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Biomedical subjects

J Huggins

Publications and source records attributed to J Huggins.

At least 19 recordsLinked to original sources
PubMed2003

Antiviral activity of cyclopentenyl nucleosides against orthopox viruses (Smallpox, monkeypox and cowpox).

An improved method for the synthesis of enantiomerically pure D-cyclopentenyl nucleosides has been accomplished and their antiviral activity against orthopox viruses have been evaluated. The key intermediate, L-cyclopent-2-enone 13 was prepared from D-ribose using a ring closing metathesis reaction in eight steps. Among the synthesized nucleosides, the adenine 2 (Neplanocin A), cytosine 14, and 5-F-cytosine 15 analogues exhibited potent anti-orthopox virus activity, including smallpox virus.

Adenosine↗
PubMed1999

A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever.

The Zaire subtype of Ebola virus (EBO-Z) is lethal for newborn mice, but adult mice are resistant to the virus, which prevents their use as an animal model of lethal Ebola infection. We serially passed EBO-Z virus in progressively older suckling mice, eventually obtaining a plaque-purified virus that was lethal for mature, immunocompetent BALB/c and C57BL/6 inbred and ICR (CD-1) outbred mice. Pathologic changes in the liver and spleen of infected mice resembled those in EBO-Z-infected primates. Virus titers in these tissues reached 10(9) pfu/g. The LD50 of mouse-adapted EBO-Z virus inoculated into the peritoneal cavity was approximately 1 virion. Mice were resistant to large doses of the same virus inoculated subcutaneously, intradermally, or intramuscularly. Mice injected peripherally with mouse-adapted or intraperitoneally with non-adapted EBO-Z virus resisted subsequent challenge with mouse-adapted virus.

Adaptation, Physiological↗
PubMed1999

Antiviral drug therapy of filovirus infections: S-adenosylhomocysteine hydrolase inhibitors inhibit Ebola virus in vitro and in a lethal mouse model.

Ebola (subtype Zaire) viral replication was inhibited in vitro by a series of nine nucleoside analogue inhibitors of S-adenosylhomocysteine hydrolase, an important target for antiviral drug development. Adult BALB/c mice lethally infected with mouse-adapted Ebola virus die 5-7 days after infection. Treatment initiated on day 0 or 1 resulted in dose-dependent protection, with mortality completely prevented at doses > or =0.7 mg/kg every 8 h. There was significant protection (90%) when treatment was begun on day 2, at which time, the liver had an average titer of 3 x 10(5) pfu/g virus and the spleen had 2 x 10(6) pfu/g. Treatment with 2.2 mg/kg initiated on day 3, when the liver had an average titer of 2 x 10(7) pfu/g virus and the spleen had 2 x 10(8) pfu/g, resulted in 40% survival. As reported here, Carbocyclic 3-deazaadenosine is the first compound demonstrated to cure animals from this otherwise lethal Ebola virus infection.

Adenosylhomocysteinase↗
PubMed1999

Substance use disorders and the risk of HIV infection in gay men.

OBJECTIVE: Previous studies have suggested that high rates of recent alcohol or drug use are associated with increased risk for HIV infection in gay men. To examine whether this relationship is mediated by substance use per se or by more enduring patterns of problematic substance use, lifetime DSM-III-R alcohol and other drug dependence disorders were ascertained and used to predict self-reported serostatus. METHOD: Gay men (N = 187) who had been tested for HIV and knew their serostatus (31 are HIV+) completed demographic, drug use and sexual practices questionnaires. Formal DSM-III-R psychiatric diagnoses were made on the basis of an individual interview, using the Structured Clinical Interview for DSM-III-R. RESULTS: Subjects had lifetime rates of alcohol dependence and drug dependence disorders that were two to three times higher than the general population, and 58% of the subjects who met criteria for alcohol dependence also met criteria for other substance dependence. Logistic regression analysis indicated that serostatus was best predicted by presence of both alcohol and drug dependence, and by race. When analyses were repeated in seronegative men, using unprotected anal sex as the outcome and recent substance use as predictors, no relationship between alcohol and behavior was found. CONCLUSIONS: Data do not support the view that alcohol use alone increases the risk of HIV infection in gay men. Finding that risk for HIV is highest in men with histories of both alcohol and drug problems suggests that the link between HIV infection and substance use may be mediated by "third variables" that may include personality characteristics and situational factors.

Adult↗
PubMed1998

DNA vaccines expressing either the GP or NP genes of Ebola virus protect mice from lethal challenge.

DNA vaccines expressing the envelope glycoprotein (GP) or nucleocapsid protein (NP) genes of Ebola virus were evaluated in adult, immunocompetent mice. The vaccines were delivered into the skin by particle bombardment of DNA-coated gold beads with the Powderject-XR gene gun. Both vaccines elicited antibody responses as measured by ELISA and elicited cytotoxic T cell responses as measured by chromium release assays. From one to four vaccinations with 0.5 microgram of the GP DNA vaccine resulted in a dose-dependent protection from Ebola virus challenge. Maximal protection (78% survival) was achieved after four vaccinations. Mice were completely protected with a priming dose of 0.5 microgram of GP DNA followed by three or four subsequent vaccinations with 1.5 micrograms of DNA. Partial protection could be observed for at least 9 months after three immunizations with 0.5 microgram of the GP DNA vaccine. Comparing the GP and NP vaccines indicated that approximately the same level of protection could be achieved with either vaccine.

