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Abstract Background Bioinformatic analyses of expression control sequences in promoters of co-expressed or functionally related genes enable the discovery of common regulatory sequence motifs that might be involved in co-ordinated gene expression. By studying promoter sequences of the human ribosomal protein genes we recently identified a novel highly specific Localized Tandem Sequence Motif (LTSM). In this work we sought to identify additional genes and LTSM-binding proteins to elucidate potential regulatory mechanisms. Results Genome-wide analyses allowed finding a considerable number of additional LTSM-positive genes, the products of which are involved in translation, among them, translation initiation and elongation factors, and 5S rRNA. Electromobility shift assays then showed specific signals demonstrating the binding of protein complexes to LTSM in ribosomal protein gene promoters. Pull-down assays with LTSM-containing oligonucleotides and subsequent mass spectrometric analysis identified the related multifunctional nucleotide binding proteins NonO and SFPQ in the binding complex. Functional characterization then revealed that LTSM enhances the transcriptional activity of the promoters in dependency of the distance from the transcription start site. Conclusions Our data demonstrate the power of bioinformatic analyses for the identification of biologically relevant sequence motifs. LTSM and the here found LTSM-binding proteins NonO and SFPQ were discovered through a synergistic combination of bioinformatic and biochemical methods and are regulators of the expression of a set of genes of the translational apparatus in a distance-dependent manner.

We tested the clinically relevant diagnostic accuracy of a new electrocardiographic (ECG) recording system incorporating all 10 ECG electrodes in a single-size glove worn on the patient's left arm and placed on the chest. The PhysioGlove (PG) was designed to allow fast, reproducible, electrode placement with only minimal training. The American College of Cardiology/American Heart Association ECG recording guidelines and others have repeatedly highlighted the unacceptable progressive deterioration in ECG accuracy mainly resulting from a performer's lack of proficiency and diligence, leading to frequent electrode misplacement. We studied 428 consenting adult patients with a broad spectrum of anthropomorphic characteristics and ECG and cardiovascular pathologic entities. The chest girth was measured to ascertain the single-size PG clinical diagnostic accuracy in ≥90% of this patient population. For each patient, a PG and standard-cable electrocardiogram were consecutively recorded and interpreted by experienced electrocardiographers. The study included 3 phases: phase 1, run-in (n = 120); phase 2, comparative diagnostic accuracy (n = 208); and phase 3, randomized, blinded, diagnostic accuracy (n = 100). Of the entire study population (n = 428), 92% fit the chest girth range of 85 to 118 cm (34 to 47 in.), representing the reference standard clinical diagnostic PG chest girth range. The phase 2 PG diagnostic accuracy was 91.3% for entire chest girth range and 95.7% for the 89.4% of patients with a chest girth within the reference range. The mean PG diagnostic accuracy in phase 3 was 93% (95% confidence interval 89% to 95%). In conclusion, compared with standard-cable electrocardiograms, the PG demonstrated excellent diagnostic accuracy (93% to 95.7%) in ≥90% of a typical western adult patient population. The PG's ease of use and minimal training requirements offer a promising tool to markedly improve ECG clinical diagnostic accuracy in most adult western patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Aim: Glucans are glucose polymers that constitute a structural part of fungal cell wall. They can stimulate the innate immunity by activation of monocytes/macrophages. In human studies it has been shown that beta glucan has an immunomodulatory effect and can increase the efficacy of the biological therapies in cancer patients. In this prospective clinical trial we assessed in vivo effects of short term oral beta glucan administration on peripheral blood monocytes and their expression of activation markers in patients with advanced breast cancer., Methods: 23 female patients with advanced breast cancer were included in the study. Median age of the patients was 52 years. Sixteen healthy females with a median age of 48 years served as the control group for comparing the initial blood samples. Peripheral blood samples were drawn on day zero and patients started receiving oral 1-3, 1-6, D-beta glucan daily. Blood samples were recollected on the 15th day. In the initial samples mean lymphocyte count was significantly lower in the patients with breast cancer (1281+/-306/mm(3) versus 1930+/-573/mm(3), p=0.04). In the patients with breast cancer, mean monocyte count which was 326+124/mm(3) at the beginning, was increased to 496+194/mm(3) at the 15th day (p=0.015). Expression of CD95 (Apo1/Fas) on CD14 positive monocytes was 48.17% at the beginning, which was increased to 69.23 % at the 15th day (p=0.002). Expression of CD45RA on CD14 positive monocytes was 49.9% at the beginning; it was increased significantly to 61.52% on day 15 (p=0.001)., Conclusion: Oral beta glucan administration seems to stimulate proliferation and activation of peripheral blood monocytes in vivo in patients with advanced breast cancer.

