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Biomedical subjects

J L Goodman

Publications and source records attributed to J L Goodman.

At least 55 records · Page 3Linked to original sources
PubMed1991

Molecular detection of persistent Borrelia burgdorferi in the urine of patients with active Lyme disease.

Current diagnostic tests for Lyme disease (LD) are dependent upon the host serologic response and are insensitive early in infection and, possibly, following antibiotic therapy. We cloned a library of Borrelia burgdorferi 297 DNA and studied one clone, Ly-1, for its potential in diagnostic and pathogenic studies. Using pulsed-field electrophoresis, we demonstrated that Ly-1 is of chromosomal origin and estimated that the B. burgdorferi chromosome is approximately 1,100 kb in size. The 3.7-kb Ly-1 clone hybridizes with geographically diverse strains of B. burgdorferi. No cross hybridization occurs with DNA from human cells, Escherichia coli, Staphylococcus aureus, Clostridium difficile, or the closely related B. hermsii. We used a dot blot assay to detect 100 pg of B. burgdorferi DNA. We partially determined the nucleotide sequence of Ly-1 and used it to select and synthesize oligonucleotides for use in the polymerase chain reaction (PCR). Two different primer pairs were found to amplify DNA from nine geographically diverse isolates. We could detect 10 fg (less than 10 molecules) of B. burgdorferi or less than five spirochetes added to human urine. Finally, we were able to use the PCR to detect B. burgdorferi DNA in the urine of four of eight patients with suspected active LD (three with arthritis and one with neurologic manifestations), all of whom responded to antibiotic treatment. In contrast, those patients who were PCR negative either had inactive disease or had been appropriately treated and did not respond to additional antibiotics, and all four control urine specimens were PCR negative. We conclude that B. burgdorferi DNA can be sensitively detected by the PCR with the primers and methods we describe and that the urinary tract is a site of persistent infection in some cases of human LD, an observation of potential diagnostic and pathogenic importance.

Adult↗
PubMed1991

Persistent cardiac and urinary tract infections with Borrelia burgdorferi in experimentally infected Syrian hamsters.

The heart can be severely affected in humans with Lyme disease, causing conduction defects and, rarely, heart failure. Although immunodeficient and young mice may develop cardiac lesions, cultivation of Borrelia burgdorferi from cardiac tissues of experimentally infected animals has not been reported previously. We infected Syrian hamsters with B. burgdorferi 297 and found a marked tropism of the spirochete for myocardial and urinary tract tissues. Fifty-six of 57 hearts (98%) and 52 of 58 bladders (90%) were culture positive. The cardiac infection was persistent and could be documented in 21 of 22 hearts (96%) cultured from days 28 to 84 postinfection. The urinary tract was also a site of persistent infection in most animals, with 18 of 23 bladders (78%) being culture positive from days 28 to 84. The persistence of spirochetes was specific for the heart and bladder, as indicated by negative cultures of specimens from the liver and spleen, in which only 1 of 23 cultures was positive from days 28 to 84. Because of the high isolation rates, tropism, and persistence that we found for B. burgdorferi in the hamster heart and bladder, these sites will be useful and important for the cultivation of spirochetes in experimental studies that evaluate the efficacies both of candidate vaccines in preventing infection and of antibiotics in eradicating organisms from privileged sites. In addition, the clear demonstration of persistent cardiac infection with B. burgdorferi may provide a useful model for studying the pathogenesis of cardiac Lyme disease.

Animals↗
PubMed1991

Altered pathogenesis in herpes simplex virus type 1 infection due to a syncytial mutation mapping to the carboxy terminus of glycoprotein B.

