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Biomedical subjects

S Baron

Publications and source records attributed to S Baron.

At least 19 recordsLinked to original sources

Further characterization of a broad-spectrum antiviral substance in human serum.

A broadly active antiviral glycoprotein (UTI beta) occurs naturally in human sera at an average antiviral titer of 50 U/ml. This inhibitor is active against all virus families tested to date, including representative poxviruses, herpesviruses, enteroviruses, paramyxoviruses, alpha-viruses, flaviviruses, bunyaviruses, and rhabdoviruses. It is a glycoprotein of approximately 60,000 +/- 10,000 Da, which is stable at pH 2 to 10 and at 80 degrees C for up to 10 min. Mild oxidation with NaIO4 and treatment with glycosidases inactivates the material. Proteolytic degradation of the inhibitor molecule releases small active components of < 1000 Da, which retain antiviral activity. This activity of the small components has increased heat stability (120 degrees C for 15 min) and is inactivated by glycosidases. The antiviral activity thus appears to reside mainly in the oligosaccharide moiety of the glycoprotein. The inhibitor does not neutralize virions, but prevents attachment of most viruses to cells. These properties occur also in highly purified preparations. These findings indicate that human serum contains significant concentrations of a broadly active antiviral glycoprotein, which is distinct from interferon and other antiviral substances naturally found in human body fluids and tissues.

Adult

The interferons. Mechanisms of action and clinical applications.

The interferons (IFN) are one of the body's natural defensive responses to such foreign components as microbes, tumors, and antigens. The IFN response begins with the production of the IFN proteins (alpha, beta, and gamma), which then induce the antiviral, antimicrobial, antitumor, and immunomodulatory actions of IFN. Recent advances have led to Food and Drug Administration approval of five clinical indications for IFN. Interferon alfa is approved for hairy-cell leukemia, condyloma acuminatum, Kaposi's sarcoma in the acquired immunodeficiency syndrome, and non-A, non-B (type C) viral hepatitis. Interferon gamma has properties distinctive from those of IFNs alpha and beta and is approved as an immunomodulatory treatment for chronic granulomatous disease. Promising clinical results with IFNs have also been reported for basal cell carcinoma, chronic myelogenous leukemia, cutaneous squamous cell carcinoma, early human immunodeficiency virus infection, hepatitis B, and laryngeal papillomatosis. Future clinical uses of IFNs may emphasize combination therapy with other cytokines, chemotherapy, radiation, surgery, hyperthermia, or hormones.

Humans

Restoration of in vitro hematopoiesis in B-chronic lymphocytic leukemia by antibodies to tumor necrosis factor.

Hematopoiesis was evaluated in 15 B-CLL patients using the mixed colony formation assay. The mean growth of all types of colonies in B-CLL peripheral blood was significantly lower than that of 10 normal controls (p less than 0.05). To investigate whether TNF is the cytokine involved in the reduced growth of hematopoietic progenitors in B-CLL, neutralizing anti-TNF antibodies (anti-TNF Abs) were added to the cultures. Anti-TNF Abs optimized in vitro hematopoiesis in 11 out of 15 B-CLL patients and a significant growth increase in all types of colonies was noted as compared to baseline cultures (p less than 0.05). In patients with stage IV disease, the increase in both mixed and erythroid colonies was more prominent than in patients with earlier disease stages. This optimization of growth was also observed in normal control cultures containing accessory cells. However, high TNF levels were measured in conditioned media from CLL patients and suppressed normal bone marrow hematopoietic progenitors growth. In contrast no TNF was detected in normal conditioned media. It is concluded that TNF and other cytokines, among them IL-3, play a role in the regulation of hematopoietic function in some B-CLL cases. These findings may have clinical applicability.

Aged

[Antibiotic treatment of acute otitis media].

The strategy of antimicrobial therapy in acute otitis media rests on bacteriologic and pharmacokinetic data. Pneumococci and Haemophilus are still the two most prevalent pathogens in acute otitis media and raise problems regarding susceptibility: 25% of Haemophilus beta-strains produce beta-lactamases and 6 to 12% of pneumococci are intermediate or resistant to penicillin. Pharmacologic features required of antimicrobials used in acute otitis media include good penetration in the ear and sustained supra-MIC levels in middle ear fluid. Kinetics of drugs in the ear are still often incompletely understood. The last selection criterion is analysis of comparative trials. Available data do not point to superiority of any drug over the others. Amoxicillin should no longer be given as first-line therapy. Amoxicillin combined with clavulanic acid (Augmentin) is effective on the entire spectrum of causative organisms. Higher levels of amoxicillin may be needed (concomitant use of amoxicillin and (Augmentin). First-generation cephalosporins are effective but may prove unsuccessful in patients with large inocula. Pediazole is clinically effective although penetration of erythromycin in the ear is delayed. The new oral third generation cephalosporins are effective in infections due to beta-lactamase-producing Haemophilus strains. A bacteriologic study should be performed routinely whenever otitis media occurs in an infant under three months of age.