Granulocyte macrophage colony stimulating factor (GM-CSF) is a powerful cytokine with multiple actions. We investigated the effects of low dose daily rhGM-CSF application on monocytes and peripheral circulating dendritic cells (DC) in malignant melanoma patients in vivo. Twenty patients were included; rhGM-CSF was given as daily subcutaneous injections for 14 days. A significant increase was noted in monocytes and granulocytes, starting on the 5th day. Expression of CD95 (Apo-1/Fas) and CD45RO on monocytes increased significantly on the 5th day, and CD4 expression on monocytes increased significantly on the 14th day. Peripheral circulating dendritic cells which were 0.94% in the beginning, increased to 1.35% (P<0.04) and to 1.96% (P<0.001) on days 5 and 14, respectively.

We present two cases of an extrapleural hematoma, on a follow-up chest X-ray after coronary artery bypass surgery using an internal mammary artery (IMA). In both cases, the finding was disclosed on a routine chest film obtained 1 month post-operatively, in a patient who was either asymptomatic or had nonspecific symptoms. Follow-up chest films showed spontaneous resolution in both patients. We emphasize the recognition and significance of such a self-limited post-operative radiological finding.

Cortical blindness has been occasionally reported as a complication after cerebral angiography, but is rare after coronary angiography. The contrast agent is believed to be responsible for the sudden development of blindness. Although the exact mechanism is unknown, it appears that the contrast agent disrupts the blood brain barrier, mostly in the occipital areas. We report a 77-year-old man who suddenly developed transient, bilateral cortical blindness 4 hours after coronary angiography. Using contrast enhancement, the CT scan showed typical, symmetrical involvement of both occipital lobes. There were no other neurological deficits. Vision and CT findings returned to normal within 48 hours.

Human tumor cells have markedly elevated activity of enzymes of the purine and pyrimidine de novo and salvage pathways. Our therapy protocol is based on these findings. Different antimetabolites (MTX, 5-FU, dFdC, AZT) were administered to hit key enzymes. Vindesine and ifosfamide were aimed to block macromolecules. Repair mechanisms were impaired by hydroxyurea and topotecan. DNA transcription was blocked by actinomycin. IFNs (alpha, gamma) and IL-2 served as immuno-modulators. 47 patients (age 61.5 years, Karnowsky score 85%) were treated in an out-patient-setting. Median number of cycles was 3. General toxicity was low. Leucocytes, platelets, and monocytes were significantly reduced during therapy, but returned to normal on day 29. Lymphocyte subtypes did not show significant changes. 3 complete clinical responses, 22 partial responses, 9 progressive diseases were observed. CR occurred in 1/4 patients with kidney, in 1/1 with bladder, and in 1/5 with breast cancer.

Background: The murmur of hypertrophic obstructive cardiomyopathy (HOCM) increases in intensity in about 80% of those patients in whom carotid sinus pressure (CSP) slows the heart rate. This does not occur in valvular aortic stenosis (AS). STUDY OBJECTIVES, DESIGN, AND PATIENTS: It was hypothesized that left ventricular (LV) obstruction increases with CSP in HOCM and not in AS. Furthermore, it was not clear whether it was the sudden bradycardia or CSP itself that was responsible for the effect noted. Therefore, studies were performed using two different interventions: (1) Doppler echocardiography was performed before and during CSP in 36 HOCM patients and 21 AS patients; (2) two patients with DDD pacemakers and HOCM were examined before and after pacemaker rate slowing. Finally, atrial pacing was performed in three HOCM patients at catheterization, and atrial pacing was either slowed or stopped (without CSP)., Results: LV outflow velocity and pressure gradient increased in 28 of 30 HOCM patients (92%) in whom heart rate decreased with CSP. The peak instantaneous pressure gradient increased from 45+/-37 to 77+/-53 mm Hg (p<0.005), and the velocity contour became more typical of HOCM. The pressure gradient increased from 30 mm Hg to 64 and 81 mm Hg, respectively, in the two patients with DDD pacemakers after pacemaker rate slowing. Similar results were seen with slowing or cessation of atrial pacing at catheterization. In contrast, the pressure gradient increased in only three of 21 AS patients (14%), to 44+/-28 from 41+/-25 mm Hg, and remained unchanged in the other 18., Conclusion: This study shows that LV outflow velocity and pressure gradient increase markedly in most HOCM patients (92%) if CSP succeeds in slowing the heart rate, but not in patients with valvular AS. A similar effect is obtained by simply decreasing the atrial rate in patients with DDD or atrial pacemakers. This increase in outflow tract obstruction is sufficient to account for the increase in murmur intensity. Decreased afterload (secondary to greater aortic decompression with the longer diastole), increased intrinsic force of contraction with the bradycardia (the Woodworth effect), and Starling's law may play independent roles in the dynamic increase in obstruction observed during CSP in patients with HOCM. Worsening of mitral regurgitation was not clearly shown to contribute to the increase in murmur, but it cannot readily be ruled out.

