Tolerance to Lower Body Negative Pressure Exposure: Comparison Between Patients with Neurocardiogenic Syncope and Controls

Lower body negative pressure exposure (LBNPE) produces hemodynamic modifications similar to those produced by head-up tilt test (HUT). Patients with vasovagal syncope are more susceptible to HUT than healthy persons. The supine position during LBNPE would facilitate the simultaneous performance of complementary methods. The aim of this study was to compare tolerance to LBNPE between a group of patients with vasovagal syncope and a group of healthy volunteers. Eleven patients with vasovagal syncope and positive HUT and 13 healthy volunteers without prior history of syncope and negative HUT were included. The following protocol was used: −10 mmHg, 1 minute; −20 mmHg, 1 minute; −30 mmHg, 3 minutes, and −40, −50, −60, and −70 mmHg, 5 minutes for each stage. Tolerance was expressed as: maximum tolerated negative pressure (Max NP), maximum tolerated time (Max T), and Σ P × T, where P = pressure and T = time. Syncope or presyncope during the test was considered positive LBNPE. LBNPE was positive at −50 or −60 mmHg in 8 of 11 patients (73%). One healthy volunteer had presyncope after 5 minutes at −70 mmHg. Tolerance, as expressed by any of the three parameters, was significantly higher for the healthy volunteers (Max NP: −59.1 ± 7.9 vs −70, P < 0.01; Max T: 19.1 ± 4.2 vs 24.4 ± 0.3, P < 0.01; Σ P × T: 836.3 ± 269.5 vs 1214.6 ± 18, P < 0.01). We conclude that patients with neurocardiogenic syncope have a significantly lower tolerance to LBNPE than subjects with no previous history of syncope.     

Paclitaxel activity for the treatment of non-Hodgkin's lymphoma: final report of a phase II trial

In order to determine the activity of paclitaxel in patients with relapsed or refractory non-Hodgkin's lymphoma (NHL), we conducted a phase II clinical trial in which eligible patients received paclitaxel 200 mg/m² intravenously over 3 h. Treatment was repeated every 3 weeks. Patients achieving complete or partial responses after two courses of paclitaxel continued to receive therapy for a maximum of eight courses, otherwise they were removed from the study. Of 96 evaluable patients, 45 (47%) had primary refractory disease, and 51 (53%) had relapsed lymphoma. The median number of prior treatment regimens was two (range one to 10 regimens). 45 patients had low-grade, 44 had intermediate-grade, and seven had mantle cell lymphoma. 24/96 patients responded (10 complete and 14 partial remissions) for an overall response rate of 25% (95% CI 17–35%). Patients with relapsed lymphoma had a higher response rate than those with primary refractory disease (19/51=37% v 5/45 =11%; P  < 0.01), and patients with relapsed intermediate-grade lymphoma had a higher response than those with relapsed low-grade lymphoma (9/18=50% v 10/31 = 32%; P  = 0.22). The treatment was very well tolerated with the most common side-effects being alopecia (100%), peripheral neuropathy (35% of ≥ grade II), and arthralgia/myalgia (25% of ≥ grade II). After the first course of paclitaxel, grade III/IV thrombocytopenia and neutropenia were observed in 21% and 23% of the patients respectively. 23 episodes of neutropenic fever developed after 250 courses of paclitaxel therapy (8%). We conclude that paclitaxel, at this dose and schedule, is an active new drug for the treatment of non-Hodgkin's lymphoma. The activity of paclitaxel combination programmes are currently under investigation.     

