Aspirin/antiplatelet agent use improves disease-free survival and reduces the risk of distant metastases in Stage II and III triple-negative breast cancer patients.

PURPOSE: The objective is to define the therapeutic role of antiplatelet agents in a triple-negative breast cancer (TNBC) population. METHODS: We performed retrospective analysis using the UTSW TNBC registry containing data from 222 Stage II-III TNBC patients treated between 1998 and 2016. Univariate analysis and multivariable logistic regression models were constructed to identify factors associated with disease-free survival (DFS), distant metastases rate (DMR), and overall survival outcomes. Antiplatelet drug use was determined by review of electronic medical records. RESULTS: A total of 65 patients used antiplatelet (AP) agents, and 157 patients did not use AP agents. Median follow-up for AP and non-AP groups was 41.3 and 40.9 months, respectively. There was an improvement in the AP group compared with the control group in 5-year DFS (80.4% at 5 years compared with 62.3% in the control group, p = 0.04) and 5-year DMR (8.8 vs. 31.9%, p = 0.007). In multivariate analysis, AP use was found to be significantly associated with improvements in DFS and DMR. CONCLUSIONS: We illustrate that antiplatelet agent use improves DMR and DFS among a stage II and III TNBC population despite our short follow-up evaluation. Longer follow-up evaluation will be required to determine additional outcome advantage for antiplatelet agent use. Our findings support consideration of investigation of antiplatelet therapy as an adjunctive therapy for TNBC at high risk for disease recurrence.

Suppression of histamine-induced tachypnoea in the rhesus monkey by sibenadet: no role for dopamine D2 receptors.

1. Sibenadet (Viozan), a dual dopamine D(2)/beta(2)-adrenoceptor agonist, suppresses histamine-induced tachypnoea in the dog by activating dopamine D(2) receptors. We here compare the effects of sibenadet and formoterol, a selective beta(2)-adrenoceptor agonist, on histamine-induced tachypnoea in the rhesus monkey. 2. Anaesthetized, spontaneously breathing, rhesus monkeys were set up for measuring airways resistance, respiratory rate, blood pressure and heart rate. 3. Both sibenadet and formoterol administered by aerosol, induced inhibition of the bronchoconstrictor response to aerosolized methacholine accompanied by tachycardia. Sibenadet, but not formoterol, also reduced blood pressure. 4. Administration of histamine by inhalation induced tachypnoea which was accompanied by bronchoconstriction. Tachypnoea to histamine was suppressed by both sibenadet and formoterol at doses which manifest anti-bronchoconstrictor activity. These effects and the accompanying tachycardia but not the hypotension induced by sibenadet were abolished by pretreatment with propranolol. 5. The dopamine D(2) receptor agonist, quinagolide, did not suppress tachypnoea to histamine despite inducing a fall in blood pressure indicating activation of dopamine D(2) receptors. 6. Thus, both sibenadet and formoterol suppress histamine-evoked tachypnoea in the rhesus monkey. The effect arises exclusively through activation of beta(2)-adrenoceptors and probably reflects the anti-bronchoconstrictor effects of these agents. The results reveal a fundamental difference in the role of dopamine receptors in the airways of dog and rhesus monkey.

First Report of Leaf Blight Caused by Phoma exigua on Acroptilon repens in Turkey.