Patients with gastric cancer have a poor prognosis. Because curative surgery is often impossible (metastatic disease) or extremely difficult (locally advanced tumors), and the majority of patients undergoing curative resection relapse, chemotherapy has been actively studied in gastric cancer. Several combination chemotherapy regimens have been developed with high activity in locally advanced and metastatic disease. Among them are 5-fluorouracil (5-FU) plus high dose methotrexate plus doxorubicin (FAMTX). It represents the reference treatment in many clinical trials. Recent schedules like etoposid plus cisplatin (EAP); etoposid plus leucovorin plus 5-FU (ELF) and epirubicin plus cisplatin plus 5-FU (ECF) show encouraging response rates, their toxicity is considerable, however. Randomized trials comparing chemotherapy with best supportive care showed an increase in overall survival and in quality-of-life. Up to now adjuvant chemotherapy has failed to improve survival as compared with surgical controls. Only half of the patients with locally advanced gastric cancer (LAGC) undergo macroscopic and microscopic tumor-free resection. Preoperative chemotherapy has shown very promising results even in patients who had primarily unresectable tumors. Approximately half undergo R0 resection after downstaging induced by active chemotherapy and the long-term survival rises to about 20%. There are hopes that the newest regimes may do this: new cytostatic drugs and the immuno-chemical approach to combine cytostatic drugs with cytokines will be of great importance.

Of 63 elderly patients with calcific aortic stenosis in whom balloon aortic valvuloplasty was performed, 26 treated with the new technique of Cribier and Letac are the subject of this report. Patients were referred for the procedure because they were at high surgical risk, or were not candidates for surgery. Seven matched patients who fit the criteria for balloon valvuloplasty but refused the valvuloplasty procedure served as controls. Aortic gradient decreased from 78 +/- 27 mm Hg to 35 +/- 20 mm Hg and aortic valve area increased from 0.47 +/- 0.16 cm2 to 0.83 +/- 0.38 cm2 (P < 0.0001). Symptomatic improvement was immediately obtained in each patient. Complications were rare, with only one patient needing vascular repair for femoral artery occlusion. Three patients died during the initial hospitalization (none during the procedure). Valvuloplasty patients were followed for a mean period of 9.6 +/- 9.4 months. Three months survival was 87%, 6 months survival was 76%, and 12 months survival was 61%. Four of seven patients in the control group (57%) died within 3 months after initial referral. Balloon aortic valvuloplasty is a useful treatment in elderly patients who are poor surgical candidates. It may have a positive influence on short-term survival.

Patients with severe coronary artery disease (CAD) sometimes complain of chest pressure upon crouching or bending-forward (pronus angina). The factors that trigger pronus angina are not clear. We therefore investigated 28 patients with CAD and 26 normal subjects in the sitting, knee-chest, stooping, and squatting positions. Systolic and diastolic blood pressures were found to increase by 13.5 and 19.5 percent (p < 0.005) in the stooping position. In addition, left ventricular (LV) ejection time index (LVETI) also increased (p < 0.005). Despite the acute rise in aortic pressure, which is expected to lengthen the pre-ejection period index (PEPI), the latter shortened slightly in 10 of 14 (71 percent) patients tested, suggesting augmentation in contractile force during the isovolumic phase. Finally, left atrial size increased (p < 0.005) during the knee-chest maneuver, suggesting that the LV size also increases upon bending forward. The effect of stooping on blood pressure was similar in magnitude to that of squatting. It is concluded that the triggering factor for "pronus angina" in severe CAD may be explained as a combination of hemodynamic events which acutely increase myocardial oxygen requirements.

