Retinoids inhibit the respiratory burst and degranulation of stimulated human polymorphonuclear leukocytes

Retinoids exhibit a wide spectrum of activities, including antiinflammatory properties. We have investigated the effect of retinoic acid (RA) and retinyl acetate (RAc) on the production of reactive oxygen metabolites and the release of lysosomal enzymes by human polymorphonuclear leukocytes (PMN). Incubation of PMN with RAc or RA (1–100 μM) caused a dose-dependent inhibition (upto 90%) in O ₂ ^? production and chemiluminescence induced by phorbol myristate acetate (PMA), N-formyl-methionylleucyl-phenylanaline (fMLP), opsonized zymosan or ionophore A23187. Both retinoids (1–100 μM) also inhibited, in a dose-dependent way, degranulation induced by fMLP (upto 85% at the highest concentration of RA). These inhibitory effects appear irreversible, since they persist after the drugs are removed and the cells washed before stimulation. Inhibitors of cyclo-oxygenase activity such as acetylsalicylic acid and indomethacin did not influence the effects of RAc. In contrast, BW755, an inhibitor of both cyclooxygenase and lipoxygenase, reversed the inhibitory action of RAc, suggesting that the effect of retinoids occurs possibly through the mediation of lipoxygenase products. The modulation of PMN oxidative metabolism and degranulation might help explain the antiinflammatory properties of retinoids.     

Conduction disorders and sites of calcification of the mitral ring: 2-dimensional echocardiographic study

The association between a calcified mitral annulus and impairment of cardiac impulse transmission is well known. However informations on the relations between the site of mitral calcification and conduction disturbance are still scanty. Twenty-nine patients (22 women and 7 men, mean age 64.4 +/- 13.1 years) with M-mode and two-dimensional echocardiographic evidence of mitral annulus calcifications were studied. The "annulus" was subdivided in 4 segments: antero-medial, antero-lateral, postero-medial and postero-lateral. Conduction disturbances were present in 15 patients (51.7%). Atrio-ventricular or intra-ventricular conduction defects were found in 12 out of 15 patients with calcifications of the antero-medial segment and only in 3 of 14 subjects without antero-medial calcifications (P less than .01). The presence of conduction defects therefore seems to be significantly increased when calcium deposition is located near the conduction system.     

Long-term therapy with deflazacort in chronic sarcoidosis.

PURPOSE: To evaluate the long-term action of deflazacort (DF), a new calcium-sparing and bone-saving corticosteroid, in chronic sarcoidosis patients needing prolonged therapy. PATIENTS AND METHODS: 40 patients with chronic histologically proved sarcoidosis requiring long-term corticosteroid therapy were treated with DF and followed for a mean period of 958 +/- 515 days (range 382-2, 068). The indication for giving corticosteroid therapy was pulmonary impairment in most (36), but also other events including hypercalcemia (2), kidney stones (5, 2 with recurrent colic), uveitis (2), lupus pernio (3), suspected heart impairment (5), hypersplenism (1), and other causes. Follow-up examination included serial ACE, chest x-ray, 67Ga lung scan, pulmonary function data, serum and urinary calcium levels. Eleven patients (UT group) were not receiving glucocorticoids when first seen at our clinic; 29 patients (PT group) were on therapy with glucocorticoids (27 wity prednisone, 2 with DF) for 870 +/- 1,128 days (range 27-4,310) RESULTS: In the PT group, DF maintained the good results previously obtained with prednisone; in this group, chest x-ray film showed improvement in 16 patients, 67Ga lung scan was better in 13, while worsening chest x-ray film findings in 1 and 67Ga lung scan in 2 was seen coincident with DF tapering. Respiratory function data showed a mild nonsignificant improvement. SACE decreased significantly from 114.6 +/- 38.7 to 91.5 +/- 37.9 nM/ml/min (p less than .05). In the UT group the results were better, as expected in a population where the action of corticosteroids did not influence the first observation. FVC increased significantly from 76.3 +/- 13.0 to 89.9 +/- 19.5 percent predicted (p less than .01); the 67Ga lung scan and chest x-ray film findings improved in all but 1 patient, and ACE dropped significantly (p less than .01) from 131.8 +/- 46.3 to 83.7 +/- 25.0. In both groups the side effects were mild, and only 2 patients discontinued the treatment, 1 for gastric ulcer, and the other for amenorrhea plus a 14 kg weight gain. CURRENT STATUS: One patient died of cancer, 9 discontinued treatment (5 because therapy was no longer necessary, 2 for the above described side effects, 2 for non-drug-related reasons), 4 dropped out and were last seen when taking DF 22.5, 18, 12 and 6 mg daily respectively. Twenty-six are continuing the drug on a long-term basis at the current mean daily dose of 12.1 +/- 7.3 mg (range 3-30). In a number of these, an attempt to discontinue DF resulted in a sarcoid relapse, and DF was restarted. CONCLUSION: DF is a good and safe approach to the long-term corticosteroid therapy of sarcoidosis.     