Electrotonic Inhibition and Active Facilitation of Excitability in Ventricular Muscle

Inhibition and Facilitation in Cardiac Muscle. Introduction: The effects of subthreshold electrical pulses on the response to subsequent stimulation have been described previously in experimental animal studies as well as in the human heart. In addition, previous studies in cardiac Purkinje fibers have shown that diastolic excitability may decrease after activity (active inhibition) and, to a lesser extent, following subthreshold responses (electrotonic inhibition). However, such dynamic changes in excitability have not been explored in isolated ventricular muscle, and it is uncertain whether similar phenomena may play any role in the activation pal-terns associated with propagation abnormalities in the myocardium. Methods and Results: Experiments were performed in isolated sheep Purkinje fibers and papillary muscles, and in enzymatically dissociated guinea pig ventricular myocytes. In all types of preparations introduction of a conditioning subthreshold pulse between two subthreshold pulses was followed by a transient decay in excitability (electrotonic inhibition). The degree of inhibition was directly related to the amplitude and duration of the conditioning pulse and inversely related to the postconditioning interval. Yet, inhibition could be demonstrated long after (> 1 sec) the end of the conditioning pulse. Electrotonic inhibition was found at all diastolic intervals and did not depend on the presence of a previous action potential. In Purkinje fibers, conditioning action potentials led to active inhibition of subsequent responses. In contrast, in muscle cells, such action potentials had a facilitating effect (active facilitation). Electrotonic inhibition and active facilitation were observed in both sheep ventricular muscle and guinea pig ventricular myocytes. Accordingly, during repetitive stimulation with pulses of barely threshold intensity, we observed: (1) bistability (i.e., with the same stimulating parameters, stimulus: response patterns were either 1:1 or 1:0, depending on previous history), and (2) abrupt transitions between 1:1 and 1:0 (absence of intermediate wenckebach-like patterns). Simulations utilizing an ionic model of cardiac myocytes support the hypothesis that electrotonic inhibition in well-polarized ventricular muscle is the result of partial activation of I_k following subthreshold pulses. On the other hand, active facilitation may be the result of an activity-induced decrease in the conductance of I_K1. Conclusion: Diastolic excitability of well-polarized ventricular myocardium may be transiently depressed following local responses and transiently enhanced following action potentials. On the other hand, diastolic excitability decreases during quiescence. Active facilitation and electrotonic inhibition may have an important role in determining the dynamics of excitation of the myocardium in the presence of propagation abnormalities.     

Intrauterine Growth Retardation of Unknown Etiology. I. Serum Complement and Circulating Immune Complexes in Mothers and Infants

ABSTRACT: Complement (C) and circulating immune complexes (CIC) levels were measured in 22 full-term pregnant women and 15 of their small-for-gestational-age (SGA) offspring in order to seek evidence supporting an immunological etiology for placental lesions related to idiopathic intrauterine growth retardation. We used 19 normal full-term pregnant women and 18 of their infants with birthweight above the 25th centile of the ponderal curve as a control population for this study. C levels were significantly lower in mothers of SGA infants than in controls (146.6 ± 46.6 and 183.6 ± 36.6 respectively, p < 0.01). CIC were present in the sera of 5 out of 22 mothers of the SGA group and in 3 out of the 15 infants sera. No CIC were found in the sera of mothers or infants from the control group. Placental lesions were observed in 14 out of the 22 (64%) cases studied in the SGA group and in 1 of 11 (9%) of the controls. Two placentas from SGA infants showed acute atherosis, and deposits of IgM and C₃ were found in their vessel walls. These data are in favor of an immunological mechanism for intrauterine growth retardation of unknown etiology.     

A FEASIBILITY STUDY OF GENE GUN MEDIATED IMMUNOTHERAPY FOR RENAL CELL CARCINOMA

PURPOSE: Gene modified autologous tumor cell vaccines have demonstrated a protective and therapeutic effect in murine tumor model systems. The majority of trials to date have used viral methods of gene transfer for vaccine construction. An alternative approach to transfer genes into tumor cells is to use the gene gun, which is a physical method of gene transfection that produces high levels of gene expression without viral agents. We establish the feasibility of generating cytokine secreting autologous renal tumor cell vaccines for use in gene therapy for metastatic renal cell carcinoma. MATERIALS AND METHODS: We obtained 1 cm3 tumor tissue from 12 patients undergoing resection of primary or metastatic renal cell carcinoma. The tumor was disaggregated and placed in culture. The phenotype of the primary renal cell lines was established by microscopy and immunohistochemistry. The 1x10(7) lethally irradiated tumor cells were transfected with plasmid deoxyribonucleic acid containing the human (h) granulocyte-macrophage colony-stimulating factor (GM-CSF) gene under control of a cytomegalovirus promoter using the gene gun. The hGM-CSF production was assayed by enzyme-linked immunosorbent assay in the cell culture media 24 hours after transfection. RESULTS: Of 12 tumor samples 8 grew rapidly to produce a mean of 1.8x10(8) cells after 4 to 5 passages in culture, which was sufficient to produce between 24 and 32 vaccines. Immunocytochemistry confirmed that all cultures were almost exclusively renal tumor cells. Gene gun mediated transfection of lethally irradiated tumor cells resulted in high levels of hGM-CSF production (mean 330 ng./10(6) cells per 24 hours). CONCLUSIONS: We have demonstrated the feasibility of producing cytokine secreting tumor cell vaccines from primary and metastatic human renal tumors, and plan to use this approach in phase I clinical trials of gene therapy for metastatic renal cell carcinoma.     

