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Biomedical subjects

A M Lerner

Publications and source records attributed to A M Lerner.

At least 73 records · Page 4Linked to original sources

Non-traumatic gram-negative bacillary meningitis in the Detroit Medical Center, 1964-1974; (with special mention of cases due to Escherichia coli).

Clinical and autopsy records of eight adults with non-traumatic gram-negative bacillary meningitis who were admitted to the hospitals of the Wayne State University--Detroit Medical Center during the years 1964 to 1974 were reviewed. There were five community-acquired cases, and five patients died. Escherichia coli was the causative enteric bacillus in six cases. Community-acquired infections were due to Esch. coli in four of the patients. Each of the patients with a community-acquired infection was a chronic alcoholic. Esch. coli bronchopneumonias, urinary infections, and bacteremias seeding the meninges were usual. Shunting contaminated portal venous blood through the liver in patients with Laennec's cirrhosis, or bypassing the liver with similar infected blood from a genitourinary source by way of Batson's perivertebral plexus draining into the cerebral dural sinuses may be important in the pathogenesis of these infrequent cases of nontraumatic gram-negative bacillary meningitis. Spontaneous gram-negative bacteremias, peritonitis, bronchopneumonias, and now "meningitis" may be a constellation of special complications of the alcoholic. Mortality among 25 patients with Esch. coli meningitis reported from 1922 to 1974 is approximately 50%, and has not changed appreciably during the antibiotic era. Mortality, however, is significantly higher in nosocomially acquired cases. Early and more recent cases have had bloody, xanthochromic pleocytoses indicative of leptomeningeal arterial and venous vasculitis, and far advanced disease. Since causative/enteric bacilli have been susceptible to antimicrobial agents employed, another mode of antibacterial administration, perhaps utilizing parenteral plus intraventricular dosing, particularly for patients acquiring their infections in the hospital, may be required.

Adult↗

Antiherpesvirus activity in human sera and urines after administration of adenine arabinoside: in vitro and in vivo synergy of adenine arabinoside and arabinosylhypoxanthine in combination.

The minimum inhibitory concentration (MIC) of adenine arabinoside (ara-A) in rabbit kidney microtiter tissue cultures (RK-13) to a prototype strain of herpes simplex virus, type 1 (E115) based upon inhibition of cytopathic effects is 1.5 mug/ml. In this system, the MIC of arabinosylhypoxanthine (ara-Hx), the major in vivo metabolic derivative of ara-A, is 75 mug/ml. Inhibition of cytopathic effects of herpes simplex virus, type 1 (HSV-1) in microtiter wells of RK-13 cells varies directly with the concentrations of ara-A or ara-Hx, and inversely with residual HSV-1. The MIC of ara-A for HSV-1 in RK-13 cells is 5-20 times lower than similar measures with vero renal, mouse embryo, or human foreskin cultures. With RK-13 tissue cultures in microtiter plates, an assay for "ara-A equivalents" in human body fluids was developed which compares in sensitivity with high pressure liquid chromatography and has the advantage of simultaneously measuring combined antiherpesvirus effects of ara-A and its major metabolic derivative, ara-Hx. In vitro checkerboard studies in RK-13 cells confirmed that ara-A and ara-Hx in combination had antiviral effects which are synergistic. The total of the fractional MIC of ara-A plus ara-Hx in combination also varies inversely with residual HSV-1 in microtiter wells. Because virus adsorption is complete at 2 h before specimens to be tested are added in this assay, and because human interferon is not measured in rabbit cells, the antiviral assay is not affected by the presence of type-specific antiherpesvirus antibody or human interferon.Antiviral activity (AVA) was assayed as ara-A equivalents in sera and urines from 10 patients with serious herpesvirus infections who received 2.5-20 mg/kg daily of ara-A by intramuscular or intravenous routes. When a dosage schedule of 10 mg/kg per day or more was used, sustained concentrations of AVA that ranged from 0.8 to 14.4 mug/ml were found. When an inhibitor of adenosine deaminase (covidarabine) was not added to the specimens, mean serum concentrations were congruent with3.0 mug/ml (10 mg/kg per day, i.v.), and 4.1 mug/ml (20 mg/kg per day). However, in a single patient given 20 mg/kg of ara-A daily with covidarabine immediately added to the sera, the mean concentration of AVA was 12.9 mug/ml. Urines contained even higher AVA. Assays of 19 sera were performed both by microbiologic assay for AVA and by high pressure liquid chromatography for ara-A and ara-Hx. AVA was greater by microbiologic assay, and was greater than that which could be accounted for by stoichiometric chromatographic measures of ara-A and ara-Hx. These results with sera of treated patients are consistent both with the in vitro synergy of ara-A and ara-Hx found by checkerboard titrations, and with the beneficial responses to ara-A of patients with herpesvirus infections reported here and elsewhere.

Adult↗

Some previously unrecognized features of herpes simplex virus encephalitis.