Acroptilon repens (L.) DC. (Russian knapweed, synonym Centaurea repens L., family Asteraceae) is becoming a noxious weed in wheat fields in Turkey. Because it is also an invasive weed in the northwestern United States, A. repens is a target of biological control efforts. In the summer of 2002, approximately 20 dying A. repens plants were found on a roadside near Cankiri, Turkey (40°21'41″N, 33°31'8″E, elevation 699 m). No healthy plants were found in the immediate area. Dying plants had irregular, charcoal-colored, necrotic lesions at the leaf tips and margins, and frequently, whole leaves and plants were necrotic. Symptomatic leaves were air-dried and sent to the Foreign Disease-Weed Science Research Unit, USDA/ARS, Fort Detrick, MD. There, diseased leaves were surface-disinfested and placed on moist, filter paper in petri dishes. Pycnidia producing one-celled hyaline conidia were observed after 4 to 5 days. Internal transcribed spacer regions 1 and 2, including the 5.8S ribosomal DNA, were sequenced for isolate 02-059 (GenBank Accession No. AY367351). This sequence was identical to sequences in GenBank from six well-characterized strains of Phoma exigua Desmaz (1). Morphology was also consistent with P. exigua (2) with the exception that material grown on alfalfa twigs produced pycnidia with 1 to 4 ostioles with necks as much as 80 µm long. Typically, pycnidia of P. exigua produced on agar have 1 to 2 ostioles that lack necks. Conidial dimensions on alfalfa were 4.1 to 7.6 × 1.7 to 3.2 µm (average 5.5 × 2.4 µm). Images of the fungus are located at http://nt.ars-grin.gov under the section 'Fungi Online'. Stems and leaves of 20 3-week-old plants were spray inoculated with an aqueous suspension (1 × 107 conidia per ml) of conidia harvested from 25-day-old cultures grown on acidified potato dextrose agar, and placed in an environmental chamber at 25°C with constant light and continuous dew for 3 days. Plants were then moved to a greenhouse bench and watered twice daily. After 6 days, symptoms were observed on all plants. Once symptoms had progressed to the midveins of the leaves, the disease progressed rapidly on the plants, indicating the possibility of systemic infection or systemic movement of toxins. Phoma exigua was reisolated from the stems, petioles, and leaves of all inoculated plants. In a separate test, 12 plants were inoculated as described above, and 8 additional plants were sprayed with water only. After inoculation, plants were handled as described above. The first lesions developed after 3 days on all except the youngest leaves of inoculated plants. After 10 days, three inoculated plants were dead, and all other inoculated plants had large necrotic lesions. No symptoms developed on control plants. This isolate of Phoma exigua is a destructive pathogen on A. repens, and severe disease can be produced by inoculation of foliage with an aqueous suspension of conidia. These characteristics make this isolate of P. exigua a potential candidate for biological control of this weed in Turkey and the United States. To our knowledge, this is the first report of P. exigua on A. repens in Turkey. A voucher specimen has been deposited with the U.S. National Fungus Collections (BPI 843350). References: (1) E. C. A. Abeln et al. Mycol. Res. 106:419, 2002. (2) H. A. Van der Aa et al. Persoonia 17:435, 2000.

Pleomorphic adenoma of the lacrimal gland: case report.

Lacrimal gland tumours are rare. We present a case of a lacrimal gland pleomorphic adenoma in a 19-year-old man. The tumour was removed and he has made an uncomplicated recovery, with no sign of recurrence after nine months of follow-up. We will keep him under long-term review.

Dendryphion penicillatum and Pleospora papaveracea, Destructive Seedborne Pathogens and Potential Mycoherbicides for Papaver somniferum.

ABSTRACT Dendryphion penicillatum and Pleospora papaveracea were isolated from blighted Papaver somniferum and Papaver bracteatum plants grown in growth chambers and the field in Beltsville, MD. The etiology of the diseases was determined, and the fungi are being investigated as potential mycoherbicides to control the narcotic opium poppy plant. P. papaveracea is known to be a highly destructive seedborne pathogen of Papaver somniferum, causing seedling blight, leaf blight, crown rot, and capsule rot. Single conidia and ascospores were isolated and cultures established from naturally infested seed and diseased foliage and pods of opium poppy from Iran, Colombia, Venezuela, Sweden, India, and the United States (Maryland and Washington). Mycelia and conidia of P. papaveracea and D. penicillatum produced on necrotic leaf tissues appear morphologically similar, and the fungi were previously considered to be anamorph and teleomorph. However, no anamorph/teleomorph connection could be established, and the fungi appear to be distinct taxa. P. papaveracea produced conidia, mature pseudothecia, and chlamydospores in vitro and on infected stems. D. penicillatum produced conidia, microsclerotia, and macronematous conidiophores. Although both fungi were pathogenic to three poppy cultivars, conidial inoculum from P. papaveracea cultures was more virulent than conidial inoculum from D. penicillatum. Eight-week-old plants became necrotic and died 8 days after inoculation with a conidial suspension of P. papaveracea at 2 x 10(5) spores per ml. Disease severity was significantly enhanced by inoculum formulations that contained corn oil, by higher conidial inoculum concentrations, and by increased wetness periods. Symptoms on plants inoculated with either pathogen included leaf and stem necrosis, stem girdling, stunting, necrotic leaf spots, and foliar and pod blight. Inoculated seedlings exhibited wire stem, damping-off, and root rot. Conidia, and less frequently pseudothecia, of P. papaveracea and conidia of D. penicillatum were produced abundantly on inoculated, necrotic foliage, pods, and seedlings. Cultures from conidia or ascospores reisolated from these tissues consistently produced fungi whose morphologies were typical of the fungus from which the inoculum was derived.

Cardiopulmonary baroreceptor control of muscle sympathetic nerve activity in heat-stressed humans.

