Eltrombopag as second line treatment in patients with primary immune thrombocytopenia: A single center real life experience.
Glucocorticoid treatment is the standard initial therapy for patients with immune thrombocytopenia (ITP). Despite a rate of 60-80% of initial remissions, only 30 to 50% of adults have a sustained response after discontinuation. Second line options are splenectomy, thrombopoietin-receptor agonists (TPO-RAs), rituximab and intravenous immunoglobulin. Third line treatments include a mix of immunosuppressive drugs (e.g. azathioprine, ciclosporin, etc.). Recently international guidelines have proposed a treatment algorithm formalizing TPO-RAs and splenectomy as second and third line respectively, confirming splenectomy as second line choice only in emergency. Here we present a single center observational retrospective study of eltrombopag as second line treatment. We evaluated 48 adult primary chronic ITP patients since 2003. Forty-four out of 48 patients received a first line treatment with glucocorticoids. Twenty-two (61%) patients needed a second line treatment: 18 received eltrombopag, 3 a second course of steroid and one patient underwent splenectomy. Every patient before starting eltrombopag or receiving splenectomy underwent bone marrow examination. Overall response rate to eltrombopag was 94% with a CR rate of 76% and a PR of 23%; only one patient was non responder, underwent splenectomy and received subsequent treatment with rituximab, romiplostim and cyclosporin obtaining CR. One patient developed an autoimmune pancytopenia about a month after starting TPO-RA and in addition to eltrombopag received steroid and rituximab with blood count improvement. After a median follow up of 21,1 months (range 0,4-64,7 months) 16 patients (89%) are still on therapy maintaining response. As regards safety, gastrointestinal side effects were rare and low grade; only one patient discontinued eltrombopag after few weeks, because of dizziness. One patient had a relapse of deep venous thrombosis while no major bleeding complications were observed. Our real-life single center experience confirms efficacy and safety of eltrombopag as second line treatment in chronic ITP patients.


Topography of the corpus callosum in the cat.
Discrete application of horseradish peroxidase to the corpus callosum in cats produced labeled neurons within a dorsoventrally elongated cortical territory. The rostrocaudal position of the territory corresponded with that of the applications. Callosal fibers from the ventral half of the frontal cortex passed through the rostrum, and those from the ventral occipital and dorsal temporal cortex passed through the ventral splenium. These results indicate a sectorial topographical correspondence between the corpus callosum and the cortex.


The effect of using blood culture bottle of bronchoalveolar larvage fluid in pneumonia.
Pneumonia is a primary cause of morbidity and mortality in infectious disease, and increasing antimicrobial resistance has raised concerns of treatment failure. Therefore, we evaluated the value of a blood culture bottle for bronchoalveolar lavage (BAL) samples on pathogen identification and on treatment modification in patients with pneumonia. We conducted a prospective study and enrolled 39 patients who were hospitalized for pneumonia. Enrolled patients underwent BAL; a 10-ml aliquot was transferred to a sterile container for standard quantitative culture, and a 5 ml aliquot was transferred to both an aerobic and an anaerobic blood culture bottle. Microbes were detected in all 39 (100 %) specimens and possible pathogens were identified in 34 patients (84.6 %) from BAL blood culture bottles. In contrast, microbes were detected in 10 patients (25.6 %) and possible pathogens were isolated in 8 patients (20.5 %) in BAL fluid using conventional culture methods. Finally, 8 of 39 (20.5 %) patients changed antibiotics according to the BAL blood culture results and pneumonia improved in 6 of these patients. Using blood culture bottles for BAL sampling in patients with pneumonia is a sensitive method to detect pathogens in order to identify an adequate antibiotic treatment regimen.


Non-target impacts of fungicide disturbance on phyllosphere yeasts in conventional and no-till management.
Fungicides reduce fungal pathogen populations and are essential to food security. Understanding the impacts of fungicides on crop microbiomes is vital to minimizing unintended consequences while maintaining their use for plant protection. However, fungicide disturbance of plant microbiomes has received limited attention, and has not been examined in different agricultural management systems. We used amplicon sequencing of fungi and prokaryotes in maize and soybean microbiomes before and after foliar fungicide application in leaves and roots from plots under long-term no-till and conventional tillage management. We examined fungicide disturbance and resilience, which revealed consistent non-target effects and greater resiliency under no-till management. Fungicides lowered pathogen abundance in maize and soybean and decreased the abundance of Tremellomycetes yeasts, especially Bulleribasidiaceae, including core microbiome members. Fungicide application reduced network complexity in the soybean phyllosphere, which revealed altered co-occurrence patterns between yeast species of Bulleribasidiaceae, and Sphingomonas and Hymenobacter in fungicide treated plots. Results indicate that foliar fungicides lower pathogen and non-target fungal abundance and may impact prokaryotes indirectly. Treatment effects were confined to the phyllosphere and did not impact belowground microbial communities. Overall, these results demonstrate the resilience of no-till management to fungicide disturbance, a potential novel ecosystem service provided by no-till agriculture.


Are complicated monochorionic twins more susceptible to indomethacin-induced fetal ductal constriction? Two cases of laser surgery for Twin-Twin Transfusion syndrome.
Indomethacin is a commonly used medication against preterm delivery. Several reports of fetal ductal constriction have been described after indomethacin use in the literature; however, there are no previously documented reports describing an association between Twin-Twin Transfusion syndrome and a constrictor effect of indomethacin on the ductus arteriosus. Two patients were referred to our department for Twin-Twin Transfusion syndrome and each underwent placental laser surgery. Constriction of the ductus arteriosus occurred as early as 20 and 24 weeks' gestation following maternal use of indomethacin after laser surgery. Spontaneous amelioration was observed after discontinuation of the drug. The constrictor effect of indomethacin on the ductus arteriosus can be observed even after a single dose and as early as 20 weeks of gestation in complicated monochorionic twin pregnancies. We emphasize meticulous use of indomethacin in complicated monochorionic twin pregnancies because the constrictive effect seems to be independent of gestational age.


Lunacy.
To assess the moon's perceived impact on emergency medicine, a survey was conducted using a modified Belief in Lunar Effects (BILE) scale. Eighty percent of the respondent emergency department nurses and 64% of the emergency physicians believe that the moon affects patients. Of these nurses, 92% find lunar shifts more stressful and indicated lunar pay differentials are warranted. Medical, social, and administrative strategies to deal with lunacy are presented.


Eosinophilia and parotitis occurring early in clozapine treatment.
Mr. S is a 32-year-old male with schizophrenia. Due to poor responses to various antipsychotic medications, he was started on clozapine with the dose titrated to 300 mg/day during a 4-week period. The weekly checks of the complete blood cell count showed gradual increases in the eosinophil count from normal values to 4320 per mm(3). Mr. S did not have any symptoms except some increased salivation. Clozapine was suspended, and eosinophils gradually began to decline to the normal range. Clozapine was subsequently re-started and there were no changes in eosinophil counts. Mr. S exhibited improvement of symptoms but complained of acute auricular pain and increased salivation, 8 weeks after clozapine rechallenge. He also developed a swelling of his both parotid glands. The diagnosis of clozapine-induced parotitis was suggested. Symptomatic medication was prescribed with a favorable outcome. We report a case of a patient who developed eosinophilia shortly after clozapine use, and then developed parotitis. There is debate in the literature over how to manage these complications of clozapine treatment. Generally they do not warrant clozapine discontinuation.


Acid infusion elicits thromboxane A2-mediated effects on respiration and pulmonary hemodynamics in the cat.
We have recently reported that infusion of stoichiometrically equal quantities of acid and base (neutral acid-base infusion) in the cat resulted in rapid, shallow breathing and in pulmonary hypertension (Orr et al., 1987). To investigate the mechanisms involved in these effects, we have measured in the anesthetized cat thromboxane (TX) B2 and 6-keto-prostaglandin (PG) F1 alpha, the stable metabolites of TXA2 and PGI2, in blood as well as cardiorespiratory parameters in response to neutral acid-base infusion. The first acid-base infusion prompted right ventricular blood pressure (Prv) to rise from 30 to a peak of about 55 mm Hg, with a concomitant rise in the right ventricular TXB2 level from below detection level to over 500 pg/ml. The second or third infusion evoked no (or small) rises in Prv and TXB2, individual values of Prv and TXB2 being tightly correlated. After blockade of TX synthesis by Dazmegrel, no changes were observed even at the first acid-base infusion in either Prv or TXB2. The TXA2 mimetic, U 46,619, caused Prv to rise with no change in TXB2, and this effect was repeatable. Increases were also observed in ventilation, particularly in respiratory rate. We conclude that acid exposure of blood stimulates TX synthesis and release from platelets, which in turn leads to pulmonary hypertension and to hyperventilation. The fact that these effects cannot be repeated within the same animal is due to a lack in TX release but not to a loss of responsiveness of the TX receptors in the lung.


Very late stent thrombosis: simultaneous two-arterial occlusions.
We describe a patient with an unusual case of very late dual Cypher stent thrombosis that caused massive acute myocardial infarction and cardiogenic shock, which were treated using emergent resuscitation and angioplasty.


The potential of dietary nanoparticles to enhance allergenicity of milk proteins: an in vitro investigation.
In recent years, the popularity of dietary nanoparticles (NPs) in the food industry as additives has raised concerns because of the lack of knowledge about potential adverse health outcomes ensuing from the interactions of NPs with components of the food matrix and gastrointestinal system. In this study, we used a transwell culture system that consisted of human colorectal adenocarcinoma (Caco-2) cells in the apical insert and Laboratory of Allergic Diseases 2 mast cells in the basal compartment to study the effect of NPs on milk allergen delivery across the epithelial layer, mast cell responses and signaling between epithelial and mast cells in allergenic inflammation. A library of dietary particles (silicon dioxide NPs, titanium dioxide NPs and silver NPs) that varied in particle size, surface chemistry and crystal structures with or without pre-exposure to milk was used in this investigation. Milk-interacted particles were found to acquire surface corona and increased the bioavailability of milk allergens (casein and β-lactoglobulin) across the intestinal epithelial layer. The signaling between epithelial cells and mast cells resulted in significant changes in the early phase and late-phase activation of the mast cells. This study suggested that antigen challenge in mast cells with the presence of dietary NPs may cause the transition of allergic responses from an immunoglobulin E (IgE)-dependent mechanism to a mixed mechanism (both IgE-dependent and IgE-independent mechanisms).


