Noninvasive assessment of the direct action of oral nifedipine and nicardipine on left ventricular contractile state in patients with systemic hypertension: importance of reflex sympathetic responses

BACKGROUND: Alveolar macrophages from patients with sarcoidosis were analyzed for their ability to secrete tumor necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-1-beta), and interleukin-6 (IL-6). RESULTS: Constitutive release of all three monokines in these patients was concomitantly increased in the active state of disease in comparison with inactive sarcoidosis or healthy control subjects. Alveolar macrophages from patients with inactive sarcoidosis compared with cells from healthy subjects showed increased spontaneous secretion of TNF-alpha and IL-6 only, whereas the constitutive release of IL-1-beta was similar as in healthy volunteers. In vitro stimulation of alveolar macrophages from healthy control subjects with lipopolysaccharide or pokeweed mitogen led to a time- and dose-dependent enhanced secretion of TNF-alpha, IL-1-beta, and IL-6. In a similar manner, with corresponding cells from patients with sarcoidosis the secretion of all three cytokines could be further increased by stimulation with lipopolysaccharide or pokeweed mitogen. CONCLUSIONS: The data presented indicate that an increased release of TNF-alpha, IL-1-beta, and IL-6 correlates to disease activity and may play a critical part in the pathogenesis of sarcoidosis.     

Brain HMPAO-SPECT and ocular microangiopathic syndrome in HIV-1-infected patients

OBJECTIVE: The pathogenesis of neurologic and neuropsychologic dysfunction in HIV-1 infection is unclear. The purpose of the study was to determine an association between cerebral perfusion and HIV-1-related ocular microangiopathic syndrome. METHODS: We studied 28 HIV-1-infected patients, seven of whom presented with asymptomatic HIV infection, nine with lymphadenopathy syndrome or AIDS-related complex, and 12 with AIDS. Cerebral perfusion was semi-quantitatively measured by single photon emission computed tomography of the brain using technetium-99 hexamethyl-propylenamine oxime (HMPAO-SPECT). The conjunctival manifestation of HIV-1-related microangiopathic syndrome was measured by a rating scale determining blood-flow sludging and, retinal cotton-wool spots were counted. CD4 count, neopterin, beta 2-microglobulin (beta 2M), haemoglobin, and age were determined as putative confounding variables. RESULTS: Mean conjunctival sludge in patients with normal HMPAO-SPECT findings was 1.3 +/- 0.5 (mean +/- s.e.m.); no cotton-wool spots were present. In patients with slightly impaired HMPAO-SPECT, it was 2.1 +/- 0.6 and mean cotton-wool spot count was 1.1 +/- 0.4. In patients with severely impaired HMPAO-SPECT, mean conjunctival sludge was 4.5 +/- 0.3 and mean cotton-wool spot count was 4.9 +/- 1.1 HMPAO-SPECT findings were closely associated with conjunctival sludge (r = 0.72; P < 0.001) and number of cotton-wool spots (r = 0.78; P < 0.001), whereas only a slight association with staging of HIV disease was found (P = 0.052). Analysis of covariance controlling for CD4 count neopterin, beta 2M, age, and haemoglobin demonstrated a significant difference between the three HMPAO-SPECT groups for both the number of cotton-wool spots (P < 0.001) and the conjunctival sludge rating (P < 0.001). CONCLUSION: There was a close association between severity of HIV-1-related ocular microangiopathic syndrome and severity of cerebral hypoperfusion. Microvascular alterations might contribute to the pathogenesis of neurological and neuropsychological symptoms in patients with HIV-1 disease. Furthermore, the conjunctival sludge rating and the number of cotton-wool spots might be appropriate indicators for severity of microvascular changes of the central nervous system [corrected].     

Collection of peripheral blood progenitor cells after the administration of cyclophosphamide, etoposide, and granulocyte-colony-stimulating factor: an analysis of 497 patients

BACKGROUND: There is great interpatient variability in the number of peripheral blood stem cells collected, as measured by CD34+ cell content, after the administration of chemotherapy and a growth factor. The ability to predict patients who fail to yield adequate quantities of CD34+ cells would be of value. However, very few reports include large numbers of patients treated in an identical fashion. STUDY DESIGN AND METHODS: Between 1991 and 1995, 497 consecutive patients with a variety of malignant diseases received cyclophosphamide (4 g/m2), etoposide (600 mg/m2), and granulocyte-colony-stimulating factor (6 micrograms/kg/day) for mobilization and collection of a target dose > or = 2.5 x 10(8) CD34+ cells per kg. Multivariate analyses were performed to determine the factors associated with failure to achieve this target harvest. RESULTS: A median of 14.71 x 10(6) CD34+ cells per kg (range, 0.08-137.55) was harvested with a median of 2 (range, 1-11) apheresis procedures. Ninety-one percent of patients yielded > or = 2.5 x 10(5) CD34+ cells per kg. Patients with Stage II-III breast cancer, who had pretreatment platelet counts > or = 150 x 10(9) per L and patients who underwent < or = 1 prior chemotherapy regimen had improved CD34+ cell yields. However, most patients with adverse risk factors yielded > or = 2.5 x 10(6) CD34+ cells per kg. CONCLUSION: A regimen of cyclophosphamide, etoposide, and granulocyte-colony-stimulating factor led to the successful collection of adequate numbers of CD34+ cells in most patients without excessive toxicity. These observations confirm previous reports that intense prior therapy adversely affects the quantity of CD34+ cells harvested. Pretreatment and posttreatment variables did not predict with any certainty the small fraction of patients who fail to yield > or = 2.5 x 10(6) CD34+ cells per kg via multiple apheresis procedures.     

Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites

OBJECTIVE: Large volume paracentesis is an effective treatment for refractory ascites, but the need for routine infusion of albumin or other volume expanders remains controversial. The aim of this study was to assess the short term effects of a single 5-L paracentesis without albumin replacement on total central blood volume, systemic and renal hemodynamics, sodium homeostasis, and neurohumoral factors. PATIENTS AND METHODS: Twelve patients with biopsy-proven cirrhosis and tense, diuretic-resistant ascites were studied before and 48 h after a single 5-L paracentesis without albumin infusion. Systemic hemodynamics and total central blood volume were assessed using radionuclide angiography. Glomerular filtration rate and effective renal plasma flow were measured by inulin and para-aminohippurate clearances, respectively. Lithium clearance was used as an index of proximal tubular reabsorption of sodium. In addition, plasma concentrations of neurohumoral factors were determined. RESULTS: Total central blood volume was 2.41 +/- 0.33 L/m2 (mean +/- SEM) before and 2.34 +/- 0.18 L/m2 48 h after large volume paracentesis (p = 0.76). Similarly, no differences were detected in the cardiac index, glomerular filtration rate, effective renal plasma flow, urinary sodium excretion, hematocrit, plasma renin activity, or concentrations of plasma aldosterone, norepinephrine, or atrial natriuretic factor. CONCLUSIONS: A single large volume paracentesis without albumin replacement causes no disturbances in systemic and renal hemodynamics 48 h after the procedure. These results suggest that a single 5-L paracentesis without albumin infusion is a safe and satisfactory short term option for the management of patients with cirrhosis and tense, diuretic-resistant ascites.     

Geographic epidemiology of gonorrhea in Baltimore, Maryland, using a geographic information system

Ws/Ws rats are deficient in both mucosal- and connective tissue-type mast cells. To study the role of mast cells in active anaphylaxis, changes in vascular permeability in the trachea upon intravenous antigen challenge with Evans blue dye were examined in Ws/Ws, heterogenic Ws/+, and normal +/ + rats sensitized with the nematode Nippostrongylus brasiliensis. Antigen challenge resulted in fatal anaphylactic shock in some +/+ and Ws/+ rats, but not in Ws/Ws rats. Marked dye leakage developed within 30 min in the trachea of +/+ and Ws/+ rats, while Ws/Ws rats showed no substantial increases in the levels of vascular permeability. Ex vivo stimulation of sensitized lung fragments from +/+ animals with specific antigen induced significant releases of histamine and leukotriene (LT) C4, while sensitized Ws/Ws rat-lung fragments did not. In Ws/Ws rats, levels of nematode-specific IgE, IgG1 and IgG2a antibodies as well as levels of lung eosinophilia were not significantly different from those in +/+ rats. These results show that mast cell-deficient Ws/Ws rats fail to develop active anaphylaxis, and this is mediated probably by the lack of mast cell-derived mediators required for initiation of the reaction.     

Quantitative analysis of the peripheral blood cytotoxic T lymphocyte response in patients with chronic hepatitis C virus infection

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) are present in the peripheral blood and liver of chronically infected patients. The current study was performed to study the relationship between the strength of the CTL response, liver disease severity, and viral load. The results may be summarized as follows: first, using CTL precursor frequency (CTLpf) analysis to quantitate the peripheral blood CTL response, chronically infected patients were less strongly sensitized to a panel of well-defined HCV epitopes than they were to an epitope within the influenza matrix protein. Second, HCV-specific CTLpf did not correlate with disease activity or viral load in the majority of patients on a cross-sectional basis, although it did increase in three patients concomitant with sharp increases in liver disease. Finally, interferon therapy did not enhance the CTLpf against the HCV epitopes studied in these patients, indicating that its antiviral effect is independent of the CTL response. Since the HCV-specific CTLpf in the blood is actually quite low, the CTL may contribute to ongoing liver disease in these patients while being quantitatively inadequate to destroy all of the infected hepatocytes, thereby facilitating HCV persistence and contributing to chronic liver disease.     

Torsemide: a new loop diuretic

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of torsemide are reviewed. Torsemide belongs to the pyridine-sulfonylurea class of loop diuretics. Its primary site of activity is the thick ascending limb of the loop of Henle, where it blocks active reabsorption of sodium and chloride, resulting in diuresis, natriuresis, and other effects. Torsemide has high bioavailability, a relatively long half-life, and a prolonged duration of activity. It is highly protein bound. Clinical trials indicate that torsemide is effective in the treatment of hypertension and of edema and other symptoms in patients with chronic renal failure (CRF), hepatic dysfunction, or congestive heart failure (CHF). Torsemide has infrequent, mild, and transient adverse effects; among the most common are orthostatic hypotension, fatigue, dizziness, and nervousness. The recommended initial oral dosages of torsemide are 10-20 mg/day for CHF, 20 mg/day for CRF, 5 mg/day for hypertension, and 5-10 mg/day (in combination with a potassium-sparing diuretic or aldosterone antagonist) for hepatic cirrhosis. In most patients, the pharmacokinetic advantages of torsemide over other loop diuretics are unlikely to translate into a substantial edge in clinical outcomes, and in practice there may be no cost advantages. Although torsemide does not offer major advantages over other loop diuretics, it may be of benefit in patients who do not respond to or cannot tolerate other agents.