A syncytial (syn) variant of herpes simplex virus type 1 strain 17 syn+ was selected by serial passage in heparin, a glycosaminoglycan which potently inhibits herpes simplex virus infectivity. This virus, 17 hep syn, is sixfold more heparin resistant than its parent. By using marker transfer techniques, its syn phenotype, but not heparin resistance, was mapped first to the BamHI G fragment (0.343 to 0.415 map units) and then to a 670-bp KpnI-PstI subclone (0.345 to 0.351 map units) encoding the carboxy terminus of glycoprotein B (gB). Three cloned syncytial recombinants were generated from cotransfections of 17 syn+ with either 17 hep syn BamHI-G or the 670-bp subclone. After footpad inoculation of mice, 17 hep syn was as virulent as its parent, despite reaching lower titers in feet, sciatic nerves, dorsal root ganglia, spinal cords, and brains. Animals infected with 17 hep syn or the gB recombinant viruses developed a unique pattern of disease that was strikingly different than that seen with wild-type virus: severe inflammation and edema of the inoculated limb and death without antecedent paralysis. Histopathologic examination revealed limitation of spinal involvement by 17 hep syn to the dorsal aspect of the cord and decreased virus-induced damage in the central nervous system. The genetically unrelated syn variant MP, in contrast, was avirulent and did not cause severe local inflammation. After intracerebral inoculation, 17 hep syn was highly virulent and replicated to high titers in the brain. Yet, unlike the parental virus, it resulted in an altered distribution of herpes simplex virus antigens, which were limited to the ependymal and subependymal regions surrounding the lateral ventricles. Despite their syncytial phenotype and pathogenic properties, the recombinant viruses, unlike 17 hep syn, were not heparin resistant. We conclude that a transferable alteration in the 670-bp carboxy-terminal portion of the glycoprotein gB gene of 17 hep syn results in both its syncytial phenotype and the unique pattern of disease that it causes but does not result in heparin resistance. These observations provide direct biological evidence for an important role for herpes simplex virus gB in pathogenic events both at the peripheral site of infection and within the nervous system.

Animals↗
PubMed1990

Attitudes of internal medicine faculty and residents toward professional interaction with pharmaceutical sales representatives.

We surveyed faculty and residents from seven hospitals affiliated with three academic internal medicine training programs about their perceptions of the informational and service benefits vs the risks of ethical compromise involved in interactions with pharmaceutical sales representatives. Questionnaires were returned by 467 (81%) of 575 physicians surveyed. Residents and faculty generally had somewhat negative attitudes toward the educational and informational value of detailing activities at their institutions but indicated that representatives supported important conferences and speakers. Residents were more likely than faculty to perceive contacts with sales representatives as potentially influencing physician decision making. Sixty-seven percent of faculty and 77% of residents indicated that physicians could be compromised by accepting gifts. More than half of the physicians who suggested that such compromise was possible indicated that acceptance of gifts worth more than +100 from drug companies would be likely to compromise a physician's independence and objectivity. A majority of both faculty and house staff favored eliminating presentations by pharmaceutical representatives at their hospitals. Only 10% thought they had had sufficient training during medical school and residency regarding professional interaction with sales representatives.

Adult↗
PubMed1990

Herpes simplex virus resistant to acyclovir. A study in a tertiary care center.

STUDY OBJECTIVE: To determine the sensitivity of herpes simplex virus isolates to acyclovir and the importance of resistant isolates in hospitalized patients. DESIGN: Retrospective incidence cohort study. SETTING: All herpes simplex virus isolates cultured over 1 year from patients followed at a tertiary care center. PATIENTS: Consecutive herpes simplex virus isolates were collected from 207 patients, including immunocompetent patients, patients with malignancy, neonates, bone marrow and organ transplant recipients, and patients seropositive for human immunodeficiency virus. MEASUREMENTS AND MAIN RESULTS: A rapid nucleic acid hybridization method was used to assess susceptibility to acyclovir. Acyclovir-resistant herpes simplex viruses were recovered from 7 of 148 immunocompromised patients (4.7%) but from none of 59 immunocompetent hosts. Clinical disease was found in all 7 patients with resistant herpes simplex virus and was more severe in pediatric patients. All resistant isolates were from acyclovir-treated patients and had absent or altered thymidine kinase activity by plaque autoradiography. CONCLUSION: Herpes simplex virus resistant to acyclovir arises relatively frequently in immunocompromised patients and may cause serious disease. Rapid detection of resistance permits antiviral therapy to be individualized. Antiviral susceptibility testing to monitor viral resistance should be encouraged, especially in tertiary care settings.

Acyclovir↗
PubMed1990

Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression.