Whole body heating decreases central venous pressure (CVP) while increasing muscle sympathetic nerve activity (MSNA). In normothermia, similar decreases in CVP elevate MSNA, presumably via cardiopulmonary baroreceptor unloading. The purpose of this project was to identify whether increases in MSNA during whole body heating could be attributed to cardiopulmonary baroreceptor unloading coincident with the thermal challenge. Seven subjects were exposed to whole body heating while sublingual temperature, skin blood flow, heart rate, arterial blood pressure, and MSNA were monitored. During the heat stress, 15 ml/kg warmed saline was infused intravenously over 7-10 min to increase CVP and load the cardiopulmonary baroreceptors. We reported previously that this amount of saline was sufficient to return CVP to pre-heat stress levels. Whole body heating increased MSNA from 25 +/- 3 to 39 +/- 3 bursts/min (P < 0. 05). Central blood volume expansion via rapid saline infusion did not significantly decrease MSNA (44 +/- 4 bursts/min, P > 0.05 relative to heat stress period) and did not alter mean arterial blood pressure (MAP) or pulse pressure. To identify whether arterial baroreceptor loading decreases MSNA during heat stress, in a separate protocol MAP was elevated via steady-state infusion of phenylephrine during whole body heating. Increasing MAP from 82 +/- 3 to 93 +/- 4 mmHg (P < 0.05) caused MSNA to decrease from 36 +/- 3 to 15 +/- 4 bursts/min (P < 0.05). These data suggest that cardiopulmonary baroreceptor unloading during passive heating is not the primary mechanism resulting in elevations in MSNA. Moreover, arterial baroreceptors remain capable of modulating MSNA during heat stress.

The role of excitatory amino acid transmission within the rostral ventromedial medulla in the antinociceptive actions of systemically administered morphine.

Two classes of neurons with distinct responses to opioids have been identified in the rostral ventromedial medulla (RVM), a region with a well-documented role in nociceptive modulation. 'Off-cells' are activated, indirectly, by opioids, and are likely to exert a net inhibitory effect on nociceptive processing. 'On-cells' are directly inhibited by opioids, and there is evidence that these neurons can, under various conditions, facilitate nociception. We showed previously that excitatory amino acid (EAA) neurotransmission is crucial to the nocifensor reflex-related on-cell burst, but plays little role in maintaining the ongoing activity of off-cells. The aim of the present study was to determine whether EAA transmission contributes to the activation of off-cells and the concomitant behavioral antinociception that follow systemic opioid administration. The non-selective EAA receptor antagonist kynurenate was infused into the RVM (1 nmol/200 nl) of lightly anesthetized rats prior to administration of morphine (1.5 mg/kg i.v). Off-cell, on-cell and neutral cell firing, as well as, tail flick response (TF) latencies were recorded. Kynurenate, significantly attenuated the characteristic opioid activation of off-cells. As a group, off-cells in kynurenate-treated animals did not become continuously active, and continued to exhibit tail-flick related pauses in firing. On-cell and neutral cell responses to opioid administration were unchanged. Opioid inhibition of the TF was also reduced, although baseline TF latency was unaffected, by RVM kynurenate. EAA-mediated activation of off-cells, thus has an important role in opioid analgesia. The present observations underscore the importance of excitatory interactions among opioid-sensitive nociceptive modulatory circuits for systemic morphine analgesia, suggesting that such interactions are a critical factor in the synergistic relationships which have been demonstrated among these sites.

The discovery of orally available thrombin inhibitors: optimisation of the P1 pharmacophore.

Thrombin inhibitors have been designed with the replacement of the strongly basic guanidine P1 pharmocophore with a group that exploits the lipophilicity of the S1 pocket. The approach has lead to the discovery of potent thrombin inhibitors demonstrating good intra-duodenal absorption.

Studies towards the identification of potent, selective and bioavailable thrombin inhibitors.

The application of selection criteria, based on potency and physicochemical parameters, to a candidate library of thrombin inhibitors is described. The utility of the approach is exemplified by the discovery of a potent, selective and bioavailable thrombin inhibitor 62.

The discovery of orally available thrombin inhibitors: studies towards the optimisation of CGH1668.

The chemical optimisation of CGH1668 1 is described employing an in vivo model of absorption to determine the influence on bioavailability of single point modifications to five key molecular templates. The discovery of an orally bioavailable and selective thrombin inhibitor, 24, highlights the utility of this approach.

Three-dimensional residual strain in midanterior canine left ventricle.