The courses of 15 brain biopsy-proven cases of herpes simplex virus encephalitis (HSVE) were followed for 6 to 67 months. Convulsive disorders were often temporary, but paralysis was permanent. Patients usually entered the hospital free of paralysis or coma, in a potentially reversible febrile confusional state. Later, paralysis and coma fixed subsequent courses. Mortality was 53.3 percent but, at follow-up, 93.3 percent (14 patients) were dead or living a vegetative existence at home or in institutions. If a definitive diagnosis of HSVE could be made at the time of hospital admission, the prognosis might be remarkably changed.

Adolescent↗

Differentiation of several isolates of Peptococcus magnus by counterimmunoelectrophoresis.

Uniform sonicated suspensions of three clinical isolates of Peptococcus magnus that were morphologically, chromatographically, and biochemically identical were used to produce hyperimmune antisera in rabbits. Similar hyperimmune serum was prepared to a single strain of Peptostreptococcus anaerobius. When these antisera and antigens were tested by counterimmunoelectrophoresis, the three isolates of Peptococcus magnus were immunologically distinct. None of the antisera to Peptococcus magnus formed precipitin lines with Peptostreptococcus anaerobius.

Animals↗

Inhibitory and lethal concentrations of 9-beta-D-arabinofuranosyladenine and its hypoxanthine-derivative versus herpes simplex virus, type 1.

Minimum inhibitory concentrations of 9-beta-D-arabinofuranosyladenine (ara-A, adenine arabinoside, vidarabine) and a purified preparation of 9-beta-D-arabinofuranosylhypoxanthine (arabinoslhypoxanthine, ara-Hx) at end points of 50% MIC50) and 100% (MIC100) reduction to challenges of approximately 50 p.f.u. of herpes simplex virus, type 1 (HSV-1) were determined in vero renal tissue cultures. Adenosine deaminase is universally present in tissue cultures and serum. These same tests were repeated in the presence of a potent inhibitor of adenosine deaminase, R-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo-4,5-d)-(1,3)-diazepin-8-ol (co-vidarabine, co-ara-A). Addition of co-ara-A to assays of MIC50 or MIC100 for ara-A ensures standard reproducible results which can be compared in different laboratories. After incubations of HSV-1 in infected cultures for 96 hours, 35 degrees C., with concentrations of ara-A or ara-Hx at the MIC100 and over, cells were scraped and sonicated. Supernates were then reinoculated into vero flasks free of antiviral agents to determine minimum lethal concentrations (MLC's). Standard values (microng/ml.) for ara-A with co-ara-A are 11.3 (MIC50), 17.0 (MIC100), and 34.0 (MLC) but are 68.1 (MIC50), 170.4 (MIC100) and 375 (MLC) for ara-Hx. These data confirm that as a virustatic agent (MIC100) ara-A is 10 times more active than ara-Hx. Ara-A and ara-Hx have virucidal potentials which require approximately two times the respective MIC100.

Arabinonucleosides↗

Microbiologic assays and neurological toxicity during use of adenine arabinoside in humans.

Patients with herpesvirus infections were given intravenous injections of 10-20 mg of adenine arabinoside (ara-A)/kg per day. When given the higher dosage, some patients with chronic hematologic conditions showed mild to moderate additional depressions in the level of hemoglobin. The number of neutrophils and platelets did not decrease, even when numbers were low at the onset of treatment with ara-A. Two patients with Hodgkin's disease who received 20 mg of ara-A/kg per day developed a transient motor aphasia resembling akinetic mutism. With the regimens of ara-A used and challenge inocula of approximately 50 plaque-forming units of virus, the minimal inhibitory concentrations of ara-A and hypoxanthine arabinoside for herpesviruses are usually not achieved in serum but may be attained in body fluids (urine and vesicular fluid). Antiviral activity in vesicular fluids is likely to involve a combination of ara-A, hypoxanthine arabinoside, and interferon.

Akinetic Mutism↗

Differential sensitivity of herpes simplex virus types 1 and 2 to human interferon: antiviral effects of interferon plus 9-beta-D-arabinofuranosyladenine.

With use of a standard assay for antiviral compounds, in which the compound to be tested is added after absorption of virus, the minimal inhibitory concentration (MIC) of human interferon for several strain of herpes simplex virus type 2 (HSV-2) is five to 10 times greater than it is for two strains of herpes simplex virus type 1 (HSV-1). This differential susceptibility of HSV types to interferon is found whether tests are done with a liquid overlay and microtiter plates or with agarose overlays and appears to be a distinguishing biological marker. When the MIC of interferon is tested by microtiter or agarose methods and interferon is allowed to incubate for 24 hr before virus is added, values for HSV-1 and HSV-2 are similar and much smaller in magnitude. These results support earlier data indicating that adenine arabinoside and interferon are synergistic against herpes simplex virus type 1 in vitro and indicate that these agents are additive but not synergistic against herpes simplex virus type 2.