Latent infection of vascular cells with herpes-viruses may play a pathogenic role in the development of human atherosclerosis. In a previous study, we found that cultured human umbilical vein endothelial cells (HUVECs) infected with herpes simplex virus 1 (HSV-1) became procoagulant, exemplified both by their enhanced assembly of the prothrombinase complex and by their inability to reduce adhesion of platelets. We now report two further procoagulant consequences of endothelial HSV infection: loss of surface thrombomodulin (TM) activity and induction of synthesis of tissue factor. Within 4 hr of infection of HUVECs, TM activity measured by thrombin-dependent protein C activation declined 21 +/- 3% (P less than 0.05) and by 18 hr, 48 +/- 5% (P less than 0.001). Similar significant TM decrements accompanied infection of bovine aortic endothelial cells. Identical TM loss was induced with HSV-2 infection but not with adenovirus infection. Decreased surface expression of TM antigen (measured by the specific binding of a polyclonal antibody to bovine TM) closely paralleled the loss of TM activity. As examined by Northern blotting, these losses apparently reflected rapid onset (within 4 hr of HSV infection) loss of mRNA for TM. In contrast, HSV infection induced a viral-dose-dependent increase in synthesis of tissue factor protein, adding to the procoagulant state. The results indicate that loss of endothelial protein-synthetic capacity is not a universal effect of HSV infection. We suggest that the procoagulant state induced by reduction in TM activity and amplified tissue factor activity accompanying HSV infection of endothelium could contribute to deposition of thrombi on atherosclerotic plaques and to the "coagulant-necrosis" state that characterizes HSV-infected mucocutaneous lesions.

Cell Transformation, Viral↗
PubMed1990

Herpes simplex virus-infected cells disarm killer lymphocytes.

Human endothelial cells or human foreskin fibroblasts infected with herpes simplex viruses (HSVs) potently inhibit the lytic activity of natural killer cells and interleukin 2-activated killer cells. The inhibition occurs after as little as 8 hr of viral infection and requires contact between effector cells and HSV-infected targets. Inhibition evidently stems from direct blockade of killer cell function because killer cells placed atop HSV-infected targets rapidly become incapable of lysing subsequently added HL-60 or K-562 cells. The impairment of killer cell function is prevented when protein glycosylation in HSV-infected cells is blocked with tunicamycin. These studies may be relevant for understanding the persistence of herpes simplex virus infections and, further, suggest a mechanism for failed immune surveillance.

Adenoviruses, Human↗
PubMed1989

Possible transmission of herpes simplex virus by organ transplantation.

Herpes simplex virus commonly reactivates in seropositive transplant recipients but has not been generally thought to be transmissible by the transplanted organ itself. We studied two consecutive cases of disseminated HSV, without mucosal lesions, occurring in a heart and in a pancreatic transplant recipient, and implicate the allografts as the source of the virus. In both cases the recipients were seronegative pretransplant by complement fixation (less than 1:4), neutralization (less than 1:2), and complement enhanced neutralization (less than 1:4), and by radioimmunoprecipitation of HSV-2 antigens with serum followed by polyacrylamide gel electrophoresis (RIPA-PAGE). Both recipients' isolates were HSV-2 by restriction mapping and each donor had antibodies directed specifically against HSV-2, as determined by differential neutralization (HSV-2/HSV-1 ratios 1.46 and 1.58, where greater than 0.85 indicates antibody to HSV-2). Posttransplant, each recipient developed an antibody response with temporal antigenic specificity and complement-enhanced neutralization consistent with primary infection. These findings have important clinical and pathogenic implications and suggest that latent or reactivated HSV-2 DNA transplanted in donor tissues may cause severe infection in seronegative and immunosuppressed transplant recipients.

Adult↗
PubMed1989

Identification, transfer, and characterization of cloned herpes simplex virus invasiveness regions.

