Improved resolution and signal-to-noise ratio in MRI via enhanced signal digitization.

The high frequency k-space data in magnetic resonance imaging is often poorly reproduced due to the finite dynamic range of an analog-to-digital converter. The magnitude of this digitization error can equal and even exceed the magnitude of the thermal noise. Under such conditions, attempts to increase image signal-to-noise ratio via signal averaging meet with diminishing success. Because the relative size of the digitization error increases at higher spatial frequencies, a reduction in image resolution is incurred as well. By adjusting the level of the analog signal sampled by the analog-to-digital converter during the course of an imaging experiment, the magnitude of the digitization artifact can be greatly reduced. The results of simulations and imaging experiments are presented which demonstrate that this strategy improves both the signal-to-noise ratio and resolution of magnetic resonance images.

Fast imaging of phosphocreatine using a RARE pulse sequence.

A technique is described for acquiring phosphocreatine (PCr) images of skeletal muscle using a rapid acquisition with relaxation enhancement (RARE) pulse sequence. All of the phosphorus metabolites other than PCr are forced to dephase within the first few echoes, whereas the Carr-Purcell Meiboom-Gill (CPMG) pulse sequence maintains a high PCr signal long enough to acquire 64 echoes in a single shot. Axial PCr images of a human forearm with a signal-to-noise ratio of 9 were acquired in 2 min. The effect of the refocusing pulse section profile on the ratio of desired to undesired metabolite signal is demonstrated.

Bilateral imaging using separate interleaved 3D volumes and dynamically switched multiple receive coil arrays.

Multiple receive coil arrays are often designed for unilateral imaging of anatomy having bilateral symmetry. A technique is described for extending the utility of such arrays to simultaneously image both bilaterally symmetric anatomical features. A separate, complete multiple receive coil array is placed at each location. Two separate, noncontiguous 3D volumes are then acquired, one at each location, in an interleaved fashion. High-impedance blocking networks are alternately activated and deactivated to minimize coupling between the arrays. It is demonstrated that there is no degradation in image quality when compared to a unilateral exam. A general method for analyzing the interactions between separate multiple coil arrays is presented.

Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.

OBJECTIVE: To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. STUDY DESIGN: Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. POPULATION: A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n = 893; generalized Wilcoxon statistic, P = .22) or among patients with shock at study entry (n = 713; generalized Wilcoxon statistic, P = .23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n = 563; linear dose-response, P = .009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n = 580; linear dose-response, P = .005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n = 411; linear dose-response, P = .002). CONCLUSIONS: There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.

A controlled clinical trial of E5 murine monoclonal IgM antibody to endotoxin in the treatment of gram-negative sepsis. The XOMA Sepsis Study Group.

OBJECTIVE: To assess the efficacy of adjunctive monoclonal antibody antiendotoxin immunotherapy in patients with gram-negative sepsis. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Thirty-three university-affiliated centers, including Veterans Affairs, community, and municipal hospitals. PATIENTS: Hospitalized adults with signs of gram-negative infection and a systemic septic response. INTERVENTION: Patients were assigned to receive either 2 mg/kg of a murine monoclonal antibody directed against gram-negative endotoxin (E5) or placebo. A second infusion was administered 24 hours later. MAIN OUTCOME MEASURES: Mortality over the 30-day study period, resolution of organ failures, and safety. RESULTS: Four hundred eighty-six patients were enrolled. Three hundred sixteen had confirmed gram-negative sepsis (54% bacteremic, 46% nonbacteremic). The survival difference was not statistically significant for all patients. Among patients with gram-negative sepsis who were not in shock at study entry (n = 137), E5 treatment resulted in significantly greater survival (relative risk, 2.3; P = .01). Resolution of individual organ failures was more frequent among these patients, occurring in 19 (54%) of 35 patients in the E5 group vs eight (30%) of 27 in the placebo group (P = .05). Four reversible allergic reactions occurred among 247 patients (1.6%) receiving E5. No other toxicity was identified. CONCLUSIONS: Treatment with E5 antiendotoxin antibody appears safe. It reduces mortality and enhances the resolution of organ failure among patients with gram-negative sepsis who are not in shock when treated.

Successful treatment of gram-negative bacillary meningitis with imipenem/cilastatin.

A patient with meningitis caused by a strain of Actinetobacter anitratus that was resistant to all commercially available antibiotics was treated with imipenem/cilastatin administered intravenously in a dose of 1 gm of imipenem every six hours. The minimal inhibitory concentration of imipenem against the isolate was less than or equal to 0.04 micrograms/ml. The patient tolerated the drug well and was cured after 12 days of therapy.