In vitro kinetics of insulin release by microencapsulated rat islets: effect of the size of the microcapsules.
Microencapsulation has been proposed to protect islets of Langerhans against immune rejection in xenogenic transplantation. However, to achieve glucose homeostasis in human diabetic patients, insulin release by microencapsulated islets must increase in response to a glucose load. We microencapsulated isolated rat islets using the alginate-polylysine procedure. Capsule size was found to range from 300 to 800 micron, and microencapsulated islets were separated according to their size. Groups of 10 microencapsulated islets, either small (350 micron) or large (650 micron) were placed in plastic microwells, in minimal Eagle's culture medium containing either 5.5 mol/l glucose (basal) or 16.5 mol/l glucose and 5.5 mol/l theophylline (stimulatory medium). The increase in insulin concentration in the surrounding medium was then serially determined over 30 min: (1) With the small capsules, insulin concentration rose from 199 +/- 20 to 297 +/- 58 microU/ml in basal medium, and from 236 +/- 23 to 510 +/- 121 microU/ml in stimulatory medium (n = 10 preparations), the difference between the data obtained with the basal or the stimulatory medium being significant (p less than 0.01) from the 5th min onwards. (2) With large capsules, insulin concentration increased from 182 +/- 9 to 266 +/- 44 microU/ml, and from 216 +/- 19 to 297 +/- 34 microU/ml in basal and stimulatory medium, respectively, with no apparent significant difference. The magnitude of insulin secretion in response to glucose by unencapsulated islets was, under similar conditions, seven-fold greater. We conclude therefore that the size of the microcapsules is an essential parameter which has to be considered for the optimisation of the microencapsulation procedure.


Decreased ligand binding to the hepatic glucocorticoid and epidermal growth factor receptors after 2,3,4,7,8-pentachlorodibenzofuran and 1,2,3,4,7,8-hexachlorodibenzofuran treatment of pregnant mice.
2,3,4,7,8-Pentachlorodibenzofuran (PeCDF) and 1,2,3,4,7,8-hexachlorodibenzofuran (HCDF) are environmental contaminants which mimic many of the toxic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Like TCDD, these polychlorinated dibenzofurans (PCDFs) induce hepatic benzo[a]pyrene hydroxylase activity (BPH) and possess high affinity for the Ah receptor. Another similarity of these PCDFs to TCDD is their ability to induce teratogenic effects such as cleft palate and hydronephrosis in mice. Recent studies have shown that TCDD modifies the equilibrium binding kinetics of the rat liver cytosolic glucocorticoid receptor (GRc) and the hepatic plasma membrane epidermal growth factor (EGF) receptor. To gain a better understanding of the action of halogenated hydrocarbons on these cytosolic and membrane-bound receptor systems during pregnancy, we investigated the biochemical effects of PeCDF and HCDF on the binding kinetics of maternal mouse liver GRc and EGF receptors and the induction of BPH activities. Pregnant C57BL/6N mice were treated once daily on gestation Days 10 through 13 with PeCDF (0-30 micrograms/kg) or HCDF (0-300 micrograms/kg). Hepatic [3H]dexamethasone and [125I]EGF equilibrium binding studies indicated that all doses of PeCDF tested (10, 20, and 30 micrograms/kg) significantly reduced the GRc and EGF receptor maximum binding capacities but did not affect the binding affinities of these receptors when compared to corn oil-treated control pregnant mice. Similar effects were observed for doses of HCDF greater than or equal to 100 micrograms/kg. These data suggest that the dibenzofuran-mediated decreases in GRc and EGF receptor binding capacities are similar to those caused by TCDD. Although the mechanism of action is not yet clear, our results indicate that halogenated aromatic compounds in addition to TCDD have profound effects on both steroid and growth factor receptor systems.


Field and energy relations in continuum electrodynamics.
The bare, or fundamental, electric and magnetic fields in a linear medium are identified. Through the energy relations for the bare fields, the electric permittivity is shown to combine the effects of the enhanced energy density and the polarization reaction field. The macroscopic Maxwell equations are modified to be consistent with the constitutive relations for the bare fields.


Engineering a carotenoid-binding site in Dokdonia sp. PRO95 Na+-translocating rhodopsin by a single amino acid substitution.
Light-driven H+, Cl- and Na+ rhodopsin pumps all use a covalently bound retinal molecule to capture light energy. Some H+-pumping rhodopsins (xanthorhodopsins; XRs) additionally contain a carotenoid antenna for light absorption. Comparison of the available primary and tertiary structures of rhodopsins pinpointed a single Thr residue (Thr216) that presumably prevents carotenoid binding to Na+-pumping rhodopsins (NaRs). We replaced this residue in Dokdonia sp. PRO95 NaR with Gly, which is found in the corresponding position in XRs, and produced a variant rhodopsin in a ketocarotenoid-synthesising Escherichia coli strain. Unlike wild-type NaR, the isolated variant protein contained the tightly bound carotenoids canthaxanthin and echinenone. These carotenoids were visible in the absorption, circular dichroism and fluorescence excitation spectra of the Thr216Gly-substituted NaR, which indicates their function as a light-harvesting antenna. The amino acid substitution and the bound carotenoids did not affect the NaR photocycle. Our findings suggest that the antenna function was recently lost during NaR evolution but can be easily restored by site-directed mutagenesis.


Immune regulator LGP2 targets Ubc13/UBE2N to mediate widespread interference with K63 polyubiquitination and NF-κB activation.
Lysine 63-linked polyubiquitin (K63-Ub) chains activate a range of cellular immune and inflammatory signaling pathways, including the mammalian antiviral response. Interferon and antiviral genes are triggered by TRAF family ubiquitin ligases that form K63-Ub chains. LGP2 is a feedback inhibitor of TRAF-mediated K63-Ub that can interfere with diverse immune signaling pathways. Our results demonstrate that LGP2 inhibits K63-Ub by association with and sequestration of the K63-Ub-conjugating enzyme, Ubc13/UBE2N. The LGP2 helicase subdomain, Hel2i, mediates protein interaction that engages and inhibits Ubc13/UBE2N, affecting control over a range of K63-Ub ligase proteins, including TRAF6, TRIM25, and RNF125, all of which are inactivated by LGP2. These findings establish a unifying mechanism for LGP2-mediated negative regulation that can modulate a variety of K63-Ub signaling pathways.


Role of cosyntropin in the management of postpartum post-dural puncture headache: a two-center retrospective cohort study.
Research suggests that postpartum post-dural puncture headache (PDPH) might be prevented or treated by administering intravenous cosyntropin. In this retrospective cohort study, we questioned whether prophylactic (1 mg) and therapeutic (7 µg/kg) intravenous cosyntropin following unintentional dural puncture (UDP) was effective in decreasing the incidence of PDPH and therapeutic epidural blood patch (EBP) after birth. Two tertiary-care American university hospitals collected data from November 1999 to May 2017. Two hundred and fifty-three postpartum patients who experienced an UDP were analyzed. In one institution 32 patients were exposed to and 32 patients were not given prophylactic cosyntropin; in the other institution, once PDPH developed, 36 patients were given and 153 patients were not given therapeutic cosyntropin. The primary outcome for the prophylactic cosyntropin analysis was the incidence of PDPH and for the therapeutic cosyntropin analysis in exposed vs. unexposed patients, the receipt of an EBP. The secondary outcome for the prophylactic cosyntropin groups was the receipt of an EBP. In the prophylactic cosyntropin analysis no significant difference was found in the risk of PDPH between those exposed to cosyntropin (19/32, 59%) and unexposed patients (17/32, 53%; odds ratio (OR) 1.37, 95% CI 0.48 to 3.98, P = 0.56), or in the incidence of EBP between exposed (12/32, 38%) and unexposed patients (6/32, 19%; OR 2.6, 95% CI 0.83 to 8.13, P = 0.095). In the therapeutic cosyntropin analysis, in patients exposed to cosyntropin the incidence of EBP was significantly higher (20/36, 56% vs. 43/153, 28%; OR 3.20, 95% CI 1.52 to 6.74, P = 0.002). Our data show no benefits from the use of cosyntropin for preventing or treating postpartum PDPH.


Revising the modified Neer classification for distal clavicle fractures: Description and reliability.
The modified Neer classification is the most widely used classification system for distal clavicle fractures. However, it provides limited information for treatment decisions. The objective of this study was to revise the modified Neer classification to make it more suitable for treatment decision-making. The revised version of the modified Neer classification has good intra- and interobserver agreements and provides an instructive treating algorithm. Cohort study METHODS: Six observers, including three experienced shoulder specialists and three junior orthopaedic residents, independently reviewed plain radiographs of 52 patients with distal clavicle fractures. They were asked to classify the fracture types according to the modified Neer classification and our revised new classification separately to determine treatment approaches for each patient. Images were mirrored and randomized to verify the intraobserver agreement. Reliabilities were measured using the Fleiss kappa values. Both the modified Neer classification and our revised version had near perfect intraobserver agreement (κ values: 0.87-1.00), whereas our revised Neer classification had a better interobserver agreement (κ values: 0.78 vs. 0.70, z = 4.70, p < 0.01) and stronger relevance to treatment decisions (coefficient of contingency: 0.70 vs. 0.44). Our study demonstrated a near-perfect intraobserver and substantial interobserver agreement of the revised new classification, indicating that our revised new classification was better than the modified Neer classification. Meanwhile, our revised classification brought few disputes in treatment selection. The modified Neer classification was revised to make it more accurate and suitable for guiding treatment. Study of diagnostic test LEVEL OF STUDY: Level II.


Assessment of using ultrasonography to teach abdominal and cervical anatomy in French medical curricula.
The objective of this work was to assess, in a quantitative and qualitative way, the teaching of cervical and abdominal anatomy via ultrasound for medical students. For several years, tutorials on the study of anatomy through use of ultrasound on the living organism have been given at the Medical School of Brest. These sessions have focused on cervical anatomy and abdominal anatomy. Students were invited to quantitatively assess these lessons by taking two tests containing questions on both cervical and abdominal anatomy and ultrasound technique: a pre-test administered at the beginning of the year and a post-test at the end of the year. In addition, a qualitative assessment was carried out at the end of the year. Ten statements were presented, and students were asked to indicate their agreement or disagreement to a four-point Likert scale. One hundred and twelve students answered all the questions on the pre-test with an average of 13.4 correct answers out of 20. Forty-eight students answered all the questions on the post-test with an average of 14.6/20. Twenty-six students who benefited from the courses gave positive feedback about the workshops on the qualitative assessment at the end of the year (median scores > = 3/4). The results of this work suggest that the use of ultrasound makes a positive contribution to the teaching of anatomy. The students interviewed think this type of tutorial should be an integral part of the anatomy curriculum at our university. In addition, this type of instruction can serve to introduce the use of ultrasound itself in a practical learning setting.


[Effect of tubocurarine on the quantum release of acetylcholine during the infrequent stimulation of a motor nerve].
The effect of d-tubocurarine on quantal release of acetylcholine elicited with nerve pulses 0.5 to 1 Hz was studied in the frog isolated cutaneous pectoris muscle. The muscle twitches were prevented either by lowering Ca++ and raising Mg++ or by cutting the muscle fibers. In none of these cases d-tubocurarine (3.10(-7) to 5.10(-6) M) was found to affect quantal release of acetylcholine.