Rotating tourniquets were once part of the traditional treatment of acute pulmonary edema. Their effectiveness has been questioned and vasodilator therapy has replaced them, but early favorable results suggested that they may play a beneficial role. A radioisotope technique was used to evaluate blood volume increments in the leg after venous occlusion at 60 mm Hg in 26 patients with left ventricular dysfunction following myocardial infarction. Mean radionuclide counts (reflecting the blood volume distal to the occlusion) increased from the preocclusion value. Thus, satisfactory trapping of blood is achieved. However, mean left ventricular ejection fraction (EF) decreased slightly but significantly and this decrease in EF was observed in 18 of 26 patients. Left ventricular end-diastolic and end-systolic volume equivalents tended to decrease slightly but not in all patients. Mean stroke volume and cardiac output equivalents were reduced by 14 percent while peripheral resistance increased significantly. The present study thus fails to support the hypothesis that preload reduction by tourniquets improves left ventricular function; the exact opposite effect may occur because of increased afterload.

The dipyridamole stress test is used with thallium-201 to detect areas of inhomogeneity of blood flow that point to coronary artery disease (CAD). It is unclear whether dipyridamole produces inhomogeneous perfusion only or whether it actually decreases net flow in the obstructed vessels and produces true ischemia. It is also unclear what effect dipyridamole has on global and segmental left ventricular function. Therefore, ejection fraction, segmental wall motion and ventricular volume equivalents were measured before and after dipyridamole in 113 patients and 32 normal subjects. Ejection fraction responded in an abnormal fashion in 98 patients (87%), decreasing from 49 +/- 11% to 43 +/- 13% (p less than 0.0001), whereas it increased in 29 normal subjects (90%) from 57 +/- 6% to 64 +/- 10% (p less than 0.0001). Wall motion worsened distinctly in 75 patients (66%), and pressure/volume ratio deteriorated in 72%. The effect of dipyridamole lasted between 10 and 25 minutes, but was promptly reversed by aminophylline. These findings indicate that dipyridamole generally induces true ischemia in CAD. Furthermore, the degree of dysfunction is related to the angiographically assessed severity of CAD. The shortness of breath (seen in 10% of patients) may be partially explained by the findings, and it seems advisable to give aminophylline to every patient in order to promptly correct left ventricular dysfunction.

To study the mechanism of altered mitral function in the presence of an isolated cleft mitral valve (ICMV) with regard to the relative roles of the cleft and of the accessory chordae, seven patients with ICMV were studied with color Doppler echocardiography. Mitral insufficiency ranging from mild to severe was demonstrated in six cases. The regurgitant jet originated in each case from the site of the cleft: in five patients the regurgitant jet had a narrow base originating exactly from the cleft; in the sixth patient, the regurgitant flow presented as a broad-based jet suggesting that accessory chordae restricted the motion of the anterior mitral leaflet. Turbulent flow in the left ventricular outflow tract, starting at the level of the accessory chordae, was found in one patient in whom a pressure drop of 44 mm Hg was detected with continuous-wave Doppler imaging. The altered function of the mitral valve cleft stems from two elements, the cleft itself and the accessory chordae. Color Doppler flow imaging showed that the cleft was the main factor causing mitral insufficiency. The accessory chordae played an additional pathogenetic role in two patients by causing restricted mitral motion or left ventricular outflow tract obstruction.

In a prospective phase III multicenter trial, 213 patients with advanced measurable or nonmeasurable gastric cancer were randomized to receive methotrexate (MTX), fluorouracil (5-FU), and Adriamycin (doxorubicin; Farmitalia Carlo Erba, Milan, Italy) (FAMTX) or 5-FU, Adriamycin, and mitomycin (FAM). The results show a significantly superior response rate (41% v 9% [P less than .0001]), and survival (median, 42 weeks v 29 weeks [P = .004]) for FAMTX. There was a cumulative thrombocytopenia in FAM and not in FAMTX. The FAMTX protocol should be the reference treatment in future clinical trials that seek to improve the therapeutic outcome in advanced gastric cancer.