Comparison of two-dimensional echocardiography, angiocardioscintigraphy and cineventriculography in the study of left ventricular wall motion in ischemic cardiopathy

Thirty-two patients with non acute myocardial infarction (inferior in twenty, anterior in ten, anterior and inferior in two) were studied with contrast left ventriculography, two-dimensional echocardiography and radionuclide angiography to assess left ventricular wall motion. We adopted the CASS criteria for the standard left ventriculography, and the Mayo Clinic classification for the echocardiographic study. Radionuclide angiography studies were obtained in left anterior oblique view; the images were evaluated with the use of Walsh-Hadamard transform; the left ventricle was divided in basal and apical septal, apical, posterolateral, posterobasal and two central segments. We tried to correlate the findings of the three techniques both for single segments and larger regions made of contiguous segments. Left ventricular angiography and two-dimensional echocardiography showed a fair concordance for both anterobasal and posterolateral left ventricular wall, whereas for the septal, apical and posterolateral regions contrast and radionuclide angiography had the best correlation. Compared to left ventricular angiography two-dimensional echocardiography shows better sensitivity than radionuclide angiography; the latter is more specific in defining left ventricular wall motion. The two non invasive techniques are therefore helpful in the evaluation of wall motion and their role is complementary.     

Spontaneous and pronase‐induced HER2 truncation increases the trastuzumab binding capacity of breast cancer tissues and cell lines

A subgroup of HER2‐overexpressing breast tumours co‐expresses p95 $^{{\rm{HER2}}}$ , a truncated HER2 receptor that retains a functional HER2 kinase domain but lacks the extracellular domain, thus impairing trastuzumab binding. We evaluated p95 $^{{\rm{HER2}}}$ expression in 99 frozen breast carcinoma samples by western blot analysis. The HER2‐positive cell line BT474 treated with pervanadate or pronase was used as a positive control for p95 $^{{\rm{HER2}}}$ expression. Immunohistochemistry was performed on parallel formalin‐fixed, paraffin‐embedded sections of the same case series using antibodies directed against either the intra‐ or extra‐cellular binding domain of HER2. In particular, biotinylated trastuzumab (BiotHER) was used to evaluate the binding capacity of the humanized antibody. To avoid a subjective evaluation of the score values and the percentage of immunostained cells, the slides were scanned and automatically analysed. The number of cases with HER2 overexpression (score 3+) and HER2 gene amplification was higher in the p185 $^{{\rm{HER2}}}$ ‐positive/p95 $^{{\rm{HER2}}}$ ‐positive samples than in the p185 $^{{\rm{HER2}}}$ ‐positive/p95 $^{{\rm{HER2}}}$ ‐negative group. Automated analysis confirmed a significantly higher percentage of 3+ scored cells in p95 $^{{\rm{HER2}}}$ ‐positive cases. Conversely, the percentage of 2+ scored cells was higher in p95 $^{{\rm{HER2}}}$ ‐negative cases. The status of the HER2 extracellular domain was then studied using flow cytometry on BT474 cells after pronase enzymatic digestion using trastuzumab and pertuzumab, while the presence of HER2‐HER3 dimers was studied using a proximity‐ligation assay. In vitro experiments showed that short‐term pronase digestion of BT474 cells produced two HER2 fragments (of 95 and 150 kDa, detectable in tissue specimens as well), increased the binding affinity of trastuzumab, reduced the rate of HER2–HER3 dimers, and did not interfere with pertuzumab‐binding capacity. In conclusion, the presence of p95 $^{{\rm{HER2}}}$ as detected by western blot analysis does not compromise the immunohistochemical detection of HER2. Our data suggest that a reduction of the receptor steric hindrance as induced by enzymatic shedding may facilitate the binding capacity of trastuzumab. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Influence of upper airway size on volume exhaled under negative pressure during evaluation of upper airway collapsibility

Study objectives  

It has been shown that volume exhaled in the first 0.5 s after application at the mouth of 5 cmH₂O negative pressure (V,NEP_0.5) during wakefulness strongly reflects critical pressure (Pcrit) during sleep but only in males with neck circumference (NC) >37 cm. The aim of this study was to establish the relationship between upper airway (UA) size and V,NEP_0.5, to obtain V,NEP_0.5 values as percent predicted and then correlate them with Pcrit obtained in the same subjects.     

