaluate the efficacy and long term prognosis of delayed reconstruction surgery, we carried out a retrospective study of 80 patients treated by this method and (Kaplan- Meier) for correlation with the local recurrence rate: sex, age, anatomic site, histologic type and existence of previous therapy. Long term results have been estimated. Among the 80 patients studied, 76 patients have been followed. The sex-ratio was 0.48. Fifty-two percent of the population was more than seventy years old. Fifty-five percent of the tumors were situated on the nose. In 32,5 p. 100 of the cases, a prior therapy (surgery, electrodessication or radiation therapy) has been carried out. Histological analysis showed 87 p. 100 basal cell carcinomas (of which 26 p. 100 of morpheaform basal cell carcinomas) and 13 p. 100 squamous cell carcinomas. After the first operative step, there was total excision in 69 p. 100 of thecases. In the remaining cases, a second excision was performed with a margin of normal tissue. Recurrences were observed (some precocious recurrences and some late recurrences) in 18.4 p. 100 of the cases. No risk factor correlated significantly with the recurrence rate. However, analysis of the survival graph suggests that the squamous cell carcinomas recurred more often than the basal cell carcinomas. Although extemporaneous examinations (Mohs' technique) remains the gold standard technique in the management of spreading cutaneous carcinomas of the face, the delayed reconstruction (two-step surgery) is a credible alternative when compared to the recurrence rates reported in the literature with the other techniques (electrodessication, radiation therapy or cryosurgery).


Distribution and dosimetry of I-123-labeled monoclonal antibody 81C6 in patients with anaplastic glioma.
Monoclonal antibody 81C6 reacts with the extracellular matrix antigen, tenascin, present on gliomas and other tumors, as well as several normal tissues, including spleen and liver tissue. Single photon emission computed tomography (SPECT) and I-123-labeled 81C6 at various protein doses were used to maximize tumor to normal tissue uptake ratios. The distribution of I-123-labeled monoclonal antibody 81C6 was determined in 16 patients with recurrent gliomas, using SPECT: Between 3.5 and 11.5 mCi of I-123 were administered to each patient, and the antibody doses were between 10.0 and 100.0 mg. Blood was obtained for pharmacokinetic studies, and patients were imaged 1 hour and 18 hours after antibody administration. All tumors were visualized readily on the SPECT study in areas that corresponded to the contrast, enhancing abnormalities on anatomic neuroimaging studies. The half-life in blood of the I-123 81C6 ranged from 16 to 37 hours. Radiation dosimetry calculations suggest that it might be possible to administer more than 700 cGy to intracranial glioma with I-131 labeled 81C6 under optimal conditions with acceptable non-neurologic organ radiation exposure. SPECT imaging with I-123 81C6 identified all tumors and suggests that, with this antibody, more favorable tumor-to-liver and tumor-to-spleen radiation dose ratios are obtained at higher protein doses.


New insights into the control of neurotrophic growth factor receptor signaling: implications for nervous system development and repair.
Neurotrophic growth factors control neuronal development by activating specific receptor tyrosine kinase positive signaling pathways, such as Ras-MAPK and PI3K-Akt cascades. Once activated, neurotrophic factor receptors also trigger a cascade of molecular events, named negative receptor signaling, that restricts the intensity of the positive signals and modulates cellular behavior. Thus, to avoid signaling errors that ultimately could lead to aberrant neuronal physiology and disease, negative signaling mechanisms have evolved to ensure that suitable thresholds of neuronal stimulation are achieved and maintained during right periods of time. Recent findings have revealed that neurotrophic factor receptor signaling is tightly modulated through the coordinated action of many different protein regulators that limit or potentiate signal propagation in spatially and temporally controlled manners, acting at specific points after receptor engagement. In this review, we discuss progress in this field, highlighting the importance of these modulators in axonal growth, guidance, neural connectivity, and nervous system regeneration.