Ovarian hydrobursitis in female camels (Camelus dromedarius): the role of Chlamydophila abortus and a trial for medical treatment.
The occurrence of Chlamydophila abortus in female camels affected with ovarian hydrobursitis and a trial for medical treatment were studied. A total of 111 cases were included in two experiments. In Experiment 1, sera from 51 affected cases were tested for C. abortus antibody using enzyme-linked immunosorbent assay (ELISA). In Experiment 2, 60 female camels affected with bilateral ovarian hydrobursitis were divided into treated and control groups (n = 30 each). Based on the bursal diameter, females of both groups were subdivided into those having small (< 5 cm), medium (5-7 cm) or large (> 7 cm) bursae. Treated group received 20 mg/kg body weight oxytetracycline intramuscular, 4% lotagen intrauterine, and 500 μg cloprostenol intramuscular. Controls did not receive any treatment. All females were observed for 90 days non-return rate (NRR) and calving rate (CR). Antibodies against C. abortus were observed in 44/51 (86.3%) of the affected females. The 90 days NRR of the treated and control groups were 13/30 (43.3%) and 0/30 (0.0%), respectively, (P = 0.001), while the CR were 10/30 (33.3%) and 0/30 (0.0%), respectively, (P = 0.01). Based on bursal size, the 90 days NRR were 11/15 (73.3%), 2/7 (28.6%) and 0/8 (0.0%) for treated females having small, medium and large bursa, while the CR were 9/15 (60%), 1/7 (14.3%), and 0/8 (0.0%), respectively, (P = 0.01). In conclusion, it seems that C. abortus may be responsible for the spreading of the ovarian hydrobursitis syndrome in dromedaries. Small sized bursa could be medically treated.


Resilience and psychological trauma among Filipino American women.
To explore the types of traumatic exposure, prevalence of posttraumatic stress disorder (PTSD), and level of resilience in a community sample of Filipino American women (FAW), as well as to investigate the relationships between their PTSD symptoms, history of traumatic exposure, and resilience. A cross-sectional study with a total of 188 adult FAW. We observed high levels of resilience and low levels of PTSD symptom severity. The most common form of traumatic exposure was non-interpersonal trauma occurring after the age of 18 years old. We also found a significant correlation between history of traumatic exposure and PTSD and between resilience and PTSD. Resilience was found to have a significant moderating effect on the relationship between traumatic exposure and PTSD. The results provide preliminary evidence on the buffering and protective properties of FAW's resilience to PTSD despite traumatic exposure.


Naratriptan efficacy in migraineurs who respond poorly to oral sumatriptan.
To determine whether 347 patients would respond to a 50-mg oral dose of sumatriptan, even though they considered themselves poor responders to this acute therapy for migraine, and to investigate whether oral naratriptan can be an effective acute therapy for migraine in the subset of patients who did not respond to sumatriptan under double-blind, well-controlled conditions. Although most migraineurs respond to sumatriptan, there remains a need for an effective alternative for those who do not respond. Naratriptan is a more potent and more lipophilic member of this class of agent and could prove beneficial in such patients. This is the first well-controlled study to assess the value of another 5-HT1B/1D agonist in this difficult patient subset. This study comprised two migraine attacks. The first (attack 1) was a single-blind assessment of the efficacy of sumatriptan (50 mg orally) in patients with a history of poor response to the drug. The second (attack 2) was a randomized, parallel group, double-blind, placebo-controlled trial of naratriptan (2.5 mg orally) in nonresponders to oral sumatriptan. Attack 1: About two thirds of this selected migraine population did not respond to sumatriptan. Attack 2: Naratriptan was statistically superior to placebo for headache relief at 2 hours and 4 hours, as well as for most other features of migraine attacks. These data suggest an intrinsic efficacy of naratriptan in this patient subset and not a coincidental response. No unexpected tolerability issues arose. Naratriptan is an alternative therapy for migraineurs who respond poorly to oral sumatriptan. No response to one "triptan" does not necessarily predict no response to them all.


Mesenchymal cell populations: development of the induction systems for Schwann cells and neuronal cells and finding the unique stem cell population.
Mesenchymal cell populations, referred to as mesenchymal stem cells or multipotent stromal cells (MSCs), which include bone marrow stromal cells (BMSCs), umbilical cord stromal cells and adipose stromal cells (ASCs), participate in tissue repair when transplanted into damaged or degenerating tissues. The trophic support and immunomodulation provided by MSCs can protect against tissue damage, and the differentiation potential of these cells may help to replace lost cells. MSCs are easily accessible and can be expanded on a large scale. In addition, BMSCs and ASCs can be harvested from the patient himself. Thus, MSCs are considered promising candidates for cell therapy. In this review, I will discuss recently discovered high-efficiency induction systems for deriving Schwann cells and neurons from MSCs. Other features of MSCs that are important for tissue repair include the self-renewing property of stem cells and their potential for differentiation. Thus, I will also discuss the stemness of MSCs and describe the discovery of a certain stem cell type among adult MSCs that can self-renew and differentiate into cells of all three germ layers. Furthermore, I will explore the prospects of using this cell population for cell therapy.


[Physical possibilities for the prophylaxis of deep vein thrombosis (author's transl)].
The optimal physical prophylaxis for deep vein thrombosis is to ride a "bed bicycle" with elevated legs and elastic stockings, when lying in bed. The venous velocities achieved in legs and pelvis are 3--4 times faster than those evoked by walking, the method usually used. The incidence of thrombosis (125I fibrinogen test) up to the 5th postoperative day was 7.7%; in the control group, 38.5%. In patients who were weak, paralyzed, unconscious, relaxed, or with one leg, we obtained with "motor cycle" exercises the same success. The frequency of pulmonary embolism (autopsy findings) was reduced from 2.5 to 0.2%.


Effects of acute X-irradiation on pre-implantation embryos and on the implantation reaction in the mouse.
Pregnant mice were treated on the 1st, 2nd, and 3rd day of pregnancy by a single dose of 300 R X-rays. Uterine dissections at day 6 p.c. topographically revealed decrease of the implantation sites from 9.67 per female in the controls to 8.00 in females irradiated on day 1, to 6.63 in females irradiated on day 2, and to 7.00 in females irradiated on day 3 p.c; Among a number of 22 implantations after irradiation on day 1, 19 after irradiation on day 2 and 11 after irradiation on day 3, however no living embryo could be detected on histological examination. The degree of damage as indicated by the total resorptions was highest (94,7%) after irradiation on day 2 p.c., and lowest (31,8%) after irradiation on day 1 p.c. Since the decidual cell reaction was either unaffected or only slightly reduced after irradiation on day 2 p.c. as indicated by cytomorphological criteria and the alkaline phosphatase reaction, not maternal effects but direct effects only of the irradiation on the embryo must account for embryonic deaths.


Canine epilepsy: what can we learn from human seizure disorders?
Epilepsy is a common neurological disorder in both dogs and humans. It is refractory to therapy in approximately one-third of canine patients, and even with the advent of new antiepileptic drugs for humans, appropriate treatment options in dogs remain limited. The pathogenesis and pathophysiology of epilepsy is being studied extensively in both human patients and rodent models of experimental epilepsy at the cellular and molecular level, but very little is known about the aetiologies of epilepsies in dogs. In this review, canine epilepsy will be discussed with reference to the human epilepsies and experimental epilepsy research. There is much work to be done in order to classify canine seizure types and breed-specific epileptic syndromes, particularly with reference to electroencephalographic abnormalities and possible genetic abnormalities. The review considers the appropriate use of antiepileptic drugs: phenobarbitone and potassium bromide are effective in most canine patients, although dosing regimes need to be carefully tailored to the individual, with serum concentration measurement. However, a significant proportion of patients remains refractory to these drugs. Work is currently underway to test the efficacy of newer antiepileptic drugs in the treatment of canine epilepsy, and preliminary data suggest that human drugs such as levetiracetam and gabapentin are of benefit in dogs with refractory epilepsy.


Dating violence in college women: associated physical injury, healthcare usage, and mental health symptoms.
College-aged women report experiencing violence from a partner within the dating experience. This study used a correlational design, to report physical injury, mental health symptoms, and healthcare associated with violence in the dating experiences of college women. A convenience sample of 863 college women between 18 and 25 years of age from a private, historically Black university in the South, and a private college in the mid-Atlantic completed the Abuse Assessment Screen, a physical injury checklist, and the Symptom Checklist-R-90. Data analysis consisted of frequencies, ANOVA, and MANOVA. Almost half (48%) (n = 412) reported violence and, of these, 39% (n = 160) reported more than one form of violence. The most commonly reported injuries were scratches, bruises, welts, black eyes, swelling, or busted lip; and sore muscles, sprains, or pulls. Victims had significantly higher scores on depression, anxiety, somatization, interpersonal sensitivity, hostility, and global severity index than nonvictims. Victims of multiple forms of violence had significantly higher mental health scores and reported greater numbers of injuries than victims of a single form of violence. Less than half of those injured sought healthcare for injuries and less than 3% saw a mental health professional. Study findings suggest the importance of screening and identification of victims of violence. Knowledge of physical and mental health effects of violence can guide intervention, prevention, and health promotion strategies. Future research is needed to describe barriers to seeking healthcare, screening practices of college health programs, and programs to identify victims.


Evidence of QTLs on chromosomes 13q and 14q for triglycerides before and after 20 weeks of exercise training: the HERITAGE Family Study.
Fasting triglyceride (TG) levels in total plasma and in lipoprotein subfractions were assessed both at baseline and after a 20-week exercise training intervention in 99 White and 101 Black families. A genome-wide multipoint variance component linkage analysis was performed separately by race, using 509 markers. The strongest evidence of linkage was for the TG subfractions of low-density lipoprotein (LDL-TG) and high-density lipoprotein (HDL-TG) rather than for overall levels of TG. For baseline levels, the maximum LOD score was 3.8 on 13q12-q14 with HDL-TG in Whites. Additional linkage evidence was found on 14q31 (LOD=3.2) and 10p14 (LOD=2.9) for baseline LDL-TG in Whites. Suggestive linkage signal at baseline in Whites was detected for HDL-TG (LOD=2.6) on 12q24 and for LDL-TG on 19p13. For training response in Whites, suggestive signal (LOD=2.2) was observed on 13q12-q14 with LDL-TG and for HDL-TG on 10q23. For Blacks, weak signals (LODs<2.0) were found either for baseline and responses to training, perhaps due to small sample sizes that reduced the power of the linkage analysis. These results represent the first report of linkage for the lipoprotein subfractions and for the lipid and lipoprotein responses to exercise training. It is interesting that the strongest signals were found for the LDL-TG and HDL-TG subfractions, given their particular relationships with the atherogenic lipid profile including dense LDL and HDL particles.