Acute Disease

[Acellular anti-pertussis vaccine].

Since several years, pertussis has increased especially in non-immunized young infants under 6 months of age, in countries where pertussis-immunization is in widespread use. The whole-cellular pertussis vaccine so far used in these countries is not well tolerated, has been indicted in adverse neurological complications, and offers significant but temporary protection partially because of the absence of late booster-shots. The necessity to improve vaccine protection has justified the development of much better tolerated acellular pertussis vaccines thus allowing repeated booster-shots. Its safety and duration of protection are still under evaluation, but preliminary results are promising.

Adolescent

Characterization of the airborne concentrations of lead in U.S. industry.

Occupational exposure to lead represents a continuing problem of significant magnitude in the United States. To characterize the problem for surveillance purposes, an analysis of the airborne concentrations of lead identified in OSHA compliance inspections was conducted for the years 1979 to 1985. The five specific objectives of the study were: 1) to examine the distribution of air lead concentration in industrial environments; 2) to determine the secular trends in air lead concentrations for high lead industries; 3) to assess which job titles had excessive airborne lead concentrations; 4) to evaluate whether there was a relationship between lead overexposure and company size, unionization, or type of inspection; and 5) to investigate the prevalence of respirator violations for lead. Fifty-two industries were identified which had more than 1/3 of their inspection medians greater than the permissible exposure limit. These included primary and secondary lead smelting, battery manufacture, pigment manufacture, brass/bronze foundries, as well as 46 other industries. There has been little if any improvement in the prevalence and severity of airborne lead concentrations for the high lead industries, battery manufacture, secondary smelting, pigment manufacture, and brass/bronze foundries. Specific high exposure job titles are identified for certain high lead industries. The job title of painting stands out as an especially problematical job title across a number of industries. The prevalence of respirator violations is approximately 20% of all lead inspections.

Air Pollutants, Occupational

The effect of an arenavirus infection on liver morphology and function.

Patients with severe Lassa fever have high serum levels of liver enzymes. Studies of the histology of the liver have shown only minor alterations, seemingly insufficient to account for death. Pichinde virus is an arenavirus which causes severe illness similar to Lassa fever in strain 13 guinea pigs, but does not cause severe illness in man. This can serve as a relatively safe model for studying the pathology and pathophysiology of fatal arenaviral infection. We used this infection to evaluate the effect of arenavirus on liver morphology and function. When guinea pigs were infected with Pichinde virus, all developed severe disease and died within 14 days of infection. The animals lost large amounts of weight. Higher levels of virus were detected in the liver than in serum. Aspartate aminotransferase and alanine aminotransferase were elevated late in the course of the disease; no elevations were seen in gamma glutamyl transpeptidase or bilirubin. Alkaline phosphatase, initially high in these growing animals, was markedly decreased early in infection. Prothrombin time and activated partial thromboplastin time were increased late in the disease, and decreased levels of Factors VIII and IX were seen relatively early. Fatty metamorphosis, indicating problems in lipid processing, occurred by day 11, but necrosis was minor and occurred late. Pichinde virus infection results in significant alterations in the metabolic and synthetic capacities of the hepatocytes early in infection in the absence of significant necrosis.

Alanine Transaminase

[Tonsillar diffusion of cefixime in children].

Cefixime was assayed by a microbiological method in the tonsils of 21 children (mean age 59 months). Tonsillectomy was performed 5 hours after a third dose of 4 mg/kg administered 12-hourly. Plasma cefixime levels were evaluated 10 hours after the second dose with a mean value of 0.84 mg/l (range: 0 to 1.35) and again after a third dose during amygdalectomy with a mean value of 1.24 mg/l (range: 0.1 to 3.9). Cefixime concentrations were 0.74 micrograms/g in the right tonsils and 0.53 micrograms/g in the left tonsils. The antibiotics could not be detected in both tonsils in 6 children and in one of the two tonsils in 11 children. The tissue penetration of cefixime in tonsils therefore was about 1 micrograms/g in those cases where cefixime was detectable. As with other beta-lactam antibiotics, this penetration is not regular, being dependent on the degree of tonsillar fibrosis inhibitin their diffusion.

Biological Transport

[Hereditary neuropathy with liability to pressure palsy].

Hereditary neuropathy with liability to pressure palsy (HNPP) is a rare nosological entity with 4 characteristics: autosomal dominant inheritance; clinical presentation as mononeuropathy simplex or multiplex, often related to minor trauma; significant slowing of motor and sensory conduction in both clinically affected and unaffected nerves; and characteristic morphological findings on sural nerve biopsy, including "tomaculous" swelling of myelin sheaths, transnodal myelination and segmental demyelination. The pathogenesis of HNPP is unknown. Clinical and neuropathological investigations were carried out in 7 members of a family with HNPP, and sural nerve biopsy in 1. The findings are related to those of about 50 families published in the literature.