Role of precise spike timing in coding of dynamic vibrissa stimuli in somatosensory thalamus

Rats discriminate texture by whisking their vibrissae across the surfaces of objects. This process induces corresponding vibrissa vibrations, which must be accurately represented by neurons in the somatosensory pathway. In this study, we investigated the neural code for vibrissa motion in the ventroposterior medial (VPm) nucleus of the thalamus by single-unit recording. We found that neurons conveyed a great deal of information (up to 77.9 bits/s) about vibrissa dynamics. The key was precise spike timing, which typically varied by less than a millisecond from trial to trial. The neural code was sparse, the average spike being remarkably informative (5.8 bits/spike). This implies that as few as four VPm spikes, coding independent information, might reliably differentiate between 10⁶ textures. To probe the mechanism of information transmission, we compared the role of time-varying firing rate to that of temporally correlated spike patterns in two ways: 93.9% of the information encoded by a neuron could be accounted for by a hypothetical neuron with the same time-dependent firing rate but no correlations between spikes; moreover, 93.4% of the information in the spike trains could be decoded even if temporal correlations were ignored. Taken together, these results suggest that the essence of the VPm code for vibrissa motion is firing rate modulation on a submillisecond timescale. The significance of such a code may be that it enables a small number of neurons, firing only few spikes, to convey distinctions between very many different textures to the barrel cortex.     

Dose-dense adjuvant chemotherapy in HER2-positive early breast cancer patients before and after the introduction of trastuzumab: Exploratory analysis of the GIM2 trial

Dose-dense adjuvant chemotherapy is standard of care in high-risk early breast cancer patients. However, its role in HER2-positive patients is still uncertain. In this exploratory analysis of the GIM2 trial, we investigated the efficacy of dose-dense chemotherapy in HER2-positive breast cancer patients with or without exposure to trastuzumab. In the GIM2 trial, node-positive early breast cancer patients were randomized to receive four cycles of (fluorouracil)epirubicin/cyclophosphamide followed by four cycles of paclitaxel administered every 2 (dose-dense) or 3 (standard-interval) weeks. After approval of adjuvant trastuzumab, protocol was amended in April 2006 to allow use of trastuzumab for 1 year after chemotherapy completion in HER2-positive patients. The efficacy of dose-dense chemotherapy in terms of disease-free survival (DFS) and overall survival (OS) was assessed according to HER2 status and trastuzumab use. Out of 2,003 breast cancer patients, HER2 status was negative/unknown in 1,551 patients; among the 452 patients with HER2-positive breast cancer, chemotherapy alone or followed by trastuzumab was given to 320 and 132 patients, respectively. Median follow-up was 8.1 years. No significant interaction between HER2 status, trastuzumab use and chemotherapy treatment was observed for both DFS (p = 0.698) and OS (p = 0.708). Nevertheless, there was no apparent benefit in the HER2-positive group treated with trastuzumab (DFS: HR, 0.99; 95% CI 0.52–1.89; OS: HR, 0.95; 95% CI 0.37–2.41). Although dose-dense chemotherapy was associated with a significant survival improvement in high-risk breast cancer patients, its benefit appeared to be smaller (if any) in patients with HER2-positive disease who received adjuvant trastuzumab.     

Axillary vein thrombosis as the first clinical manifestation of inflammatory breast cancer: report of a case

Inflammatory breast cancer is a rare and aggressive form of breast cancer. Venous thromboembolism is often related to cancer conditions but this report presents a case in which the thromboembolic event predicted the diagnosis of cancer. A 48-year-old female was admitted with the evidence of acute right axillary vein thrombosis. There was also erythema and edema of the skin of the right breast. Further evidence revealed a case of inflammatory breast cancer. The patient underwent anticoagulant therapy, and neoadjuvant systemic chemotherapy was initiated. The patient underwent extensive unilateral mastectomy following neoadjuvant chemotherapy. Follow-up (after 2 months of anticoagulation therapy for deep vein thrombosis) revealed recanalization of the right axillary vein, without evidence of residual thrombus. A case of acute vein thrombosis as the first manifestation of breast cancer may delay the diagnosis and subsequent appropriate treatment.     

Low molecular weight heparin improves healing of chronic venous ulcers especially in the elderly

Venous ulcers are common, especially in the elderly, accounting for more than 50% of all lower extremity ulcers with important socioeconomic problems. Improving extracellular matrix functioning, by heparin administration, seems to be a way to support wound healing. A total of 284 patients with venous ulcers were recruited in a 4‐year period. All patients were subjected to the most appropriate treatment after considering their preference (compression therapy followed or not by vein surgery). Patients were randomised into two groups of 142 persons in each (group A and group B as cases and controls, respectively). Patients of group A, in addition to the basic treatment as described earlier, received administration of nadroparin 2850 IU/0.3 ml through subcutaneous injection once a day for 12 months, whereas group B patients received basic treatment alone. Healing was assessed by means of direct ulcer tracing with computerised planimetry. Group A showed a healing rate of 83·80% at 12 months, whereas that of group B was 60·56%. Results by age group surprisingly showed that the group of older patients took the most advantage from long‐term treatment with low molecular weight heparin; this group also had lowest recurrence rate.