Very low frequencies of human normal CD34+ haematopoietic progenitor cells express the Wilms' tumour gene WT1 at levels similar to those in leukaemia cells.
The Wilms' tumour gene, WT1, is expressed at high levels in leukaemia cells and plays an important role in leukaemogenesis. WT1 is also expressed in human normal CD34+ bone marrow (BM) cells at about 100 times lower levels than in leukaemia cells. To identify and characterize WT1-expressing cells in CD34+ BM cells, they were sorted into single cells and analysed for WT1 expression using two kinds of single-cell reverse transcriptase polymerase chain reaction (RT-PCR) methods. Using the semiquantitative single-cell polyA-PCR + sequence-specific (SS)-PCR method, WT1 expression was detected in four (1.3%) out of 319 CD34+ BM single cells. To confirm the above results, a single-cell nested sequence-specific (NSS)-RT-PCR method that was less quantitative but more sensitive than the polyA-PCR + SS-PCR method was also performed, and WT1 expression was detected in 15 (1.1%) out of 1315 CD34+ BM single cells. In total, WT1 expression was found in 19 (1.2%) out of 1634 CD34+ BM single cells. No significant differences in the frequencies of WT1-expressing cells were found between CD34+CD38- and CD34+CD38+ BM single cells. Furthermore, WT1-expressing CD34+ BM single cells expressed WT1 at levels similar to those in K562 leukaemia single cells. Analysis of lineage-specific and cell cycle gene expression in WT1-expressing CD34+ BM single cells showed that the WT1 gene could be expressed in both uncommitted, dormant CD34+CD38- and lineage-committed, proliferating CD34+CD38+ BM cells. Our results could indicate that these WT1-expressing CD34+ BM cells were normal counterparts of leukaemia cells.


The DYD-RCT protocol: an on-line randomised controlled trial of an interactive computer-based intervention compared with a standard information website to reduce alcohol consumption among hazardous drinkers.
Excessive alcohol consumption is a significant public health problem throughout the world. Although there are a range of effective interventions to help heavy drinkers reduce their alcohol consumption, these have little proven population-level impact. Researchers internationally are looking at the potential of Internet interventions in this area. In a two-arm randomised controlled trial, an on-line psychologically enhanced interactive computer-based intervention is compared with a flat, text-based information web-site. Recruitment, consent, randomisation and data collection are all on-line. The primary outcome is total past-week alcohol consumption; secondary outcomes include hazardous or harmful drinking, dependence, harm caused by alcohol, and mental health. A health economic analysis is included. This trial will provide information on the effectiveness and cost-effectiveness of an on-line intervention to help heavy drinkers drink less. International Standard Randomised Controlled Trial Number Register ISRCTN31070347.


Using whole-genome sequencing data to derive the homologous recombination deficiency scores.
The homologous recombination deficiency (HRD) score was developed using whole-genome copy number data derived from arrays as a way to infer deficiency in the homologous recombination DNA damage repair pathway (in particular BRCA1 or BRCA2 deficiency) in breast cancer samples. The score has utility in understanding tumour biology and may be indicative of response to certain therapeutic strategies. Studies have used whole-exome sequencing to derive the HRD score, however, with increasing use of whole-genome sequencing (WGS) to characterise tumour genomes, there has yet to be a comprehensive comparison between HRD scores derived by array versus WGS. Here we demonstrate that there is both a high correlation and a good agreement between array- and WGS-derived HRD scores and between the scores derived from WGS and downsampled WGS to represent shallow WGS. For samples with an HRD score close to threshold for stratifying HR proficiency or deficiency there was however some disagreement in the HR status between array and WGS data, highlighting the importance of not relying on a single method of ascertaining the homologous recombination status of a tumour.


The effects of the recurrent social isolation stress on fear extinction and dopamine D2 receptors in the amygdala and the hippocampus.
The present study assessed the influence of recurrent social isolation stress on the aversive memory extinction and dopamine D2 receptors (D2R) expression in the amygdala and the hippocampus subnuclei. We also analyzed the expression of epigenetic factors potentially associated with fear extinction: miRNA-128 and miRNA-142 in the amygdala. Male adult fear-conditioned rats had three episodes of 48 h social isolation stress before each fear extinction session in weeks intervals. Ninety minutes after the last extinction session, the D2R expression in the nuclei of the amygdala and the hippocampus (immunocytochemical technique), and mRNA levels for D2R in the amygdala were assessed (PCR). Moreover, we evaluated the levels of miRNA-128 and miRNA-142 in the amygdala. It was found that recurrent social isolation stress decreased the fear extinction rate. The extinguished isolated rats were characterized by higher expression of D2R in the CA1 area of the hippocampus compared to the extinguished and the control rats. In turn, the isolated group presented higher D2R immunoreactivity in the CA1 area compared to the extinguished, the control, and the extinguished isolated animals. Moreover, the extinguished animals had higher expression of D2R in the central amygdala than the control and the extinguished isolated rats. These changes were accompanied by the increase in miRNA-128 level in the amygdala in the extinguished isolated rats compared to the control, the extinguished, and the isolated rats. Moreover, the extinguished rats had lower expression of miRNA-128 compared to the control and the isolated animals. Our results suggest that social isolation stress impairs aversive memory extinction and coexists with changes in the D2R expression in the amygdala and hippocampus and increased expression of miRNA-128 in the amygdala.


Can Epstein-Barr virus DNA load in nasopharyngeal brushings or whole blood predict recurrent nasopharyngeal carcinoma in a non-endemic region? A prospective nationwide study of the Dutch Head and Neck Oncology Cooperative Group.
This study estimated the value of quantitative measurements of EBV markers in the clinical management of nasopharyngeal carcinoma in a non-endemic area. The aim was to predict prognosis and detect recurrent and residual disease. In 72 patients, EBV DNA load in blood and nasopharyngeal brushes, and IgA VCA-p18 and EBNA1 in plasma were measured at different time points. At diagnosis and post-treatment, a cut-off value was used for detecting disease [positive (PPV) and negative (NPV) predictive value]. The markers were correlated as a continuous variable with tumor stage, disease-free survival (DFS) and overall survival (OS). The Cox hazard ratio model assessed hazard ratios. At diagnosis, the markers were above the COV in 45, 92, 85 and 83 % of the patients, respectively. Post-treatment, DNA load test in blood and brush had the best discriminating power (blood DNA load test: PPV 39 % and NPV 97 %, brush for local disease: PPV 75 % and NPV 99 %). Post-treatment, DNA load in blood was the best predictor for OS and DFS [hazard ratio 3.2 (95 % CI 1.51-3.5) and 2.3 (95 % CI 1.72-5.8)]. Assessing the EBV DNA load in blood has significant prognostic value, although the clinical value is for discussion. The EBV DNA load in the brush might improve early detection of local failures post-treatment.


Transcriptional regulation of the gilthead seabream (Sparus aurata) interleukin-6 gene promoter.
Interleukin-6 (IL-6) has been identified and characterized from several fish species and its mRNA expression is induced by pathogen-associated molecular patterns (PAMPs) and cytokines in immune cells and tissues. However, the transcriptional regulation of the IL-6 gene in fish is not well understood. In the present study, we have cloned and sequenced a 1028 bp 5'-flanking DNA region from the IL-6 gene in seabream (Sparus aurata). Sequence analysis of the seabream IL-6 promoter (sbIL-6P) evidenced the presence of a conserved TATA motif and conserved response elements for NF-κB, C/EBPβ (NF-IL6), AP-1 and GRE, similar to other vertebrate IL-6 promoters. Functional characterization of sbIL-6P was performed by cloning sbIL-6P into a luciferase expression vector and by transfecting it into L6 muscle cells, a mammalian cell line shown previously to express IL-6 in response to pro-inflammatory stimuli. We show here that the activity of sbIL-6P was significantly induced by pro-inflammatory cytokines such as tumor necrosis factor alpha (TNFα), IL-6 and IL-2, as well as by lipopolysaccharide (LPS), but significantly repressed by dexamethasone. In addition, the stimulatory effects of TNFα on sbIL-6P activity appeared to be mediated by the NF-κB, p38 MAPK and JNK signaling pathways. Deletion analyses of sbIL-6P suggested that activation of sbIL-6P by TNFα and IL-6 required the presence of binding motifs present in the proximal promoter (-171 to -84) whereas activation by IL-2 required binding motifs present in the distal promoter (-1024 to -864). The results from this study indicate, for the first time in fish, that pro-inflammatory cytokines, LPS and glucocorticoids can regulate the activity of the IL-6 gene at a transcriptional level and identify important regions in its response to cytokines.


Modulation of neutrophil function by lysozyme. Potential negative feedback system of inflammation.
Host responses to infectious organisms should be modulated so that tissue-damaging products of inflammatory cells do not produce excessive destruction of normal tissue. Lysozyme, which is continuously secreted by monocytes, which, in turn, migrate relatively late to inflammatory areas, was found to significantly dampen several responses of neutrophils to inflammatory stimulants. Thus, human lysozyme obtained and purified from the urine of patients with monocytic leukemia (but not its structurally similar and comparably cationic analogue, eggwhite lysozyme) depresses chemotaxis of normal neutrophils to activated complement, bacterial supernate, and N-formylmethionyl-phenylalanine. In addition, human (but not eggwhite) lysozyme depresses oxidative metabolism (hexose monophosphate shunt activity) and superoxide generation of neutrophils. The specificity of the suppressive effects was indicated by inhibition studies with rabbit antihuman lysozyme antibody, and with the trisaccharide of N-acetylglucosamine, a specific inhibitor of lysozyme. The results suggest that lysozyme, a product of inflammatory cells themselves, may function in a negative feedback system to modulate the inflammatory response.


Design, synthesis and biological evaluation of benzo[1.3.2]dithiazolium ylide 1,1-dioxide derivatives as potential dual cyclooxygenase-2/5-lipoxygenase inhibitors.
3-(4-Bromophenyl)-6-nitrobenzo[1.3.2]dithiazolium ylide 1,1-dioxide (5) was discovered as a new prototype for dual inhibitors of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). Thus, the structure-activity relationships of benzo[1.3.2]dithiazolium ylide 1,1-dioxide skeleton were carried out. The 6-NO(2) group played an essential role in the inhibitory activity. In addition, moderate-sized lipophilic substituents at the para-position of the 3-aryl moiety were required for dual COX-2/5-LOX inhibitory activity. Among the identified potent dual inhibitors, 3-(4-tbutylphenyl) derivative 30c (IC(50) values of 0.27 μM and 0.30 μM against COX-2 and 5-LOX, respectively) and 3-(4-biphenyl) derivative 30f (IC(50) values of 0.50 μM and 0.15μM against COX-2 and 5-LOX, respectively) were the most potent dual COX-2/5-LOX inhibitors. Intraperitoneal administration of 30c at 100mg/kg demonstrated potent acute anti-inflammatory activity. As a result, benzo[1.3.2]dithiazolium ylide 1,1-dioxide represented a novel scaffold for the exploitation in developing dual COX-2/5-LOX inhibitors.