Antiviral Agents↗

Interferon and neutralizing antibody in sera of exercised mice with coxsackievirus B-3 myocarditis.

Weanling ICR albino Swiss mice were inoculated ip with 1.9 x 10(4) PFU of coxsackievirus B-3 (Nancy) and subsequently forced to swim vigorously daily in a preheated pool (33 degrees). Viremias and virus in hearts of exercised mice were respectively 75 x 1000 x greater than in infected, but not exercised mice. At 24 hr after inoculation, pooled serum from mice that had been swum had no circulating interferon, while infected but not swum mice had interferon activity at a dilution of 1:10. At 72 hr after infection, circulating interferon disappeared from infected (not swum) mice, but continued to be present in high titers through the sixth day in sucklings forced to swim. Interferon was first detected in the hearts of both groups at 48 hr. Quantities in both infected groups were generally similar. Neutralizing antibodies were found in these baby mice on the 13th day of infection and were 16 x greater in nurslings that were not exercised. Measures of corticosterone taken at 4 PM daily were similar in infected, infected-swum, and uninfected mice.

Animals↗

An estimate of the course of herpes simplex virus encephalitis.

Serologic responses, physical findings, and survival were studied in 51 cases of proved (14 patients) or presumptive (37 patients) herpes simplex encephalitis occurring in North America between 1965 and 1972. On the basis of a statistical analysis of 16 serological parameters tested in both groups, presumptive cases are likely similar to definitive cases. Using this assumption, the following tentatives conclusions are possible. Complement-fixing antibodies may be more sensitive measures of rises in anti-herpes simplex virus antibodies than are conventional or complement-requiring neutralizing or passive hemagglutinating antibodies. Mortality in herpes simplex virus encephalitis may vary from 0 to 80% and may be predictable depending upon the occurrence of seizures, paralysis and coma. Coma seems to dictate the dour prognosis. When 51 cases of herpes simplex virus encephalitis reported in the literature by others between 1944 and 1972 were analyzed by this method, a comparably varied mortality was obtained. It did not appear that treatment with idoxuridine increased the likelihood of survival.

Antibodies, Viral↗

Anicteric carbenicillin hepatitis. Eight episodes in four patients.

Carbenicillin disodium was temporally associated with eight episodes of a mild reversible anicteric hepatitis characterized by nausea, vomiting, and a tender, somewhat enlarged liver. Serum glutamic and oxaloacetic transaminase as well as alkaline phosphatase levels rose, but serum bilirubin values remained normal. There usually were no signs of concomitant allergy to penicillin, and other penicillins could be given subsequently without ill effects. Biopsy specimens of the liver showed spotty liver cell necrosis with no cholestasis.

Adult↗

Antiviral activity of an adenosine deaminase inhibitor: decreased replication of herpes simplex virus.

A unique seven-membered heterocyclic-ring inhibitor of adenosine deaminase was studied. One preparation of the compound inhibited replication of herpes simplex virus in the absence of adenine arabinoside. In this capacity, the minimal inhibitory concentration of deaminase inhibitor for herpes simplex virus type 1 (HSV-1), with 50 percent reduction of plaque-forming units as the end point, was 37.7 mug/ml. This activity compared favorably with the inhibitory activity of ara-hypoxanthine (34.1 mug/ml). Another preparation of deaminase inhibitor lacked antiviral activity. On the other hand, the adenosine deaminase inhibitor was active at a concentration of 0.009 mug/ml as a potentiator of the inhibition of HSV-1 by adenine arabinoside. The potentiation of adenine arabinoside by deaminase inhibitor is about 4,000 times more potent than the activity of the direct inhibitory effect on HSV-1. The nature of the possible contaminant of the preparation in question is unknown. Coformycin, another inhibitor of adenosine deaminase, had no antiviral activity in the absence of adenine arabinoside.

Adenosine Deaminase Inhibitors↗

Absence of idoxuridine and persistence of herpes simplex virus in brains of patients being treated for encephalitis.

Thirty-two specimens of brain from five patients with encephalitis suspected to be caused by herpes simplex virus, type 1 (HSV-1) were assayed for antiviral activity. Each patient received 60-80 mg/kg/day of idoxuridine (IDU) by intravenous infusion. The antiviral assay does not measure anti-HSV-1 antibodies. Biopsies of brain in every patient taken before IDU was used, and portions of several regions of the brain at autopsy were available during courses of treatment in four of the five patients. The last patient died 7 days after completing treatment. A significant concentration of IDU (833 mug/ml) was measured transiently in the cerebrospinal fluid of one patient. Meninges and brains showed inflammatory changes. Within the sensitivity of the test (larger than or equal to 6 mug/g) all specimens contained no IDU. As given, IDU does not achieve therapeutic concentrations in human brain. Further clinical use of IDU in therapy of herpes simplex virus encephalitis is not indicated.

Adult↗