Following peripheral inoculation of experimental animals, herpes simplex virus type 2 (HSV-2) strains are more virulent than HSV-1 strains, and clinical studies suggest that they possess enhanced virulence in humans. One dramatic type-specific difference in virulence is observed following inoculation of the chorioallantoic membrane (CAM) of the chicken embryo: HSV-2, but not HSV-1, makes large pocks on the CAM, invades the mesoderm, generalizes in the embryo, and kills the chicken. These properties have been believed to be specific for HSV-2, and their molecular basis is unknown. We now report that an HSV-1 strain, ANG, behaves even more efficiently than HSV-2. In addition, we have transferred restriction fragments of ANG DNA to another HSV-1 strain, 17 syn+, conferring the CAM virulence phenotype on the normally CAM-avirulent 17 syn+. Like ANG, these recombinant viruses are 10(6)-fold more virulent (PFU/50%) lethal dose [LD50] ratio, less than or equal to 10(2)) than the parental 17 syn+ strain (PFU/LD50 ratio, greater than or equal to 10(8)). A molecularly cloned library of ANG DNA was used to identify two distinct regions containing the virulence functions. Transfer of sequences contained in either cloned ANG EcoRI fragment A (0.49 to 0.64 map units) or F (0.32 to 0.42 map units) DNA to 17 syn+ confers CAM virulence, whereas other cloned regions of the ANG genome do not. Using cloned DNA, we derived and plaque purified several virulent recombinant viruses with inserts from either the ANG EcoRI fragment A (INV-I) or F (INV-II) areas. In each instance, the transfer of the cloned INV-I or INV-II sequences enhanced virulence for the chicken embryo 10(6)-fold (PFU/LD50 ratio, less than or equal to 10(2]. In addition, the transfer of the cloned ANG EcoRI-F INV-II sequences resulted in a 10(3)-fold enhancement of neuroinvasiveness and virulence for mice. Following footpad inoculation, these recombinants kill mice with a PFU/LD50 ratio of approximately 10(3) (similar to HSV-2 strains) compared with 10(6) for 17 syn+. Thus, we have identified, cloned, and transferred two DNA regions from HSV-1 ANG which contain virulence genes (INV-I and INV-II) important in mesodermal invasiveness on the CAM and, in the case of INV-II, neuroinvasiveness in the mouse. In each instance, the recombinant HSV-1 viruses have attained enhanced virulence beyond that described for HSV-1 strains and similar to that seen with HSV-2.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Herpes simplex virus inhibits endothelial cell attachment and migration to extracellular matrix proteins.

Herpes simplex virus (HSV) infection may be involved in various endothelial-injury syndromes, including vasculitis and atherosclerosis. In a previous study, it was reported that HSV-infected human umbilical endothelial cells are more vulnerable to detachment mediated by granulocyte-secreted proteases. To elucidate the molecular basis of this observation, the authors examined the interaction of infected endothelial cells with the purified basement membrane proteins, fibronectin, laminin, and type IV collagen. HSV-infected endothelial cells exhibited defects in their ability to adhere, spread, and migrate on all three matrix components. This defective adhesion could be partially overcome by increasing concentrations of fibronectin; in contrast, no abrogation of deficient binding occurs with increased levels of laminin or collagen type IV. This suggests that endothelial cells may use different surface constituents for binding to the three proteins and use multiple "receptors" for adhesion to the fibronectin molecule--"receptors" that are variably affected by HSV infection. The authors investigated this supposition by assaying adhesion of normal and infected endothelial cells to two non-overlapping cell-adhesion promoting fragments of fibronectin: 1) a 75 kd motility-promoting fragment which contains the arginyl-glycyl-aspartylserine (RGDS) adhesion sequence, and 2) a 33 kd carboxyl-terminal heparin binding fragment, which promotes cell adhesion by an RGDS-independent mechanism. Normal endothelial cells adhered and spread on both purified fragments. In contrast, while infected endothelial cells could adhere, albeit rather poorly, to high coating concentrations of the 75 kd fragment, these cells did not bind to the 33 kd heparin binding fragment of fibronectin at all. These results support the concept that endothelial cells adhere to multiple domains of fibronectin, and that HSV infection preferentially abrogates binding to the heparin-binding domain, while leaving relatively intact receptors for the RGDS-containing domain. In support, soluble RGDS significantly blocked fibronectin adhesion of infected, but not control, endothelial cells. It is concluded that HSV infection inhibits the interaction of endothelial cells with basement membrane proteins and weakens their tethering to substratum. This tethering is inadequate for proper cell spreading or movement to occur and may result in both excessive endothelial lift-off and impaired vascular repair in HSV infections.

Cell Adhesion↗
PubMed1989

Granulocyte-mediated injury to herpes simplex virus-infected human endothelium.