Generation of nonspecific murine cytotoxic T cells in vitro by purified human interleukin 2.
Murine spleen cells developed into nonspecific cytotoxic cells within 72 hr of culture in the presence of highly purified sources of human interleukin 2. In whole spleen cell cultures, human interleukin 2 generated effector cells which were Thy 1.2+, Lyt 2.2+, resistant to gamma irradiation (1000 R), and capable of lysing both H-2 compatible and incompatible targets. The effector cells generated in this manner were not restricted to classical natural killer cell-sensitive targets. If thymus-derived cells (T cells) were depleted from the spleen cell population before culture with human interleukin 2, the effector cells generated were enriched in effectors capable of lysing natural killer cell-sensitive targets. Interferon was not produced in interleukin 2-stimulated spleen cell cultures. In addition, heterologous antibody to murine gamma-interferon did not abrogate the generation of cytotoxic cells by human interleukin 2. These and additional data suggest that human interleukin 2 is capable of stimulating gamma-irradiation-sensitive Thy 1.2+ cell(s) capable of lysing a variety of target cells regardless of inherent sensitivities to classical natural killer cells. Thy 1.2- cells were also stimulated by human interleukin 2 and lysed only natural killer cell-sensitive targets. Human interleukin 2 caused some Thy 1.2- cells to become susceptible to lysis by anti-Thy 1.2 serum and complement.


Reovirus type 2 in domestic cats: isolation and experimental transmission.
Five reovirus isolates were recovered in MA104 cell cultures from the faeces of three cats with nictitating membrane protrusion and diarrhoea, one cat with diarrhoea only and from one healthy cat. Four of these isolates were characterised as reovirus type 2 and one as reovirus type 3 by haemagglutination-inhibition and serum neutralization tests. Reovirus type 2 has not been reported previously in cats. Mild clinical signs of diarrhoea were noted in kittens infected experimentally with one of the feline reovirus type 2 isolates.


Chemokine Receptor-Targeted Therapies: Special Case for CCR8.
Immune checkpoint blockade inhibitors (CBIs) targeting cytotoxic T lymphocyte associated protein-4 (CTLA-4) and program death receptor-1 (PD-1) or its ligand-1 (PD-L1) have transformed the outlook of many patients with cancer. This remarkable progress has highlighted, from the translational point of view, the importance of immune cells in the control of tumor progression. There is still room for improvement, since current CBI therapies benefit a minority of patients. Moreover, interference with immune checkpoint receptors frequently causes immune related adverse events (irAEs) with life-threatening consequences in some of the patients. Immunosuppressive cells in the tumor microenvironment (TME), including intratumoral regulatory T (Treg) cells, tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), contribute to tumor progression and correlate with a negative disease outlook. Recent reports revealed the selective expression of the chemokine receptor CCR8 on tumor Treg cells, making CCR8 a promising target in translational research. In this review, I summarize our current knowledge about the cellular distribution and function of CCR8 in physiological and pathophysiological processes. The discussion includes an assessment of how the removal of CCR8-expressing cells might affect both anti-tumor immunity as well as immune homeostasis at remote sites. Based on these considerations, CCR8 appears to be a promising novel target to be considered in future translational research.


Clinical and radiologic assessments to predict breast cancer pathologic complete response to neoadjuvant chemotherapy.
To prospectively compare the ability of clinical examination, mammography, vascularity-sensitive ultrasound, and magnetic resonance imaging (MRI) to determine pathologic complete response (CR) in breast cancer patients undergoing neoadjuvant chemotherapy. Participants were women with primary measurable, operable invasive breast cancer (Stages I-III) who presented to the University of Michigan Breast Care Center. Eligibility criteria were based on clinical need for chemotherapy as part of the overall treatment plan. The chemotherapy consisted of doxorubicin and docetaxel administered every 3 weeks for four cycles. Tumor size measurements by physical examination and by the three imaging modalities were performed before chemotherapy was initiated and after its completion, prior to definitive surgery. Response criteria were pre-specified in this prospective design, and study radiologists analyzed the mammographic, sonographic and MRI image sets blinded to information from the other modalities and blinded to final histological diagnosis. The pathologic CR rate obtained by the clinical and imaging modalities was compared to pathologic CR as determined pathologically. 41 of 43 enrolled patients had a determination of pathologic response, and 4 patients had a pathologic CR to this chemotherapy (9.8%). The accuracy of physical examination, mammography, ultrasound, and MRI in determining pathologic CR was 75, 89, 82, and 89% respectively (NS). Biopsy after neoadjuvant chemotherapy remains absolutely necessary to determine pathologic CR to neoadjuvant chemotherapy, as the accuracy of current imaging modalities is insufficient to make this determination. The accuracy of mammography, vascularity-sensitive ultrasound, and MRI were not observed to be significantly different.


Ultrafine carbon black disturbs heart rate variability in mice.
Previous epidemiological and toxicological studies have reported the associations between ambient particulate matter (PM) exposure and changes in heart rate variability (HRV), a marker of cardiac autonomic nervous system (ANS) function. However, both the responsible components in PM and their mechanisms affecting HRV remain uncertain. We propose that carbon black (CB), one of the main components in PM, may affect HRV through mechanisms independent of cardio-pulmonary and systemic inflammation and/or injury. Male C57BL/6 mice were exposed by intra-tracheal instillation to ultrafine CB (once every two days for three times) at doses of 0, 0.05, 0.15 and 0.6 mg/kg. HRV indices, standard deviation of all normal R-R intervals (SDNN) and the square root of mean of sum of squares of differences between adjacent normal R-R intervals (RMSSD), showed significant decreases in 0.15 and 0.6 mg/kg CB exposed groups. Slight pulmonary inflammation and myocardial injury were only observed in 0.6 mg/kg CB exposed group. We conclude that CB can disturb cardiac ANS function in mice, indicated by the withdrawal of parasympathetic modulation, through mechanisms independent of apparent myocardial and pulmonary injury.


Theophylline in rats during maintenance phase of post-ischemic acute renal failure.
We have shown previously that theophylline increases both renal plasma flow (RPF) and glomerular filtration rate (GFR) during the initiation phase of post-ischemic acute renal failure (ARF) in rats. The purpose of the present experiments was to determine the effects of theophylline during the maintenance phase of ARF, five days after initiation. Clearance techniques were used to measure renal function in a control group of pentobarbital anesthetized rats (group C) and in three experimental groups, five days after subjecting the left kidney to a thirty-minute period of complete ischemia. Group SS received saline during both the ischemic episode and the clearance measurements; group ST received saline during ischemia and theophylline, acutely, during the clearance measurements; group TS received theophylline during ischemia and saline during the clearance measurements. In comparison with the values for the control group (group C), RPF and GFR of the post-ischemic left kidneys of group SS were approximately half normal. In groups ST and TS, RPF and GFR of the left kidneys were higher than in group SS. Collectively, these results demonstrate that pretreatment with theophylline during the initiation phase of ischemia-induced ARF leads to increased RPF and GFR during the maintenance phase, and that acute theophylline treatment during the maintenance phase acutely increases RPF and GFR. Since increases in GFR were associated with increases in RPF, and since theophylline is an adenosine receptor antagonist, these results are consistent with the hypothesis that adenosine-mediated hemodynamic changes play a pathogenic role in ischemia-induced ARF in rats.


Comparative efficacy of seven Chinese patent medicines for early diabetic kidney disease: A Bayesian network meta-analysis.
Bailing Capsule (BLC), Jinshuibao (JSB), Huangkui Capsule (HKC), Uremic Clearance Granule (UCG), Tripterygium glycosides (TG), Compound Xueshuantong Capsule (CXC), and Shenyan Kangfu Tablet (SYKFT) as classic Chinese patent medicines (CPMs), have been widely used and shown beneficial effects on the treatment of early diabetic kidney disease (DKD). However, the comparative efficacy of seven CPMs in the treatment of early DKD remains unknown. To evaluate and compare the efficacy of seven CPMs (BLC, JSB, HKC, UCG, TG, CXC, SYKFT) combined with angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) on early DKD by a Bayesian network meta-analysis (NMA) of randomized controlled trials (RCTs). A comprehensive and systematic literature search was performed in PubMed, Embase, Cochrane Library, Web of Science, Clinical Trials.gov, China Biology Medicine, Chinese National Knowledge Infrastructure, Chinese Scientific Journal, and Wanfang databases from inception to March 14, 2021, for full-text RCTs that evaluated the efficacy of seven CPMs combined with ACEI/ARB on patients with early DKD. Two reviewers independently screened studies for eligibility, extracted data, and assessed the risk of bias. Agreement between reviewers was measured using kappa statistics. Mean difference (MD) and odds ratio (OR) were calculated to evaluate continuous variables and dichotomous, respectively. The random effect modeling NMA was performed and the ranking probability of interventions in various outcomes was also conducted based on the surface under the cumulative ranking curve (SUCRA). Begg's and Egger's tests were used to evaluate publication bias. The certainty of the evidence for outcomes was evaluated according to the GRADE system. A total of 62 RCTs with 5362 patients with early DKD were identified. The value of Kappa calculated for the various parameters extracted by the two investigators was 0.821 (P < 0.001). Among these CPMs, UCG + ACEI/ARB showed the best effectiveness for urinary albumin excretion rate (UAER) (MD 32.25, 95% CrI 19.11-45.67, low certainty) with SUCRA 92%. JSB + ACEI/ARB showed the highest effectiveness for 24-h urinary total protein (24-h UTP) (MD 76.92, 95% CrI 53.54-100.58, low certainty) with SUCRA 97%. CXC + ACEI/ARB showed the highest effectiveness for serum creatinine (SCr) (MD 26.02, 95% CrI 6.10-45.95, low certainty) with SUCRA 96%. HKC + ACEI/ARB showed the highest effectiveness for blood urea nitrogen (BUN) (MD 1.46, 95% CrI 0.42-2.54, very low certainty) with SUCRA 86%. BLC + ACEI/ARB showed significant differences in triglyceride (TRIG) (MD - 1.17, 95% CrI - 1.93 to - 0.43, low certainty) with SUCRA 90%, total cholesterol (TC) (MD - 1.17, 95% CrI - 1.97 to - 0.39, very low certainty) with SUCRA 90%, and C-reaction protein (CRP) (MD - 0.90, 95% CrI - 1.51 to - 0.32, very low certainty) with SUCRA 76%. CPMs + ACEI/ARB might be positive efficacious interventions from which patients with DKD will derive benefit. UCG + ACEI/ARB, JSB + ACEI/ARB, CXC + ACEI/ARB, and HKC + ACEI/ARB might be potentially the preferred intervention for reducing UAER, 24-h UTP, SCr, and BUN levels, respectively. BLC + ACEI/ARB has a better impact on lowing TRIG, TC, and CRP levels in patients with early DKD. However, more high-quality, large-scale, multi-center RCTs and stronger head-to-head trials are required to confirm these findings.