Penetration of aztreonam into human cerebrospinal fluid in the presence of meningeal inflammation.

Cerebrospinal fluid of aztreonam were measured in 11 patients with meningeal inflammation. Two to eight hours after a single 2 gm intravenous dose, CSF aztreonam levels ranged from 0.76 to 16.6 mg/l. The mean CSF concentration in four patients with viral meningitis was 1.28 mg/l, which was lower than the mean concentration of 7.2 mg/l in the five with bacterial, cryptococcal or carcinomatous meningitis. Two patients with infected subdural drains were also sampled serially and had CSF levels greater than 1 mg/l between 1 and 8 h post dose. Penetration of aztreonam into the CSF in the presence of meningeal inflammation appears adequate to warrant therapeutic trials in patients infected with susceptible organisms.

Twice-daily intramuscular ceforanide therapy of Staphylococcus aureus endocarditis in parenteral drug abusers.

Twice-daily intramuscular ceforanide therapy of Staphylococcus aureus endocarditis in parenteral drug abusers was compared in a randomized prospective trial with intravenous cephapirin therapy. Dosage regimens were ceforanide, 1 g every 12 h, and cephapirin, 2 g every 4 h. Mean minimal inhibitory and bactericidal concentrations of ceforanide for S. aureus treated with ceforanide were 0.78 and 1.56 microgram/ml compared to cephapirin for patient isolates of 0.08 and 0.14 microgram/ml, respectively. Serum killing levels with ceforanide were 1:5.7 and 1:1.5 at peak and trough levels, compared to 1:134 (peak) and 1:4.2 (trough) with cephapirin. Despite this apparent in vitro advantage of cephapirin, patients treated with ceforanide did as well as those with cephapirin. Of 16 ceforanide-treated patients, all responded initially to therapy, and 15 were cured with 28 days of therapy. One patient relapsed at the end of therapy. Of 16 cephapirin-treated patients, 1 was a clinical and microbiological failure, and 3 other relapsed at the end of therapy. In addition, one ceforanide-treated patient and two cephapirin-treated patients developed central nervous system abscesses. These were cured with drainage and continuation of antibiotic therapy. Ceforanide was well tolerated by the intramuscular route. Cost analysis suggests that therapy with intramuscular ceforanide would result in an approximate 70% decrease in drug therapy cost when compared to intravenous cephapirin. Ceforanide appears to be a safe, efficacious, convenient, and relatively inexpensive drug for treating staphylococcal endocarditis in parenteral drug abusers.

Toxoplasma encephalitis in recent Haitian entrants.

We evaluated clinical features of five cases of Toxoplasma encephalitis (TE) occurring in recent Haitian entrants into the United States. None of the patients had any underlying malignancy or known immunosuppressive therapy. Histopathologic findings of TE at autopsy were confirmed by peroxidase-antiperoxidase method. Four patients had an antecedent episode of disseminated tuberculosis and all five were receiving antituberculous therapy when neurologic manifestations of lethargy, seizures, and motor weakness first developed. These symptoms progressed into coma and death within 15 days. Peripheral lymphocytopenia was noted in all patients; three were anergic. Parenchymal lesions were identified by CT brain scans and total proteins were elevated in spinal fluid in all cases. TE appears to be a manifestation of the acquired immune deficiency syndrome in Haitians; it should be suspected in those with a febrile illness and multiple focal lesions of the central nervous system.

Clinical evaluation of piperacillin with observations on penetrability into cerebrospinal fluid.

Piperacillin, a new semisynthetic penicillin, was evaluated for efficacy and safety in 26 patients, most of whom had pneumonia. Included were four patients with gram-negative meningitis in whom the penetration of piperacillin into cerebrospinal fluid was determined. Cure was achieved in 11 of 17 patients with pneumonia; another 4 were improved. One relapse and one failure occurred among nine patients with gram-negative pneumonia. Cure or improvement occurred in seven of nine patients with gram-negative infection in various extrapulmonary sites. Piperacillin given by continuous infusion in a dosage ranging from 324 to 436 mg/kg of body weight per day to four patients with meningitis resulted in a mean cerebrospinal fluid level of 23 micrograms/ml at 24 h; the mean penetration of piperacillin into the cerebrospinal fluid was 32% at this interval. Levels of piperacillin in cerebrospinal fluid collected later during the course of therapy were also adequate. Adverse effects were noted in six patients, but only one episode of granulocytopenia was serious. Emergence of resistance to piperacillin did not occur, and only one superinfection was noted. Piperacillin appeared to be efficacious in the treatment of pneumonia. It penetrated well into the cerebrospinal fluid of patients with meningitis and may be useful for treatment of selected gram-negative infections in extrapulmonary sites.