Animals↗
PubMed1998

Laparoscopic myomectomy-an unusual cause of meralgia paresthetica.

Meralgia paresthetica may be associated with diabetes, trauma, infection, and use of self-retaining retractors. Our patient experienced left upper thigh paresthesia after undergoing laparoscopic myomectomy with extensive dissection of the left retroperitoneal space. Neurologic evaluation confirmed meralgia paresthetica. The patient was observed for 4 months, by which time the neuropathy resolved spontaneously.

Adult↗
PubMed1998

A mouse model for evaluation of prophylaxis and therapy of Ebola hemorrhagic fever.

The Zaire subtype of Ebola virus (EBO-Z) is lethal for newborn mice, but adult mice are resistant to the virus, which prevents their use as an animal model of lethal Ebola infection. We serially passed EBO-Z virus in progressively older suckling mice, eventually obtaining a plaque-purified virus that was lethal for mature, immunocompetent BALB/c and C57BL/6 inbred and ICR (CD-1) outbred mice. Pathologic changes in the liver and spleen of infected mice resembled those in EBO-Z-infected primates. Virus titers in these tissues reached 10(9) pfu/g. The LD50 of mouse-adapted EBO-Z virus inoculated into the peritoneal cavity was approximately 1 virion. Mice were resistant to large doses of the same virus inoculated subcutaneously, intradermally, or intramuscularly. Mice injected peripherally with mouse-adapted or intraperitoneally with non-adapted EBO-Z virus resisted subsequent challenge with mouse-adapted virus.

Animals↗
PubMed1997

Naked DNA vaccines expressing the prM and E genes of Russian spring summer encephalitis virus and Central European encephalitis virus protect mice from homologous and heterologous challenge.

Naked DNA vaccines expressing the prM and E genes of two tick-borne flaviviruses, Russian spring summer encephalitis (RSSE) virus and Central European encephalitis (CEE) virus were evaluated in mice. The vaccines were administered by particle bombardment of DNA-coated gold beads by Accell gene gun inoculation. Two immunizations of 0.5 to 1 microg of RSSE or CEE constructs/dose, delivered at 4-week intervals, elicited cross-reactive antibodies detectable by enzyme-linked immunosorbent assay and high-titer neutralizing antibodies to CEE virus. Cross-challenge experiments demonstrated that either vaccine induced protective immunity to homologous or heterologous RSSE or CEE virus challenge. The absence of antibody titer increases after challenge and the presence of antibodies to E and prM, but not NS1, both before and after challenge suggest that the vaccines prevented productive replication of the challenge virus. One vaccination with 0.5 microg of CEE virus DNA provided protective immunity for at least 2 months, and two vaccinations protected mice from challenge with CEE virus for at least 6 months.

Animals↗
PubMed1994

Antiviral and immunomodulating inhibitors of experimentally-induced Punta Toro virus infections.

A major component of a US Army Medical Research and Development Command-supported program to discover and develop new drugs for the treatment of Rift Valley fever, sandfly fever, and Crimean-Congo hemorrhagic fever has been to study candidate test materials against hepatotropic infections of C57BL/6 mice induced by the related but less biohazardous Punta Toro virus (PTV). The effects of 75 compounds, some of which were considered immunomodulators in their primary mechanism of activity, were studied in the PTV infection model. Of these, ribavirin, ribamidine, ribavirin 2',3',5'-triacetate, tiazofurin, tiazofurin-5'-monophosphate, tiazofurin-2',3',5'-triacetate, selenazofurin, pyrazofurin, 3-deazaguanine, and 3-deazaguanosine were considered significantly inhibitory, acting against the infection by a direct antiviral (non-immunomodulatory) fashion. These compounds had therapeutic indices (TI) ranging from > or = 5 to 65, using increased survivors as the evaluation parameter. Immunomodulators considered significantly inhibitory to this infection were poly (ICLC), ampligen, human recombinant interferon-alpha-A/D, MVE-1, MVE-2, AM-3, AM-5, mannozym, bropirimine, CL246,738, phenyleneamine, and 7-thia-8-oxoguanosine. Utilizing increased survivor numbers as measure of activity, these inhibitors had TI ranging from > or = 16 to 1000. Other antiviral effects exerted by the active compounds included reduction of hepatic icterus, lowered serum glutamic oxaloacetic and pyruvic acid transaminases, and inhibition of recoverable serum and liver virus titers. The active immunomodulators were significantly effective when therapy was initiated as late as 48 h after virus inoculation, at a time when clinical signs of the PTV disease were being manifested in the animal.

Adjuvants, Immunologic↗
PubMed1992

Construction and characterization of chimeric tick-borne encephalitis/dengue type 4 viruses.