Biopsy

Inhibition of human immunodeficiency virus (HIV-1) infection by diphenylhydantoin (dilantin) implicates role of cellular calcium in virus life cycle.

Details of the molecular interactions between human immunodeficiency virus (HIV-1) and its host cell during the infection process are not entirely clear. Building on recent reports by Lehr and Zimmer (1986, DMW 111, 1001-1002) that the membrane-reactive, anti-epileptic drug diphenylhydantoin (dilantin or phenytoin) (PHT) inhibited binding of HIV to lymphocytes, we hypothesized that understanding the relevant effects of this drug on cells may shed light on aspects of HIV-1 infection. We found that PHT inhibited, in a dose-dependent manner, de novo infection of various T-cell lines as well as a monocytic cell line. Moderate inhibition of HIV-1 infection was observed with drug concentrations that are therapeutic in vivo for epilepsy (approximately 20 micrograms/ml), and no concentrations used induced deleterious effects on cell growth or viability. Surprisingly, treatment of chronically infected H9 cells reduced HIV p24 expression within 1-6 weeks according to dose. This apparent induction into latency was not inhibited by cotreatment of the chronically infected cells with 5-azacytidine, which indicated that PHT was not inducing latency by induction of methylation of the viral DNA. Flow cytometric analysis demonstrated that PHT did not significantly reduce cell-surface expression of CD4. The possibility remained that the drug inhibited HIV infection due to its known effects on calcium-dependent cellular processes. Subsequent measurements of intracellular calcium demonstrated that an increase of [Ca2+]i occurred at least 24 hr postinfection, prior to synthesis of detectable viral structural protein p24, and that this virus-induced increase in [Ca2+]i was not due to binding of HIV to the cell. This HIV-induced rise in [Ca2+]i was significantly inhibited by PHT. PHT demonstrated variable inhibitory effects on infection of normal PHA-stimulated PBLs cultured in vitro, but it was synergistic to low-dose AZT (0.01 microgram/ml) in inhibiting infection of cell lines. Because of the known inhibitory effects of PHT on calcium-dependent biochemical processes in the cell, inhibition of HIV-1 infection by PHT suggests that calcium may play a role in HIV infection and maintenance. The drug may also be a candidate therapy for individuals infected with HIV.

CD4-Positive T-Lymphocytes

Characterization of lympho-myeloid-erythroid-megakaryocytic stem cells in peripheral blood of hairy cell leukemia patients.

Circulating stem cells with lympho-myeloid-erythroid differentiative capacity have been described in the peripheral blood of hairy cell leukemia (HCL) patients (Michalevicz R. & Revel M. (1987) Interferons regulate the in vitro differentiation of multilineage lympho-myeloid stem cells in Hairy Cell Leukemia. Proc. natn. Acad. Sci. U.S.A. 84, 2307.) The aim of the present work was to enrich the progenitors and characterize their antigenic and growth properties. Peripheral blood (PB) from HCL patients was stained with antibodies (BI3C5 (CD34) and/or My10 as well as RFB7 (CD20) and RFT12 (CD7) and sorted using flow cytometry (FCM) into positive and negative fractions. Peripheral blood cells from several patients showed 4-16% cells positive for the BI3C5/My10. The positive fraction contained all the colony-forming cells and LGEM/LG/LGM colonies were enriched approximately ten-fold as compared to the unsorted population. No colony was found in the negative fraction. All colony forming cells were in the RFB7 and RFT12-negative fractions. Thus, circulating stem cells with lymphoid/myeloid potential can be isolated from PB of HCL patients.

Antibodies, Monoclonal

Arenavirus infection in the guinea pig model: antiviral therapy with recombinant interferon-alpha, the immunomodulator CL246,738 and ribavirin.

Human arenaviral infections have a high mortality, and are dangerous to work with in the laboratory. There is a need for good antiviral agents to treat these infections. Pichinde virus infection of the inbred strain 13 guinea pig is a relatively safe, good animal model for human arenavirus infections. Mortality is consistently 100% between days 12 and 25 (mean 14.8) days after infection. When infected animals were treated with recombinant human interferon alpha A, or with CL246,783, an immunomodulator known to induce interferon, no beneficial effect was noted. When animals received ribavirin, 25 mg/kg/day for the first 14 days of infection, the course of infection was prolonged, with death occurring a mean of 22.5 days after infection. If ribavirin was administered for 28 days, mortality was reduced to 25%, with those animals dying a mean of 21.0 days after infection. These results confirm the studies that indicate that ribavirin is a useful agent for treating arenaviral infections. However, treatment with this agent must be prolonged. They also demonstrate the potential usefulness of Pichinde virus infection in strain 13 guinea pigs as an animal model of human disease.