Some endothelial-injury syndromes, including atherosclerosis, may involve herpes simplex virus (HSV) infection. Examining the mechanism of injury, we found adherence of unstimulated granulocytes to HSV infected endothelium to be twice that to uninfected endothelium (34.8 +/- 1.1 versus 18.8 +/- 0.5%; mean +/- SEM; p less than 0.001) which further increased in the presence of anti-HSV antibodies. Enhanced adhesion was accompanied by excessive granulocyte-mediated lysis of 51Cr-labeled, HSV-infected endothelium (16.4 +/- 0.9%, HSV-infected versus 0.9 +/- 4.5% for uninfected endothelium; p less than 0.01). HSV infection also increased granulocyte-mediated endothelial cell detachment from its substratum (14.7 +/- 1.7% versus 3.3 +/- 0.3% for uninfected endothelium; p less than 0.001), which further increased (p less than 0.01) in the presence of immune complexes (IgG-sensitized erythrocytes). This suggests that neo-Fc receptors of infected endothelium bind IgG-coated particles, which, in turn, attract and stimulate granulocytes. In support, granulocyte-mediated detachment was not enhanced by immune complexes if endothelium was infected with a mutant HSV strain (E3/3) that does not produce glycoprotein E, the viral glycoprotein having Fc-receptor activity. Exaggerated endothelial detachment correlated with poor binding of infected endothelial cells to the substratum matrix protein, fibronectin. Resuspended, virus-infected endothelial cells bound significantly less well to tissue-culture wells coated with both low (p less than 0.001) and high (p less than 0.05) concentrations of fibronectin as compared with uninfected endothelial cells, a dichotomy further worsened in the presence of granulocyte-released elastase. We conclude that HSV-infected human endothelium is vulnerable to granulocyte-mediated injury by opposing alterations in its adhesive properties: its increased binding of granulocytes and its weakened tethering to matrix fibronectin, particularly when exposed to secreted granulocyte proteases, such as elastase.

Cell Adhesion↗
PubMed1989

Energy expenditure of young Swazi women as measured by the doubly-labelled water method.

The energy expenditure of a group of young (age 18-28 years) Swazi women resident at an agricultural college was measured using the doubly-labelled water (DLW) method. This was a baseline study to evaluate feasibility of the protocol under field conditions in Swaziland and to determine energy needs of sedentary women under well controlled conditions. Measurements were based on saliva samples collected over a 10-d period using the two-pair method. Two pairs of data points (days 2-9 and 3-10) were used to calculate expenditure. The two sets of data points were within 2.5 per cent of each other. Dietary intake was measured by self-report diaries for 5 study days and was not significantly different from the DLW measurements. Energy expenditure averaged 1735 kcal (7252 kJ)/d and 44 kcal (185 kJ)/kg fat-free mass, lower than other groups similarly measured. Intake averaged 1738 kcal (7265 kJ)/d. Low levels of expenditure observed probably reflect inactivity.

Adolescent↗
PubMed1988

Enhanced thrombin generation and platelet binding on herpes simplex virus-infected endothelium.

Atherosclerotic lesions have been reported to contain herpes simplex virus 1 (HSV-1) genomic material. This, and other previous evidence, suggests that latent viral infection may be an atherogenic trigger. Moreover, active HSV-1 lesions manifest marked fibrin deposition in microvessels. In this report we show that very early infection of human endothelial cells with HSV-1 appears to alter surface conformation as detected by merocyanine 540 staining. Concomitantly, the efficiency of prothrombinase complex assembly increases, resulting in a 2- to 3-fold accelerated rate of thrombin generation on the cell surface. Increased thrombin generation is probably doubly procoagulant, since we also demonstrate that thrombin-induced platelet accumulation on HSV-infected endothelium (50.7 +/- 9.3%) is increased compared to uninfected endothelium (9.5 +/- 2.1%; P less than 0.002). Associated with HSV infection, prostacyclin secretion in response to thrombin is diminished by a factor of 20, probably explaining the enhanced platelet attachment. We conclude that HSV infection shifts endothelial cell properties from anticoagulant to procoagulant, both by promoting prothrombinase complex formation and function and by increasing platelet binding, well before cell disruption takes place. Virus-induced changes in the endothelial plasma membrane and diminished prostacyclin secretion are suggested as the pathways for this pathophysiologic mechanism, which may be germane to atherosclerotic thrombosis as well as HSV-mediated tissue necrosis.