A fatal case of Legionnaire's disease following a total laryngectomy.

Legionnaire's disease (LD) has been responsible for the death of many patients in several outbreaks in the United States and abroad. The Legionnaire's bacterium is still unclassified. Deoxyribonucleic acid studies of its genes have not yet found a near relative. A case of a 63-year-old man who had a total larynegectomy for cancer of the larynx is reported. He had an extensive postoperative pneumonia, secondary to LD. The diagnosis was made while the patient was alive, but he died on the 35th hospital day in spite of erythromycin treatment.

Staphylococcal endocarditis in addicts.

We retrospectively reviewed 55 episodes that fulfilled criteria for Staphylococcus aureus endocarditis in 50 drug addicts. The most common presenting symptoms were fever(90%), chest pain(58%), and cough(43%). All patients had evidence of right-sided heart involvement, and a murmur of tricuspid insufficiency was noted in 42%. Evidence of left-sided heart involvement was present in only 5%. The most helpful laboratory aid in facilitating an early clinical diagnosis of endocarditis was the chest x-ray film. Roentgenographic evidence of septic pulmonary emboli was present in 67% of initial chest films and eventually in 87% of all cases. All but five patients completed at least four weeks of intravenous antibiotic therapy. No patients required cardiac surgery and there were no deaths. The apparent predilection of S aureus for the right side of the heart and infrequent left-sided involvement may explain why addicts with endocarditis have a favorable response to antibiotic therapy.

Amikacin therapy of gram-negative bacteremia and meningitis. Treatment in diseases due to multiple resistant bacilli.

The therapeutic efficacy of amikacin was evaluated in patients with serious hospital-acquired infections caused by Gram-negative bacilli susceptible to amikacin, but usually resistant to kanamycin, gentamicin, and tobramycin. The infections for which amikacin was given were Gram-negative bacteremia in 15 patients and Gram-negative meningitis in two patients. Therapy with amikacin resulted in a cure in 13 patients, improvement in 1, and failure in 3. Continuous intravenous infusion of amikacin yielded a high cerebrospinal fluid to serum ratio of amikacin in one case of meningitis and intrathecally administered amikacin yielded high ventricular fluid levels in another case of meningitis. The emergence of resistance to amikacin was noted in one patient treated with amikacin in whom Serratia bacteremia persisted. Treatment with amikacin was usually tolerated well. This study indicates that amikacin is an effective antibiotic in the treatment of serious Gram-negative infections caused by gentamicin-resistant organisms.

Lung biopsy in immunocompromised hosts.

Ninety-five lung biopsy procedures in 78 immunocompromised patients yielded treatable diagnoses in 35 per cent of the needle aspirates, 46 per cent of the cutting needle biopsies and 65 per cent of the open thoracotomies. Complication rates of bleeding or pneumothorax were comparable to those previously described in nonimmunocompromised patients. In patients with coagulation defects, the risk of having bleeding complications was high. Among 44 patients with primary lymphoma, 22 (50 per cent) had a lymphomatous infiltrate in the lung. Twenty-two patients with severe hypoxemia were studied and their mortality, although significantly greater than in the patients without hypoxemia, was marginally improved when a treatable lung lesion was found. The over-all recovery rate was 70 per cent when a treatable diagnosis was made in contrast to 25 per cent when there was no specific diagnosis. Hence lung biopsy, particularly by thoracotomy, appears to be a valuable procedure in immunocompromised patients who have otherwise undiagnosable lung lesions.

Antibiotic combinations in the treatment of experimental Staphylococcus aureus infection.