Acridines

The in vivo antiviral effect of CL246,738 is mediated by the independent induction of interferon-alpha and interferon-beta.

An interferon (IFN) inducer and immunomodulator, CL246,738 [3,6-bis(2-piperidinoethoxy)acridine trihydrochloride], protected mice from lethal infection with Semliki Forest (SFV) and Banzi (BZV) viruses. A single oral dose of CL246,738 (5-150 mg/kg) administered 24 h before intraperitoneal challenge with SFV or BZV fully protected mice from lethal infection. Dose-dependent levels of circulating IFN peaked at 24 h in the serum and peritoneal fluid of CL246,738-treated mice. The circulating IFN of CL246,738-treated mice consisted of IFN-alpha and was produced by spleen cells. Peritoneal exudate cells (PEC) obtained from CL246,738-treated mice produced IFN-beta. Treatment in vivo with anti-IFN-alpha/beta and anti-IFN-beta reversed the protective effect of CL246,738 against lethal SFV encephalitis.

Acridines

Postinfection therapy of arbovirus infections in mice.

Most antiviral agents are efficacious prophylactically in vivo, and a few are efficacious for postinfection (p.i.) therapy. To explore possibilities for p.i. therapy of encephalogenic Banzi virus (BZV) and Semliki Forest virus infections in mice, we evaluated candidate antiviral therapies after development of the first clinical signs of infection. The earliest clinical indication of BZV viremia in mice is a rise in core body temperature beginning on day 3 p.i. BZV-infected mice showing elevated core body temperatures (greater than or equal to 37.3 degrees C) on days 3 and 4 p.i. were treated intraperitoneally with the interferon inducer poly(ICLC) (80 micrograms per mouse) and/or specific antiserum. Combined therapy on day 3 of a BZV infection protected over 75% of mice showing clinical evidence of viral disease before treatment. Protection against early brain infection must occur on day 4 p.i., since by that day BZV has started multiplying in the brains of the mice. Significant protection occurred with antiserum alone and increased with poly(ICLC). Similar protection was obtained during Semliki Forest virus viremia, but this infection is so rapid that the first clinical signs are reliably detectable only after viremia.

Animals

Long-term killing of natural killer-resistant target cells by interferon-alpha-, interferon-gamma-, and interleukin-2-activated natural killer cells.

The sensitivity of target cells to natural killer (NK) cell-mediated cytotoxicity was investigated. Five target cell lines were examined for susceptibility to killing by activated NK cells in a 4-hour cytotoxicity assay: one of them (K562) was highly sensitive, while the other four were resistant. However, the four NK-resistant target cell lines were fully susceptible to lysis when the assay was extended to 24 h. The cytotoxic cells that killed the NK-resistant target cells in a 24-hour assay were plastic- and nylon wool-nonadherent human peripheral blood mononuclear cells (PBMC) and their cytotoxicity was increased by interferon-alpha, interferon-gamma, and interleukin-2. Further, the cytotoxic activity of PBMC in the long-term assay was associated with large granular lymphocytes purified on a Percoll gradient, that killed the NK-sensitive cell line K562 in a 4-hour assay. All of the above are general criteria to qualify the cytotoxic cells as NK cells. Thus, the NK-resistant phenotype may not reflect absolute immunity to NK-mediated lysis, but it may reflect the different rates at which various target cell lines can be killed.

Cell Line

Granulocytic macrophage colony stimulating factor restores in vitro growth of granulocyte-macrophage bone marrow hematopoietic progenitors in dyskeratosis congenita.

In vitro 14-day cultures of bone marrow from a patient with dyskeratosis congenita showed virtually no growth of colonies. The addition of recombinant granulocyte-macrophage colony stimulating factor (rGM-CSF) promoted a significant increase in the number of GM colonies (CFU-GM). Interleukin 3 also increased GM colony formation but to a lesser extent. GM-CSF may have a therapeutic implication for pancytopenia in dyskeratosis congenita.

Adult

[Clinical and pharmacokinetic study of ceftizoxime in newborn infants and children].

Ceftizoxime was evaluated in the treatment of 49 children and 15 neonates. The average dosage was 150 mg/kg/d for newborns and 115 mg/kg/d for children, administered IV, 3 or 4 times daily. Clinical and bacteriological cure was achieved in 93% children and 92% neonates. The clinical and biological tolerance was very good. Pharmacokinetic parameters were studied in 17 patients, including 2 neonates. In children the mean serum peak was 40 mug/ml and the mean half life was 2.2 +/- 0.6 H, after a dose of 30 mg/kg. In both neonates the half life was 3.1 H and 3.6 H. In urine, mean concentration of 4 g/l has been obtained in the first 2 hours after IV.

Adolescent