Arteriosclerosis↗
PubMed1987

A time-resolved photoacoustic calorimetry study of the dynamics of enthalpy and volume changes produced in the photodissociation of carbon monoxide from sperm whale carboxymyoglobin.

The dynamics of the enthalpy and volume changes produced in the photodissociation of carbon monoxide from sperm whale myoglobin is investigated by time-resolved photoacoustic calorimetry. The enthalpy and volume changes for the formation of the geminate pair, which occurs within 50 ns of photolysis, are delta H = -2.2 +/- 2.8 kcal/mol and delta V = -10.0 +/- 1.0 mL/mol relative to carboxymyoglobin. The enthalpy and volume changes associated with formation of deoxymyoglobin and solvated carbon monoxide, formed with a half-life of 702 +/- 31 ns at 20 degrees C, are delta H = 14.6 +/- 3.4 kcal/mol and delta V = 5.8 +/- 1.0 mL/mol relative to carboxymyoglobin.

Animals↗
PubMed1987

Potentiated adherence of sickle erythrocytes to endothelium infected by virus.

Systemic viral infection is a known precipitant of vasocclusive crisis in sickle patients, but the mechanism underlying this clinical observation is unknown. In the present studies, human umbilical vein endothelial cells were infected with Herpes simplex virus type 1 (HSV) to model systemic viral disease. The already abnormal adherence of sickle erythrocytes to control endothelium is enhanced 1.8 +/- 0.4-fold to HSV-infected endothelium (P less than 0.001). This component of potentiated adherence is eliminated by maneuvers that block Fc receptors, it is prevented by tunicamycin, and it is not seen using a mutant HSV that is unable to express the Fc receptor glycoprotein. Thus, the incremental adherence seen here occurs due to expression of Fc receptor activity on HSV-infected endothelium and the consequent recognition of abnormal amounts of IgG on sickle erythrocytes. We conclude that systemic viral infection potentially can induce a novel mechanism for enhancement of erythrocyte adherence to endothelium and that this may increase the likelihood of vasocclusion during viral infection.

Anemia, Sickle Cell↗
PubMed1986

Passage of herpes simplex virus type 1 on chick embryo fibroblasts confers virulence for chick embryos.

The pathogenesis of chorioallantoic membrane (CAM) infection with herpes simplex virus 1 and 2 (HSV-1 and HSV-2) as well as chick embryo fibroblast (CEF) passaged HSV-1 was studied. It was found that HSV-2 is at least a million-fold more virulent than HSV-1 as measured by pfu/LD50 ratios for the embryo. Serial passage of HSV-1 in vitro on CEF cells selected for a virus (CEFP10) which, unlike its parental HSV-1 strain, is able to kill the embryo. The restriction endonuclease maps of CEFP10 and its parental strain are indistinguishable and the mechanism of the increased virulence of CEFP10 was demonstrated to be its enhanced replication in chick embryo cells both in vivo and in vitro. In contrast, despite its inferior replicative ability, HSV-2 was found to have a biologically important specific invasiveness function that is not simply related to overall viral replication. Finally, the ability to isolate HSV-1 (CEFP10) virulent for the chick embryo after passage in vitro illustrates that tissue culture passage of HSV in appropriate cells may actually increase virulence for the animal host.

Animals↗
PubMed1983

Pneumocystis with normal chest X-ray film and arterial oxygen tension. Early diagnosis in a patient with the acquired immune deficiency syndrome.

A patient with Kaposi's sarcoma and the acquired immune deficiency syndrome became acutely febrile and dyspneic. Although chest roentgenograms and findings from arterial blood oxygenation studies were normal, bronchoscopy disclosed heavy Pneumocystis carinii infection. The patient was treated with trimethoprim-sulfamethoxazole with a rapid clinical response. It has been distinctly unusual to diagnose Pneumocystis without roentgenographic or blood gas abnormalities. Pneumocystis infection probably occurs as a wide spectrum of disease ranging from subclinical infection to frank pneumonitis. In the appropriate clinical setting, clinically significant Pneumocystis infection may be diagnosed despite the absence of an infiltrate or hypoxemia and early treatment may be beneficial.

Acquired Immunodeficiency Syndrome↗