Acquired coronary artery fistula after open heart surgery for congenital heart disease.
Most coronary artery fistulas were reported as congenital. Acquired coronary artery fistula occurring after cardiac surgery has rarely been reported. From 1998 to 2003, 10 patients with coronary artery fistula detected by echocardiography after open heart surgery for congenital heart disease were included. Their ages ranged from 2 months to 41 years (median 4.2 years). The underlying heart disease was tetralogy of Fallot in five patients, ventricular septal defect in three, double chamber right ventricle in one, and transposition of the great arteries with ventricular septal defect in the remaining one. Of these 10 patients, the coronary artery fistula originated from the left coronary artery in four, right coronary artery in two, and unknown origin in the remaining four. The coronary artery fistula drained into the right ventricle in nine and into the left ventricle in the remaining one. The incidence of acquired coronary artery fistula after open heart surgery for congenital heart disease was 0.44% (8/1832). The identified risk factors for acquired coronary artery fistula were reoperation and right ventricular muscle resection in ventricular septal defect. After follow-up for 0.5-12 years (mean 4.1+/-3.3 years), the coronary artery fistula persisted, but neither symptoms nor significant left-to-right shunt was noted. Acquired coronary artery fistula is a rare complication after cardiac surgery. Reoperation and resection of right ventricular hypertrophic muscle increase the risk of this complication. Although shunt flow did not increase during follow-up, the significance of acquired coronary artery fistula needs further investigation.


The nevoid basal cell carcinoma syndrome: sensitivity to ultraviolet and x-ray irradiation.
Demographic studies in patients with skin cancer have demonstrated the importance of exposure to ultraviolet and x-ray irradiation. This paper describes in vitro studies in peripheral lymphocytes from three patients with the nevoid basal cell carcinoma syndrome. Particular stress was placed on the following factors: (1) the distribution of the lymphocyte subsets, (2) the frequency of spontaneous sister chromatid exchange, (3) the effect of ultraviolet C (UVC) (254 nm) on deoxyribonucleic acid (DNA) synthesis, (4) the effect of UVC on the phytohemagglutinin-stimulated lymphocyte proliferation, and (5) the capacity to repair x-ray-induced DNA damage. Our data indicate that the distribution of the peripheral lymphocytes was normal, while the frequency of spontaneous sister chromatid exchange was high. The capacity of the lymphocytes to repair x-ray-induced DNA damage was low in all three patients. In two patients the UVC-induced DNA synthesis was reduced, while an increased UVC-induced inhibition of lymphocyte proliferation was observed. These cellular responses in vitro to ultraviolet and x-ray irradiation correspond to the clinical features of the nevoid basal cell carcinoma syndrome. A clearly defective in vitro cellular response to x-ray irradiation, reflecting the clinically evident x-ray sensitivity in the nevoid basal cell carcinoma syndrome, has not been reported previously.


Serum angiopoietin-1 concentration does not distinguish patients with ischaemic stroke from those presenting to hospital with ischaemic stroke mimics.
A previous study found that circulating angiopoietin-1 (angpt-1) concentrations were significantly lower in patients who had a recent ischaemic stroke compared to healthy controls. The primary aim of this study was to assess whether serum angpt-1 could be used as a diagnostic test of ischemic stroke in patients presenting to hospital as an emergency. Exploratory analyses investigated the association of proteins functionally related to angpt-1 (angpt-2, Tie-2, matrix metalloproteinase-9 and vascular endothelial growth factors A, C and D) with ischaemic stroke diagnosis. Patients presenting to Townsville University Hospital for emergency assessment of stroke-like symptoms were consecutively recruited and provided a blood sample. After assessment by a consultant neurologist, patients were grouped into those who did, or did not have ischaemic stroke. The potential for serum angpt-1 to diagnose ischaemic stroke was assessed using receiver operator characteristic (ROC) curves. Cross-sectional analyses appraised inter-group differences in the serum concentration of other proteins. One-hundred and twenty-six patients presenting to Townsville University Hospital for emergency assessment of stroke-like symptoms were recruited (median time from symptom onset to hospital presentation: 2.6 (inter-quartile range: 1.2-4.6) hours). Serum angpt-1 had poor ability to diagnose ischaemic stroke in analyses using the whole cohort, or in sensitivity analyses (area under the ROC curve 0.51 (95% CI: 0.41-0.62) and 0.52 (95% CI: 0.39-0.64), respectively). No associations of serum angpt-1 concentration with ischaemic stroke severity, symptom duration or aetiology were observed. Serum concentrations of the other assessed proteins did not differ between patient groups. Serum angpt-1 concentration is unlikely to be useful for emergency diagnosis of ischaemic stroke.


Larvicidal activity against Aedes aegypti of pacharin from Bauhinia acuruana.
The aim of the present study was to evaluate the activity of pacharin isolated from the ethanol extract from roots of Bauhinia acuruana on third-instar larvae of Aedes aegypti Linn. (Diptera: Culicidae). The crude ethanol extract showed larvicidal activity at the concentration of 500 μg/mL. Given this larvicidal activity, this extract was submitted to chromatographic fractionation on a silica gel column eluted with n-hexane, dichloromethane, ethyl ether, ethyl acetate, and methanol in order to isolate the active compound(s). Pacharin, obtained in pure form from fraction eluted with ethyl ether, was evaluated for their larvicidal effects against A. aegypti. In these bioassays, the larvae were exposed at concentrations of 500, 250, 100, 50, and 25 μg/mL of the crude ethanol extract or pacharin. After 24 h, the number of dead larvae was counted and the LC₅₀ values for larval mortality were calculated. Pacharin showed LC50 value of 78.9 ± 1.8 μg/mL. The structure of isolated compound was identified on the basis of their spectral data (IR, 1D- and 2D-NMR) and by comparison with literature spectral data. The results indicate pacharin as a potential natural larvicide.


Midsummer solar UV-radiation in Finland compared with the UV-radiation from phototherapeutic devices measured by different techniques.
Midsummer solar UV-radiation in southern Finland was measured by a spectroradiometer, polysulphone film dosimeters, and a solid-state UV-meter. Solar UV-irradiance was compared with radiation from different phototherapy devices (UVB, SUP, and PUVA therapy equipment). Measured by the spectroradiometer, the solar UVB irradiance at noon was 55 microW/cm2; it varied from 60 to 79 microW/cm2 according to the doses received by the film dosimeters on clear, sunny days in June. A solid-state detector gave a markedly overestimated UVB irradiance of 235 microW/cm2. Solar UVB radiation would lead to 1.5 MEDs in 2 hours around midday, 2.9 MEDs in 4 h and 8 MEDs in 12 h in midsummer at latitudes in southern Finland. Solar UVB radiation corresponds to that emitted from PUVA treatment devices, but the UVA (315-400 nm) radiation of the latter is about 3-fold that of solar radiation. The UVA radiation from SUP and PUVA treatment devices resembled each other but the former emitted more radiation at the lower wavelengths of 315-340 nm. The UVB irradiance of the UVB therapeutic device was 25-55 times the irradiance of the sun.


Maximal clenching effort influence on the electromyographic activity of the trapezius muscle in healthy subjects.
Alteration of the occlusion and the position of the jaw can affect the muscles of the neck, due to a relationship between the masticatory and cervical systems. Thus, the objective of this study was to verify whether the bite in maximal clenching effort, in centric occlusion, in individuals with clinically normal occlusion, and without a history of dysfunction in the masticatory system, influences the electromyographic activity of the upper trapezius muscle. A total of 19 normal individuals participated in the study, 14 of which were women (average age of 25.4 ± 4.14 years), and 5 were men (average age of 24.11 ± 3.28 years). The root mean square (RMS) amplitude and median frequency (MF) of the upper trapezium muscle with 40% and 60% of maximal voluntary contraction were analyzed under pre- and post-maximal clenching effort conditions in centric occlusion. The electromyographic signal was collected with a sampling frequency of 2 kHz and the value in RMS was obtained by a moving window of 200 ms. The paired Student's t-test was used to compare RMS amplitude and MF under pre- and post-maximal clenching effort conditions. The level of significance for each comparison was set to p<0.05. This study concluded that in individuals without a history of dysfunction of the masticatory system, maximum clenching effort in centric occlusion does not alter the electromyographic signal of the upper trapezius.


Rhabdomyosarcoma of the bile ducts.
Rhabdomyosarcoma is a rare malignant neoplasm of the biliary tract. Including all the historical recent probable, and established cases that are carefully classified by Hayes and Synder, only 24 cases have been reported to date. Because of the extreme rarity of this tumor in this location, correct diagnosis was not made until second laparotomy or autopsy in several reported cases. The present report describes a child who recently underwent excision of such a tumor at our institution.


Endovenous laser ablation: an experimental study on the mechanism of action.
The aim of this experimental study was to investigate the mechanism of action of endovenous laser ablation (EVLA) using an 810-nm diode laser. We compared intermittent and continuous delivery of laser energy and studied the absorption of laser light by blood, intravascular temperatures in ex vivo human vein segments using an intravascular thermography catheter and heat dissipation in a model tissue using the Schlieren technique. Laser light is absorbed by blood and converted to heat leading to coagulation, vaporization and carbonization, and forming an isolating layer at the fibre tip. Laser energy is then absorbed into the isolating layer forming black patches that burned on the laser fibre. Intravascular temperature increased rapidly above carbonization temperatures (300 degrees C) after the fibre tip reached the thermocouple, stayed at this temperature for a few seconds and decreased gradually to around 30 degrees C, 10 s after the fibre tip passed the thermocouple. Schlieren techniques revealed that heat spread from the laser was locally distributed and closely around the laser fibre tip while heat dissipation is minimal and comparable for both exposures. Compared with intermittent exposure, continuous exposure results in more carbonization, higher mean maximum intravascular temperature (128 +/- 7 vs. 75 +/- 4 degrees C), and long-lasting temperature of 100 degrees C (1.2 +/- 0.4 vs. 0.1 +/- 0.1 s). In this experimental study, application of endovenous laser shows to be dominated by carbonization at the fibre tip. Although intraluminal laser-induced heat was heterogeneously distributed, with laser tip temperatures up to 1200 degrees C, heat dissipation was minimal. Continuous exposure of laser light appears to be better suited in EVLA than intermittent.


Transgenic mice expressing human fibroblast growth factor-19 display increased metabolic rate and decreased adiposity.
The fibroblast growth factors (FGFs), and the corresponding receptors, are implicated in more than just the regulation of epithelial cell proliferation and differentiation. Specifically, FGF23 is a regulator of serum inorganic phosphate levels, and mice deficient in FGF receptor-4 have altered cholesterol metabolism. The recently described FGF19 is unusual in that it is nonmitogenic and appears to interact only with FGF receptor-4. Here, we report that FGF19 transgenic mice had a significant and specific reduction in fat mass that resulted from an increase in energy expenditure. Further, the FGF19 transgenic mice did not become obese or diabetic on a high fat diet. The FGF19 transgenic mice had increased brown adipose tissue mass and decreased liver expression of acetyl coenzyme A carboxylase 2, providing two mechanisms by which FGF19 may increase energy expenditure. Consistent with the reduction in expression of acetyl CoA carboxylase 2, liver triglyceride levels were reduced.