Intracoronary Radiation Post PTCA Prevents Late Arterial Constriction

Vascular constriction post PTCA is a major component in the mechanism of restenosis following intervention. Ionizing radiation demonstrated reduction of neointima formation after injury in animal models and lowered the restenosis rates in pilot clinical studies. To determine the effect of intracoronary radiation therapy on vascular remodeling, angiograms from two radiation trials were analyzed by QCA methods. Patients in these trials had de novo lesions and were treated with balloon angioplasty followed by either beta or gamma radiation. All patients were studied angiographically at 6 months; patients with total occlusion at the treated artery were excluded from the analysis. In the gamma trial, 192-Iridium was utilized in 14 patients (15 lesions) with doses between 20-25 Gy. In the beta trial, 90-Sr/Y was utilized in 17 patients (17 lesions) with doses between 12-16 Gy. The QCA analysis from these studies demonstrated negative late loss and late loss index at six months for patients from the beta (-0.02 ± 0.3) and the gamma (-0.19 ± 0. 3) study. The effect of positive remodeling was maintained at 24 months, -0.16 ± 0.4 in the gamma group. Larger MLD at follow-up compared to the immediate post MLD were demonstrated in 50% of the patients from both studies. Thus, intracoronary radiation resulted in lower late loss and late loss index rates than previously reported following balloon angioplasty alone suggesting a positive vascular remodeling effect of intracoronary radiation.     

Molecular analysis of HLA DR4-/β1 gene in malaria vaccinees. Typing and subtyping by PCR technique and oligonucleotides

The combination of the PCR technique and the synthetic oligonucleotides has proved to be a useful tool in the molecular analysis of HLA class II genes, allowing recognition of as little as a single nucleotide modification in the sequence of the gene. The molecules encoded by these genes have been associated with genetic control of the immune response and with susceptibility to certain diseases. Studies carried out in our laboratory have shown three patterns of humoral immune response in the human volunteers vaccinated with the synthetic protein SPf 66; high, intermediate and low responders. Approximately 73.3% of the low responders were serologically typed as HLA DR4 and 42% as DQw6. These results moved us to look for a subtype (Dw) correlation between the DR4 positive individuals and the different humoral immune response patterns. Using oligo-typing methods after previous amplification of the DR4 B1 exon, we subtyped 20 DR4 volunteers, classified as high, intermediate and low responders. We did not find any direct association between the HLA DR4 Dw special subtype in the high or low responders immunized with the SPf 66 vaccine.     

The destruction of virulent Entamoeba histolytica by activated human eosinophils

Unlike normal (i.e., non-activated) human eosinophils that are unable to destroy virulent Entamoeba histolytica even in the presence of antibodies and complement, activated eosinophils effectively destroy the parasite in vitro without the help of opsonins, yet increase this capacity with their assistance. Many activated eosinophils succumb in the process as well, probably victims of toxic products released by dying amoebae. Human activated eosinophils thus behave more like activated macrophages than like neutrophil polymorphonuclear leucocytes that are notoriously incompetent in dealing with virulent amoebae. As a regular constituent of early inflammatory reactions, and notwithstanding the absence of blood and tissue eosinophilia in invasive amoebiasis, the activated eosinophil may play a role in the defence against E. histolytica.