All previous studies of residual strain in the ventricular wall have been based on one- or two-dimensional measurements. Transmural distributions of three-dimensional (3-D) residual strains were measured by biplane radiography of columns of lead beads implanted in the midanterior free wall of the canine left ventricle (LV). 3-D bead coordinates were reconstructed with the isolated arrested LV in the zero-pressure state and again after local residual stress had been relieved by excising a transmural block of tissue. Nonhomogeneous 3-D residual strains were computed by finite element analysis. Mean +/- SD (n = 8) circumferential residual strain indicated that the intact unloaded myocardium was prestretched at the epicardium (0.07 +/- 0.06) and compressed in the subendocardium (-0.04 +/- 0.05). Small but significant longitudinal shortening and torsional shear residual strains were also measured. Residual fiber strain was tensile at the epicardium (0.05 +/- 0.06) and compressive in the subendocardium (-0.01 +/- 0.04), with residual extension and shortening, respectively, along structural axes parallel and perpendicular to the laminar myocardial sheets. Relatively small residual shear strains with respect to the myofiber sheets suggest that prestretching in the plane of the myocardial laminae may be a primary mechanism of residual stress in the LV.

Functional foods.

The concept of functional foods containing specific physiologically active components originated in Japan as a means of improving the health of the nation and thus, reducing the drain on the economy caused by escalating health costs. Some aspects of the Japanese physiologically functional foods programme will be discussed. There is a growing interest in this area from food manufacturers both in Europe and the USA, and a few functional food products are appearing on the market. It is likely that there will be competition between the food industry and the pharmaceutical industry in the grey area of overlapping interest. The regulatory aspects concerning functional foods have yet to be satisfactorily resolved, both in Europe and the USA, but consumer pressure promises to accelerate the incorporation of the concept of functional foods into western food regulations. There are early indications that in Europe, consumer perception of the benefits of functional foods compared to normal foods will not be the same as in Japan, nor will the consumer be as receptive. Some consumer groups question the necessity of such foods from a health point of view and see the concept rather as a marketing tool. We are likely to see a number of foods for which anti-carcinogenic and other well defined properties are likely to be claimed. The active components will be present in the raw materials or produced or enhanced by the manufacturing process.

Comparison of two techniques for measuring two-dimensional strain in rat left ventricles.

Measurements of regional deformation in the left ventricle are needed to understand the structural basis of ventricular function. Two techniques were employed to measure two-dimensional strain in the intact, beating rat heart. Rats were anesthetized and ventilated, and the chest of each rat was opened. Homogeneous two-dimensional strains were measured during the cardiac cycle relative to end diastole with either a triangle of miniature (0.3-0.5 mm) piezoelectric crystals implanted at midwall or with three epicardial surface markers imaged with a 60-Hz video system. Average heart rate was 303 +/- 37 beats/min, end-diastolic pressure was 2 +/- 2 mmHg, and peak-systolic pressure was 106 +/- 31 mmHg in all of the hearts. In general, strains during the cardiac cycle showed similar trends to those previously reported in the dog. The magnitudes of peak systolic cardiac strains on the epicardium and at midwall were -0.076 +/- 0.055, -0.068 +/- 0.014 (circumferential), -0.102 +/- 0.040, -0.082 +/- 0.039 (longitudinal), and 0.065 +/- 0.016, 0.064 +/- 0.043 (in-plane shear). There were mechanical side effects due to the crystal implantation that may limit the usefulness of this technique in its present form in the contracting rat heart. The epicardial surface technique does not have these side effects and will allow measurements of regional systolic cardiac function in rats with pathological interventions or genetic modifications that may alter regional ventricular function.

The use of thromboembolic prophylaxis in oral and maxillofacial surgery.

OBJECTIVES: To investigate the use of thromboembolic prophylaxis in oral and maxillofacial surgery. DESIGN: Postal questionnaire. SETTING: Oral and maxillofacial surgery departments in the UK. SUBJECTS: Consultant Oral and Maxillofacial surgeons as listed in the BAOMS Handbook of Hospitals, Oral and Maxillofacial Surgery. MAIN OUTCOME MEASURES: Factors used in the decision to use thromboembolic prophylaxis and the methods of prophylaxis used. RESULTS: The response rate was 73%. Previous thromboembolism (85% of respondents), prolonged immobilisation (79%) and length or magnitude of operation (78% and 74%) were the most commonly used risk factors, in the decision to use prophylaxis against DVT. Pre-operative trauma, cardiovascular disease and varicose veins were the risk factors most infrequently used. No forms of prophylaxis were used by 18% of respondents, with the remaining respondents using a variety of methods. The most widely used methods were graduated elastic compression stockings (74%) and low dose subcutaneous heparin (73%). CONCLUSION: The majority of known risk factors were taken into account when considering the use of prophylaxis against DVT. The methods of thromboembolic prophylaxis used in oral and maxillofacial surgery are considered to provide a satisfactory degree of protection, in moderate and low risk patient groups.

Direct bonding of arch bars in the management of maxillomandibular injuries.

The shortcomings of the conventional arch bars for the treatment of maxillomandibular injuries are described. A mesh-backed arch bar bonded to the teeth is recommended as a means of overcoming these problems.