Galectin-1 Prevents Infection and Damage Induced by Trypanosoma cruzi on Cardiac Cells.
Chronic Chagas cardiomyopathy caused by Trypanosoma cruzi is the result of a pathologic process starting during the acute phase of parasite infection. Among different factors, the specific recognition of glycan structures by glycan-binding proteins from the parasite or from the mammalian host cells may play a critical role in the evolution of the infection. Here we investigated the contribution of galectin-1 (Gal-1), an endogenous glycan-binding protein abundantly expressed in human and mouse heart, to the pathophysiology of T. cruzi infection, particularly in the context of cardiac pathology. We found that exposure of HL-1 cardiac cells to Gal-1 reduced the percentage of infection by two different T. cruzi strains, Tulahuén (TcVI) and Brazil (TcI). In addition, Gal-1 prevented exposure of phosphatidylserine and early events in the apoptotic program by parasite infection on HL-1 cells. These effects were not mediated by direct interaction with the parasite surface, suggesting that Gal-1 may act through binding to host cells. Moreover, we also observed that T. cruzi infection altered the glycophenotype of cardiac cells, reducing binding of exogenous Gal-1 to the cell surface. Consistent with these data, Gal-1 deficient (Lgals1-/-) mice showed increased parasitemia, reduced signs of inflammation in heart and skeletal muscle tissues, and lower survival rates as compared to wild-type (WT) mice in response to intraperitoneal infection with T. cruzi Tulahuén strain. Our results indicate that Gal-1 modulates T. cruzi infection of cardiac cells, highlighting the relevance of galectins and their ligands as regulators of host-parasite interactions.


Half of nurses considering leaving NHS, survey finds.
More than half of nurses (52%) are considering quitting the NHS as work pressures continue to mount, an exclusive survey by Nursing Standard and the Sunday Mirror reveals.


Investigation on the chemical space of the substituted triazole thio-benzoxazepinone RIPK1 inhibitors.
As a key upstream kinase involved in the activation of necroptosis, receptor-interacting protein kinase 1 (RIPK1) plays a vital role in the treatment of relevant inflammatory diseases. Recently, we described the thio-benzoxazepinones as RIPK1 necroptosis inhibitors. On this basis, we further explored the chemical space of the thio-benzoxazepinones by introducing substitutions on the triazole group and evaluated their anti-necroptotic activity. The structure-activity relationship (SAR) was extended for this series of new derivatives. The best compound 2 with methyl and compound 10 with fluoroethyl were obtained and both specifically inhibited necroptosis rather than apoptosis with EC50 values of 2.5 and 8.9 nM, respectively. They blocked the downstream necroptotic pathway to prevent cell lysis and prevent in vivo inflammation in a dose-dependent manner. This work provides that substituted thio-benzoxazepines can better occupy the hydrophobic cavity and enhance the hydrophobic interaction as promising lead compounds to enhance the in vivo activity of this class of compounds.


Construction of a Gene-Deletion Mutant in Tannerella forsythia.
Tannerella forsythia, a gram-negative anaerobic bacterium, is one of the most important pathogens in periodontal disease. However, it has been difficult to construct a gene-deletion mutant in this organism, which may serve as a useful tool in microbiological research. We reported a highly efficient method to construct a gene-deletion mutant of T. forsythia in 2007, and it was accomplished by preparing competent cells from a colony grown on an agar medium instead of a broth culture. Here, we describe the same method with some improvements.


Multidisciplinary analysis of patients with extratemporal complex partial seizures. I. Intertest agreement.
In 15 patients we hypothesized the origin of epilepsies to be 'extratemporal' based on videotaped seizures and surface EEG. Neuropsychological tests and neuroimaging (CAT, MRI, and PET scans) were then compared to the hypothesized ictal sites. Neuropsychological tests were abnormal in 86.6% and FDG-PET scans were abnormal in 73%. The neuropsychological tests and PET localized or lateralized areas of dysfunction to the same sites as electroclinical characteristics did in 85% of patients (P less than 0.01, Fisher exact test). No statistically significant correlation between lesion sites on CT and MRI and the ictal origin was observed due to the high proportion of normal or non-specific scans. These observations should be verified in a larger series of extratemporal seizures.


Personal exposure to 1,3-butadiene in a petrochemical plant, assessed by use of diffusive samplers.
This study assessed personal exposure to 1,3-butadiene in a petrochemical plant after the threshold limit value (TLV) had been lowered to 1 part per million (ppm). Air samples were collected from the breathing zone of ten workers by use of diffusive samplers. The number of samples per participant was from three to 18. Samples were collected by use of 3M 3500 passive monitors and analysed with a gas chromatograph (GC). Sampling proved to be simple and inexpensive, and laboratory analysis of 1,3-butadiene (BD) permits the analysis of 0.01 ppm in an 8 h sample. Altogether, 117 samples were analysed, of which 32 samples were under the limit of quantification (LOQ), 81 samples were between the LOQ and 1 ppm, and four samples exceeded the TLV. This study draws a new picture about the exposure level during BD production and how well adherence to the new TLV is being implemented. The data demonstrated that the TLV was rarely exceeded.


An iterative method for the deconvolution of microcalorimeter thermograms.
An iterative method for the deconvolution of microcalorimetry thermograms suitable for small digital computers is presented. The method employs a measured impulse response function directly as the deconvolution kernel, thus explicit system simulation is not required. Data are presented showing the performance of the method and the exchange of signal-to-noise ratio for time resolution that is made when deconvolution techniques are employed. An improvement in the system time resolution of fifty times is demonstrated with measured data.


Silenced Myeloblastosis Protein Suppresses Oral Tongue Squamous Cell Carcinoma via the microRNA-130a/Cylindromatosis Axis.
Oral tongue squamous cell carcinoma (OTSCC) represents oral epithelial cell damage. Myeloblastosis (MYB) is involved in OTSCC. This study tried to probe roles of MYB in OSCC with potential axis. Expression of MYB and miR-130a in OTSCC was detected. Western blot analysis was utilized to determine epithelial-mesenchymal transition-related protein levels. Dual-luciferase reporter gene assay certified the target relation between miR-130a and CYLD. Moreover, xenograft tumors in nude mice were applied to confirm the in vitro experiments. Both MYB and miR-130a were highly expressed in OTSCC, which promoted cell growth. Meanwhile, silenced miR-130a discouraged cell development enhanced by overexpressed MYB. CYLD was poorly expressed in OTSCC and targeted by miR-130a. Additionally, MYB knockdown activated CYLD to suppress OTSCC by downregulating miR-130a. Our experiment supported that silenced MYB suppressed OTSCC malignancy by inhibiting miR-130a and activating CYLD. This investigation may provide novel insights for OTSCC treatment.


Characterization of 4,5-dihydro-1H-pyrazole derivatives by (13) C NMR spectroscopy.
The (13) C NMR resonances of 19 1-acyl-3-(2-nitro-5-substitutedphenyl)-4,5-dihydro-1H-pyrazoles, and 19 1-acyl-3-(2-amino-5-substituted)-4,5-dihydro-1H-pyrazoles, were completely assigned using the concerted application of one- and two-dimensional NMR experiments (DEPT, gs-HSQC and gs-HMBC).


Clinical and biochemical response to single infusion of clodronate in active rheumatoid arthritis--a double blind placebo controlled study.
To investigate the efficacy and tolerability of intravenous clodronate in patients with rheumatoid arthritis (RA). Twenty-six patients with active RA were randomly allocated to receive either a single iv. infusion of placebo or 600 mg clodronate. Efficacy and safety were assessed weekly during the following three weeks by clinical and laboratory evaluations. Serum osteocalcin and carboxyterminal propeptide of type I procollagen (markers of bone metabolism) were significantly decreased in the clodronate group at the end of the study, whereas the indices of disease activity including number of swollen joints, number of tender joints, patient's and doctor's estimation of condition (visual analogue scale), erythrocyte sedimentation rate and serum C-reactive protein level were not affected by clodronate treatment. No serious adverse effects were observed. A single infusion of clodronate in patients with RA was safe and caused a decline in the markers of bone metabolism, but this short-term treatment did not suppress disease activity. Results from recent clinical and preclinical studies, however, suggest that the anti-inflammatory efficacy of clodronate requires liposome encapsulation.


Immune response to 13-valent pneumococcal conjugate vaccine with a reduced dosing schedule.
The 7-valent pneumococcal conjugate vaccine (PCV7) has demonstrated effectiveness against pneumococcal illnesses when administered as 3 infant doses plus a toddler dose (3+1 schedule) or as an abbreviated schedule of 2 infant doses plus a toddler dose (2+1 schedule). The 13-valent pneumococcal conjugate vaccine (PCV13) is approved and World Health Organization-prequalified for administration in a 2+1 schedule when used as part of routine immunization programs. To summarize immunologic responses elicited by PCV13 administered in a 2+1 schedule and following 2 doses in a 3+1 schedule. Studies were double-blind, randomized, active-controlled, multicenter studies except the Mexico study (open-label, single-arm). In 2+1 studies, PCV13 was administered at 2, 4, and 12 (UK) or 3, 5, and 11 (Italy) months. In 3+1 studies (Spain and Mexico), assessment was made postdose 2 of the primary series (2, 4, and 6 months). The primary immunogenicity endpoint was the proportion of participants achieving serotype-specific antipolysaccharide immunoglobulin (Ig)G concentrations ≥ 0.35μg/mL (i.e., responders) 1 month postdose 2. Pneumococcal IgG geometric mean concentrations (GMCs), opsonophagocytic activity (OPA), and concomitant vaccine responses were assessed. PCV13 and PCV7 elicited comparable immune responses for the 7 common serotypes after 2 infant doses. The proportion of PCV13 responders postdose 2 was >85% for most of the 7 common and 6 additional serotypes, except common serotypes 6B (27.9-81.4%) and 23F (55.8-77.5%) and additional serotypes 3 (73.8-96.9%) and 6A (79.2-94.4%). Serotypes 6B and 23F elicited lower IgG GMCs postdose 2 compared with other serotypes; all serotypes demonstrated boosting posttoddler dose. All serotypes demonstrated functional activity; >95% of participants achieved OPA levels ≥ 1:8 postdose 2. Concomitant vaccine responses were similar between PCV13 and PCV7 groups. Immune responses elicited by PCV13 following 2 infant doses support transition from PCV7 to PCV13 in countries using a 2+1 schedule.