[The pharmacological regulation of physiological functions in space medicine].
There are considered the physiological systems of the body which are the most sensitive to the action of weightlessness and are subject to pharmacological correction at different stages of a space flight. Particular emphasis is given to the development and practical use of the cardiovascular drugs, the agents for prevention of movement disease and also the agents influencing the metabolic processes and mineral saturation of the bony tissue. The possibility of using the drugs intended for the application during space flights and in medical practice is emphasized.


The association between consuming bivalves, and acute gastroenteritis and norovirus in Tokyo, Japan.
A prospective matched case-control study was conducted to evaluate associations between dietary histories, including consumption of bivalves, diarrhea, and norovirus positive diarrhea in adult ambulatory patients at an outpatient clinic of a hospital in Tokyo, Japan. Ambulatory cases with diarrhea were matched with nondiarrheal control patients, who visited the same clinic. A standardized questionnaire was used to obtain patients' information, including histories of food consumption and clinical information. Norovirus infection was confirmed using real-time reverse transcription polymerase chain reaction. A total of 207 patients, including 69 diarrheal cases and 138 nondiarrheal cases were included in the analysis. Among them, 60 (29.0%) participants reported consuming bivalves. Norovirus was detected in 35% (24/69) of diarrheal cases. Of those, 10 (41.7%) reported consumption of bivalves and of those, 6 (60.0%) consumed raw bivalves. The proportion of those who consumed raw bivalves was significantly higher in norovirus-positive diarrheal cases than in norovirus-negative diarrheal cases (25.0% vs 6.7%; odds ratio [OR], 4.67; 95% confidence interval [CI], 1.1-20.7) and matched nondiarrheal controls (25.0% vs 6.3%, OR: 5.00; 95% CI, 1.1-22.2). The attributable fraction of consuming raw bivalves for norovirus-associated diarrhea to matched nondiarrheal controls was 20.0%. Consuming raw bivalves was substantially attributed to norovirus-associated diarrhea in adult ambulatory patients and preventive measures for reducing the risk associated with consumption of raw bivalves could decrease the incidence of norovirus-associated diarrhea.


The Effects of Elexacaftor, Tezacaftor, and Ivacaftor (ETI) on Blood Glucose in Patients With Cystic Fibrosis: A Systematic Review.
Cystic fibrosis (CF) is an autosomal recessive genetic disorder resulting from defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which in turn results in a multi-systemic disorder. There are numerous known CF alleles associated with different mutations of the CFTR gene, with the most common CF allele being a three-base-pair deletion known as ΔF508. One common manifestation of CF is glycemic dysregulation associated with decreased insulin secretion, often progressing into a distinct form of diabetes known as cystic fibrosis-related diabetes (CFRD). In the past decade, a class of drugs known as CFTR modulators has entered clinical practice. These drugs interact with the CFTR protein to restore its function, with different modulators (or combinations of modulators) suitable for patients with different CFTR mutations. Previous research has established that the modulator ivacaftor is effective in decreasing blood glucose and sometimes resolving CFRD in patients with certain CFTR mutations (class III mutations). However, early modulator therapies for individuals with the common ΔF508 mutation (e.g., a combination of the modulators lumacaftor and ivacaftor) have largely proven ineffective in improving glucose regulation. More recently, a combination therapy of three modulators, namely elexacaftor, tezacaftor, and ivacaftor (ETI), has entered clinical practice for patients with the ΔF508 mutation. However, it is not clear whether this therapy is effective in treating dysglycemia. We searched for studies of any design that examined the effects of ETI on measures of blood glucose. All available studies were observational studies comparing patients before and after initiating ETI therapy. Measures of daily-life blood glucose (those obtained with continuous glucose monitoring systems or by measuring glycated hemoglobin (HbA1c)) and post-prandial glucose spikes from oral glucose tolerance tests showed significant improvements in at least some studies. The majority of studies showed significant improvements from pre- to post-ETI in one or more blood glucose measures. While the interpretation of this evidence is complicated by the lack of randomized controlled trials, it appears that ETI therapy is associated with improved glucose regulation for at least some patients with the ΔF508 mutation.