Three phase I/II trials were performed in patients with metastatic colorectal cancer using immunochemotherapy--a combination of recombinant interferon beta and gamma with low doses of cytostatic drugs. The third regimen, consisting of a cytostatic component containing 5-fluorouracil plus carboplatin plus mitomycin C besides the interferons, produced a high remission rate of 47%: 14/30 patients responded. The tolerability of this protocol was good and it could be administered on an out-patient basis.

Six patients with advanced disseminated malignant lymphomas of the skin were treated with cytostatics using the method of partial synchronisation of the tumor cell growth phases. Though five patients had already shown a resistance against the usual chemo- and/or radiotherapy, all patients responded to this therapeutical principle. Full remission was achieved in four patients. We proved that vincristine effectively synchronizes the growth of proliferating human tumor cells in vivo. Treatment was applied in two steps. First a partial synchronisation of tumor cell growth was induced by vincristine as a pharmacologic means. Then the cytostatics were applied in killing doses at the calculated time. For this purpose we determined the average length of each generation of cells and developed individual therapy schemes. To get the best results with this method usually several therapy cycles were used. In case of a relapse the therapy scheme was adjusted to the altered cellular kinetics. This principal of partial synchronisation is suitable for treating malignant lymphomas with high efficiency, especially those with rapid proliferation even in advanced states.

In a phase II trial we tried to evaluate the efficacy of a sequential combination of high-dose methotrexate (MTX) and 5-fluorouracil (5-FU) combined with Adriamycin (ADM). In a pilot study we had found high-dose MTX effective as a single agent in gastric cancer. MTX and 5-FU were combined sequentially because Cadman et al had shown synergism for this combination. The therapy protocol consisted of high-dose MTX, 1.5 g/m2 of body surface, and high-dose 5-FU, 1.5 g/m2. MTX was administered 1 hr prior to 5-FU. Both drugs were given as a bolus. Twenty-four hours after MTX administration, citrovorum factor rescue was started, 15 mg/m2, q.6h. X 12, orally. Forty-eight hours after MTX administration, serum concentration of the drug was measured by high performance liquid chromatography (HPLC). Fourteen days after MTX was given, ADM, 30 mg/m2, was injected as a bolus. This protocol was repeated every 28 days. Patients eligible for this treatment should have a creatinine clearance of greater than 60 ml/min. The study included 30 patients with metastasizing gastric cancer and performance status between 40% and 70%. The response rate was 63% (19 of 30 patients). Two of 30 patients had complete remissions, which are still maintained. The median survival for responders is not yet evaluable: 68% are living after 17+ mo. The median survival for nonresponders was only 5 mo. The difference in survival curves is significant at a level of p less than 0.05. Cytostatic treatment was well tolerated. Fifty percent of the patients could be treated on an outpatient basis. Total alopecia was observed in only 10% of the patients. Severe leukopenia, thrombocytopenia, and kidney disorders were not observed.

Two hundred thirty cases of malignant non-Hodgkin's lymphomas were reclassified in a retrospective study according to the New Working Formulation for Clinical Usage of the NCI as compared to the Rappaport and Kiel classifications. The reproducibility for the individual schemes this study was 81% (Rappaport), 79% (Kiel), and 85% (New Working Formulation). In keeping with the results of the NCI international study, all lymphomas were subdivided into 3 prognostic groups: (1) low-grade malignancy (6.0 years median survival); (2) intermediate-grade malignancy (3.5 years median survival); and (3) high-grade malignancy (1.4 years median survival). The NCI-proposed New Working Formulation for Clinical Usage is thus recommended as practical and unprejudicing classification scheme for general application; however, its usefulness as tool for translating one classification scheme into another appears limited.