Modeling optical and thermal distributions in tissue during laser irradiation.
The propagation of light energy in tissues is an important problem in phototherapy, especially with the increased use of lasers as light sources. Often a slight difference in delivered energy separates a useless, efficacious, or disastrous treatment. Methods are presented for experimental characterization of the optical properties of a tissue and computational prediction of the distribution of light energy within a tissue. A standard integrating sphere spectrophotometer measured the total transmission, Tt, total reflectance, Rt, and the on-axis transmission, Ta, for incident collimated light that propagated through the dermis of albino mouse skin, over the visible spectrum. The diffusion approximation solution to the one-dimensional (1-D) optical transport equation computed the expected Tt and Rt for different combinations of absorbance, k, scattering, s, and anisotropy, g, and by iterative comparison of the measured and computed Tt and Rt values converged to the intrinsic tissue parameters. For example, mouse dermis presented optical parameters of 2.8 cm-1, 239 cm-1, and 0.74 for k, s, and g, respectively, at 488 nm wavelength. These values were used in the model to simulate the optical propagation of the 488-nm line of an argon laser through mouse skin in vivo. A 1-D Green's function thermal diffusion model computed the temperature distribution within the tissue at different times during laser irradiation. In vitro experiments showed that the threshold temperature range for coagulation was 60 degrees-70 degrees C, and the kinetics were first order, with a temperature-dependent rate constant that obeyed an Arrhenius relation (molar entropy 276 cal/mol-degrees K, molar enthalpy 102 kcal/mol). The model simulation agreed with the corresponding in vivo experiment that a 2-s pulse at 55 W/cm2 irradiance will achieve coagulation of the skin.


[Situation of pertussis in Valencian Community: an epidemic revival?].
Pertussis is a highly contagious vaccine-preventable disease. An increasing incidence has been reported in several countries around the world in the last few years. The aim of this study is to analyze the situation of pertussis in the Valencian Community (Spain), with the purpose of verifying the increased incidence of the illness. A descriptive analysis of probable and confirmed cases detected during 2011 was conducted. Methods used for Bordetella pertussis detection from clinical samples were: culture isolation, polymerase chain reaction (PCR)-based detection of bacterial DNA, and/or detection of specific IgM antibodies. The disease incidence and other epidemiological variables were estimated. These results were compared to data collected in previous years (2008-2010). The Epidemiological Surveillance Analysis and Microbiological Surveillance Network integrated systems of the regional Department of Health were used as sources of information. In 2011, 249 cases of pertussis were detected (incidence rate of 4.89×10(5) inhabitants). This rate is statistically significantly higher than those reported in 2008 (0.73×10(5) inhabitants), 2009 (0.53×10(5) inhabitants), and 2010 (0.53×10(5) inhabitants). The highest incidence rate was observed in cases younger than one year old (252.97×10(5) inhabitants), with marked differences compared to the rest of age groups. More than two-thirds (69%) of reported cases were confirmed by a laboratory test. Detection of specific serum IgM antibodies was positive in 10% of cases, culture isolation was positive in 17%, and PCR-based detection of bacterial DNA in 35% of cases. The results of this study show a clear increase of pertussis incidence in the Valencian Community during 2011.


Lactobacillus paracasei from koumiss ameliorates diarrhea in mice via tight junctions modulation.
Probiotics are gaining interest as alternative options for antibiotic or antiinflammatory drugs. Probiotics can affect the health of the host through metabolites and competitive inhibition adhesion of pathogenic microorganisms. Koumiss is an important part of the diet of Asian nomads, and is rich in a broad array of probiotics that can benefit the body. Mongolians have developed koumiss therapy to assist in the treatment of various diseases. In the present study, we investigate the beneficial effect of Lactobacillus paracasei, a strain isolated from koumiss, on a mouse model of diarrhea induced by Escherichia coli O8 (E. coli O8). Probiotics were isolated from Mongolian koumiss. The resistance of probiotics against acid, bile salts, gastric juice, and intestinal juice was evaluated. The mouse model of diarrhea was established by the intragastric administration of E. coli O8 after NaHCO3 treatment. L. paracasei was intragastrically administered before or after E. coli O8 exposure in mice. The plasma levels of diamine oxidase and zounlin were quantified using an enzyme-linked immunosorbent assay, and the integrity of the intestinal barrier and goblet cells of mice with diarrhea were observed using hematoxylin and eosin and Alcian blue periodic acid-Schiff staining. The expression of tight junction (TJ) proteins was detected by immunohistochemistry and Western blot. A total of five lactic acid bacteria and two yeast strains were isolated from koumiss, and L. paracasei was screened for animal experiments. Experimental results showed that L. paracasei could reduce the increase in diamine oxidase and zonulin caused by E. coli (P < 0.05); increase goblet cells and the expression of TJ proteins ZO-1, occludin, and claudin-1 (P < 0.05); increase the expression of mucin 2, oligomeric mucus/gel-forming (P < 0.05) protein; and reduce the level of inhibitor kappa B-alpha and myosin light-chain kinase. L. paracasei reduced the intestinal permeability, induced the expression of mucin 2, oligomeric mucus/gel-forming protein, and increased the number of goblet cells in mice by the upregulation of the expression of TJ proteins via the nuclear factor kappa B cells-myosin light-chain kinase signaling pathway.


Chronic idiopathic thrombocytopenic purpura (ITP) is a surgical disease.
We designed a study to assess the safety and long-term efficacy of laparoscopic splenectomy (LS) for the treatment of chronic idiopathic thrombocytopenic purpura (ITP). Over a period of 55 months, 104 patients underwent LS for chronic ITP. The perioperative course was documented and the long-term follow-up data were recorded. The mean age was 36.9 years (range, 8-83) and 72 patients were female. Patients were operated on with a mean platelet count of 110,000/ml. Fifty-one patients were operated on with a platelet count of < 100,000; 18 of them had a count of < 50,000/ml and 11 had a count of < 10,000/ml. There were no conversions to laparotomy. Bleeding occurred in 14 patients, and five of them received a blood transfusion. The mean operating time was 56.5 min (range, 25-240). There were minor complications in five patients and major complications in three. The mean hospital stay was 2.1 days (range, 0-13). Over a mean follow-up period of 36 months (range, 4-62), all but four patients were available for follow-up. Eighty-four patients are in complete remission. Seven patients are in partial remission, with a platelet count of 50,000-100,000 \ml without medical treatment. Eleven patients did not respond or relapsed following a short initial response; three of them underwent later removal of an accessory spleen, two with partial response. All but two relapses occurred within 70 days of the operation. LS is safe and effective for the treatment of chronic ITP and yields excellent long-term results. Until another form of treatment emerges, LS should be considered the treatment of choice for this disease and recommended to the patient at an early stage of the disease.


The influence of nanotopography on cell behaviour through interactions with the extracellular matrix - A review.
Nanotopography presents an effective physical approach for biomaterial cell manipulation mediated through material-extracellular matrix interactions. The extracellular matrix that exists in the cellular microenvironment is crucial for guiding cell behaviours, such as determination of integrin ligation and interaction with growth factors. These interactions with the extracellular matrix regulate downstream mechanotransductive pathways, such as rearrangements in the cytoskeleton and activation of signal cascades. Protein adsorption onto nanotopography strongly influences the conformation and distribution density of extracellular matrix and, therefore, subsequent cell responses. In this review, we first discuss the interactive mechanisms of protein physical adsorption on nanotopography. Secondly, we summarise advances in creating nanotopographical features to instruct desired cell behaviours. Lastly, we focus on the cellular mechanotransductive pathways initiated by nanotopography. This review provides an overview of the current state-of-the-art designs of nanotopography aiming to provide better biomedical materials for the future.


Characterization of an hyperpigmenting mutant of Monascus purpureus IB1: identification of two novel pigment chemical structures.
Monascus purpureus IB1 produces about 50-fold higher levels of azaphilone pigments than M. purpureus NRRL1596. Differently pigmented mutants were obtained from M. purpureus IB1 by nitrosoguanidine treatment. A highly pigmented strain, M. purpureus HP14, was found to lack the formation of the classical yellow and orange azaphilones and was found to produce only about 10% of the red azaphilone pigments. The intense color was associated with novel pigments as shown by high-performance liquid chromatography (HPLC). The addition of hexanoic acid to M. purpureus IB1 resulted in higher volumetric and specific red pigment productivity, but in a complete absence of the classical orange azaphilones, while the classical yellow and red azaphilone pigments were severely reduced; new peaks corresponding to less hydrophobic pigments were found in hexanoic-supplemented cultures by HPLC. Purification of pigments from hexanoic-supplemented cultures showed the presence of five new pigments as indicated by the absorption spectra and HPLC analysis. Two of them, R3 and Y3, were characterized by nuclear magnetic resonance as 9-hexanoyl-3-(2-hydroxypropyl)-6a-methyl-9,9a-dihydro-6H-furo[2,3-h]isochromene-6,8(6aH)-dione and 4-[2,4-dihydroxy-6-(3-hydroxybutanethioyloxy)-3-methylphenyl]-3,4-dihydroxy-3,6-dimethylheptanoic acid. These pigments were also found to be present in cultures of the high-producing mutant M. purpureus HP14. These new pigments are less hydrophobic than the classical azaphilones and may have better properties as natural colorants in the food industry.


Hyperparathyroidism presenting as a large bone tumour. A case report.
A 59-year-old man, who presented to hospital with a large expansile bone tumour over the left elbow and a mass in the right side of the neck, was eventually found to have parathyroid adenoma manifesting clinically as severe hypercalcaemia. Histological examination of a section of the neck mass showed parathyroid adenoma and the bone biopsy specimen revealed a 'brown tumour', consistent with hyperparathyroid bone disease.


Valorization of waste streams and C1 gases for sustainable food nutrients and value-added compounds production: Acetate as a promising intermediate.
Resource recovery from waste streams and C1 gaseous substrates (CO2, CO and CH4) are of extensive interest due to the insufficient utilization and threats to the environment. From a perspective of sustainability, valorization of waste streams and C1 gases into target energy-rich value-added products in a sustainable way offers tempting approaches for simultaneously alleviating the environmental problems and achieving a circular carbon economy, while it still suffers from the complicated compositions of feedstocks or the low solubility of gaseous feeds. Recently, a C2 feedstock-based biomanufacturing serving acetate as potential next-generation platform has received much attention, where different gaseous or cellulosic wastes are recycling into acetate and then be further processed into a wide range of valuable long-chain compounds. The different alternative waste-processing technologies that are being developed to generate acetate from various wastes or gaseous substrates are summarized, in which gas fermentation and electrochemical reduction from CO2 represent the most promising routes for achieving high acetate yield. The recent advances and innovations in metabolic engineering for acetate bioconversion into various bioproducts ranging from food nutrients to value-added compounds were then highlighted. The challenges and promising strategies to reinforce microbial acetate conversion were also proposed, which conferred a new horizon for future food and chemical manufacturing with reduced carbon footprint.