A penicillin-sensitive strain of Staphylococcus aureus was used to evaluate the efficacy of six antibiotic combinations in the therapy of an experimental infection in mice. One hour after intraperitoneal infection, animals were treated with penicillin G, erythromycin, clindamycin, gentamcicin, or tobramycin singly or in various combinations of two of these drugs. Penicillin in combination with tobramycin, gentamicin, or ertyromycin significantly reduced mortality was compared with therapy with a single drug. Survival of animals treated with the combinations of penicillin and clindamycin, clindamycin and gentamicin, and erythromycin and gentamicin was not different from that seen with single-drug therapy. Pencillin plus either gentamicin or erythromycin significantly reduced the number of culturable organisms from livers and spleens of infected animals when compared with penicillin, gentamicin, or erythromycin alone. In vitro studies correlaed with some aspects of in vivo results but conflicted with others. Thus the combination of penicillin with either an aminoglycoside antibotic or erythromycin is more effective than a single drug in the therapy of infection caused by the Smith strain of S. aureus.

DNA of a human hepatitis B virus candidate.

Particles containing DNA polymerase (Dane particles) were purified from the plasma of chronic carriers of hepatitis B antigen. After a DNA polymerase reaction with purified Dane particle preparations treated with Nonidet P-40 detergent, Dane particle core structures containing radioactive DNA product were isolated by sedimentation in a sucrose density gradient. The radioactive DNA was extracted with sodium dodecyl sulfate and isolated by band sedimentation in a preformed CsCl gradient. Examination of the radioactive DNA band by electron microscopy revealed exclusively circular double-stranded DNA molecules approximately 0.78 mum in length. Identical circular molecules were observed when DNA was isolated by a similar procedure from particles that had not undergone a DNA polymerase reaction. The molecules were completely degraded by DNase 1. When Dane particle core structures were treated with DNase 1 before DNA extraction, only 0.78-mum circular DNA molecules were detected. Without DNase treatment of core structures, linear molecules with lengths between 0.5 and 12 mum, in addition to the 0.78-mum circles were found. These results suggest that the 0.78-mum circular molecules were in a protected position within Dane particle cores and the linear molecules were not within core structures. Length measurements on 225 circular molecules revealed a mean length of 0.78 +/- 0.09 mum which would correspond to a molecular weight of around 1.6 x 10(6). The circular molecules probably serve as primer-template for the DNA polymerase reaction carried out by Dane particle cores. Thermal denaturation and buoyant density measurements on the Dane particle DNA polymerase reaction product revealed a guanosine plus cytosine content of 48 to 49%.

DNA polymerase in the core of the human hepatitis B virus candidate.

Experiments were done to show that the human hepatitis B antigen (HBAg)-associated DNA polymerase is a component of Dane particles and their antigenically distinct cores prepared by Nonidet P-40 detergent treatment of Dane particles. Before detergent treatment, the DNA polymerase was precipitated by serum containing anti-HB surface antigen (anti-HB(s)) but not with serum containing anti-HB core antigen (anti-HB(c)). After detergent treatment, the enzyme was precipitated by anti-HB(c)- and not by anti-HB(s)-containing serum. Highly purified 16- to 25-nm HBAg particles blocked only the precipitation of DNA polymerase in untreated HBAg preparations. The 110S structure with which the DNA reaction product remains associated in Nonidet P-40-treated preparations was identified as Dane particle core by immunoprecipitation with serum containing anti-HB(c). The DNA polymerase and the radioactive DNA reaction product were used as markers for core in immunoprecipitation tests for anticore. In such assays, 8 of 11 human sera with anti-HB(s) activity and all of 10 sera from chronic HBAg carriers were found to contain anti-HB(c) activity.

DNA polymerase associated with human hepatitis B antigen.

DNA polymerase activity was detected in each of eight preparations of concentrated human hepatitis B antigen (HBAg) rich in Dane particles prepared by high-speed centrifugation of antigen-positive human plasma and in none of seven control preparations prepared in the same way from HBAg-negative plasma. The incorporation of (3)H-thymidine-methyl-5'-triphosphate into DNA was dependent on four deoxyribonucleoside triphosphates and MgCl(2). Treatment of the concentrated HBAg preparations with the nonionic detergent Nonidet P-40 (NP40) more than doubled the enzyme activity. Fractionation of the concentrated HBAg preparation in sucrose density gradients after treatment with NP40 revealed that the enzyme activity appeared within the density range of Dane core antigen but at a slightly higher density than the average for core antigen. The only particles observed by electron microscopy in this region of the gradient were typical 28-nm cores, suggesting that the DNA polymerase activity was associated with a subpopulation of cores. No DNA polymerase activity was found in purified 20-nm HBAg particles. The DNA product of the reaction remained associated with the 110S core and was not susceptible to DNase digestion when associated with the core. Inhibition of the reaction by actinomycin D and daunomycin suggested that the reaction was dependent on a DNA template associated with the core.