In a phase II trial we tried to evaluate the efficacy of a sequential combination of high-dose (HD) MTX and 5-FU combined with Adriamycin (ADM). In a pilot study we found HDMTX effective as a single agent in gastric cancer. MTX and 5-FU were combined sequentially because Cadman and Bertino had shown synergism for this combination. The treatment protocol consisted of HDMTX, 1.5 g/m2 of body surface, and HD5-FU, 1.5 g/m2. MTX was administered 1 hour prior to 5-FU. Both drugs were given as a bolus. 24 hours after MTX administration, citrovorum factor rescue was started, 15 mg/m2, q6h x 12, orally. 48 hours after MTX administration, the serum concentration of the drug was measured by HPLC. 14 days after MTX was given, ADM, 30 mg/m2, was injected as a bolus. This protocol was repeated every 28 days. Patients eligible for this treatment were required to have a creatinine clearance of greater than 60 ml/min. 116 patients with metastasized gastric cancer and a performance status between 40 and 70% were treated. The response rate was 58% (67/116 patients). 14/116 patients (12%) had complete remission. The median survival probability for all patients was 9 months, for responders 15 months, while for patients with complete response it has not been reached. The median survival for nonresponders was only 4 months. Around 10% of all patients lived longer than 6 years. The median follow-up-time was 4 years. Cytostatic treatment was relatively well tolerated. The deaths of 3 patients were drug-related. A quarter of all patients could be treated on an outpatient basis.

The effectiveness of synchronization therapy was tested on 88 patients who had already undergone some form of treatment for lymphogranulomatosis (stage III B and IV), generalized reticulum cell sarcoma or lymphosarcoma. This therapeutical concept is based on a partial synchronic increase in tumor cells induced by noncytocidal doses of vincristine, followed by cytostatic or cytocidal treatment with cyclophosphamide during DNA synthesis of the partially synchronized tumor cells. The therapeutic plan is similar to a single-agent therapy. In lymphogranulomatosis, complete remission could be achieved in 14 out of 19 cases (stage III B) and in 9 out of 24 cases (stage IV). The mean remission period during an orally administered cytostatic maintenance therapy was 15 1/2 months. The highest rate of remission was found in the mixed cell type of granulomas (23 out of 24 patients). In the non-Hodgkin's lymphomas, complete remission was achieved in 13 out of 30 cases (lymphosarcoma) and in 19 out of 15 cases (reticulum cell sarcoma). The mean remission period for orally administered cytostatic maintenance therapy was 16 months for lymphosarcoma and 11 1/2 months for reticulum cell sarcoma. These therapeutic results are comparable to those achieved by very effective schemes of combination chemotherapy but the toxic side-effects of synchronization therapy are considerably lower.

It is not generally appreciated in the Western world that organophosphorus poisoning may be associated with a serious and often fatal cardiac complication: Q-T interval prolongation with malignant ventricular arrhythmias of the "torsade de pointes" type. This insidious complication may lead to delayed, sudden death after the patients appears to be well on the way to recovery from the other, more dramatic respiratory and neurologic symptoms. In this study 15 patients with organophosphorus poisoning are described. Q-T prolongation was observed in 14 and malignant tachyarrhythmias in 6. In view of the dismal prognosis of these patients, ventricular pacing, previously used with success in other conditions associated with this syndrome, was tried in four patients and successfully shortened the Q-T interval and eliminated the arrhythmias. Isoproterenol did the same in a fifth patient. Awareness of this lethal, but preventable complication of organophosphorus poisoning is called for. Careful electrocardiographic monitoring is necessary until the Q-T interval returns to normal. Electrical pacing appears to be the treatment of choice for the tachyarrhythmias.

The sensitivity and specificity of ST-segment elevation in the right precordial lead V4R as an early indicator of right ventricular infarction were examined in a consecutive series of 110 patients admitted for acute inferior myocardial infarction. The sensitivity was 82.7%, the specificity 76.9% and the positive predictive value 70% in 58 patients with right ventricular infarction documented by autopsy or a combination of radionuclide ventriculography and one or more of the following tests: echocardiography, technetium-99m pyrophosphate scintigraphy and hemodynamic monitoring. The negative predictive value was 87.7%. Because of its simplicity and its high sensitivity and specificity, recording of V4R should be an intrinsic part of the early evaluation and electrocardiographic examination of acute inferior wall infarction.

A patient is reported in whom an intravenous bolus injection of 50 mg lignocaine produced extreme sinus bradycardia (rate 14 to 20/min). Only 2 patients with such a response to a similarly small dose have been previously reported, but these reports indicate clearly that careful electrocardiographic monitoring is advisable when lignocaine is administered.