Dengue type 4 virus (DEN4) cDNA was used as a vector to express genes of the distantly related tick-borne encephalitis virus (TBEV). Full-length chimeric TBEV/DEN4 cDNAs were constructed by substituting TBEV genes coding for proteins such as capsid (C); pre-membrane, which is the precursor of membrane (M); envelope (E); or nonstructural protein NS1 for the corresponding DEN4 sequences. RNA transcripts prepared from cDNAs were used to transfect permissive simian cells. Two viable chimeric viruses that contained TBEV CME or ME genes were recovered. Compared with DEN4, chimeric TBE(ME)/DEN4 virus [designated vTBE(ME)/DEN4] produced larger plaques and grew to higher titer in simian cells. In contrast, vTBE(ME)/DEN4 produced smaller plaques on mosquito cells and grew to lower titer than DEN4. Analysis of viral RNA and proteins produced in vTBE(ME)/DEN4- and DEN4-infected mosquito or simian cells revealed that the chimera was restricted in its ability to enter and replicate in mosquito cells. In contrast, vTBE(ME)/DEN4 entered simian cells efficiently and its RNA was replicated more rapidly in these cells than was parental DEN4 RNA. Following intracerebral inoculation, vTBE(ME)/DEN4 caused fatal encephalitis in both suckling and adult mice, while nearly all mice inoculated by the same route with DEN4 did not develop disease. Unlike wild-type TBEV, vTBE(ME)/DEN4 did not cause encephalitis when adult mice were inoculated by a peripheral route. Adult mice previously inoculated with the chimera by a peripheral route were completely resistant to subsequent intraperitoneal challenge with 10(3) times the median lethal dose of TBEV, whereas mice previously inoculated with DEN4 were not protected. These findings indicate that (i) the TBEV M and E genes of the chimeric virus are major protective antigens and induce resistance to lethal TBEV challenge and (ii) other regions of the TBEV genome are essential for the ability of this virus to spread from a peripheral site to the brain. Success in constructing a viable TBEV/DEN4 chimera that retains the protective antigens of TBEV but lacks its peripheral invasiveness provides a strategy for the development of live attenuated TBEV vaccines.

Amino Acid Sequence↗
PubMed1992

Potential role of immunomodulators for treatment of phlebovirus infections of animals.

Rift Valley fever (RVFV) is a major phlebovirus-induced epizootic disease of domestic animals (primarily cattle and sheep) in Africa. No therapies for the disease are known. A related phlebovirus, Punta Toro virus (PTV), has been adapted to induce an RVFV-like disease in C57BL/6 mice. This PTV infection has been used as a model for RVFV because it is reasonably safe and does not require high-level biologic containment. The infection model has been used to study the potential role of immunomodulating substances as therapies. A spectrum of immunomodulators has been studied; those immunomodulators most capable of preventing death and other disease manifestations are ampligen, bropirimine, poly (ICLC), AM-3, P-136, and 7-thia-8-oxoguanosine. An immunologic parameter common to all these substances has been their ability to induce interferon. Timing studies have indicated that these active substances may be administered therapeutically as well as prophylactically to inhibit markedly the progress of the disease. Further work is needed in the development of these materials for use in treating viral infections in domestic animals. As a next step, studies need to be run to compare the immunologic profiles induced by each substance in domestic animals and in mice.

Adjuvants, Immunologic↗
PubMed1992

Unexpected adverse reactions during a clinical trial in rural west Africa.

Ribavirin has been used widely in various clinical trials, without significant adverse effects beyond reversible, mild anemia. Since 1978 intravenous ribavirin has been used to treat Lassa fever in a remote area of Eastern Sierra Leone, West Africa. In March 1991, brief episodes of rigors in patients receiving ribavirin were reported. An immediate investigation found that 27/93 patients (29%) had records in 1990/91 of at least one episode, the strongest association being with survival of Lassa fever (P = 0.0001). The occurrence or number of rigors in an individual patient was unassociated with sex, age, weight, volume of loading dose, cumulative dose, administration of other drugs, use of intravenous lines or heparin traps. In a review of 12 years of ribavirin administration, 74/2117 injections sampled (3.5%) were associated with a record of rigors. Most occurred before 08.00 h (P less than 0.0001), between 0 and 30 min after injection, lasted 2-45 min, and clustered towards the end of the treatment course (P less than 0.0001). There was no association with drug lot or individual vials. Drug was being given as a bolus (less than 1 min). Since slowing the infusion rate, no further episodes have been reported. Epidemiologic techniques are important tools in rapid assessment of unexpected events particularly when conducting trials in remote locations.

Humans↗
PubMed1991

Effect of human, recombinant interleukin 2 on Punta Toro virus infections in C57BL/6 mice.

The effect of human recombinant interleukin-2 (rIL-2) on Punta Toro virus (PTV) infection was investigated in C57BL/6 mice. Immunologic and viral parameters were assessed after mice were treated i.p. with rIL-2 for 5 days. Treatment of mice with 25000 and 12500 units/mouse of rIL-2 resulted in significant inhibition of the disease as indicated by increases in survival of mice as well as decreases in liver and serum virus titers. Serum glutamic oxalic acid and pyruvic acid transaminase levels were also lowered indicating reduced liver damage. Murine IL-2 production returned to normal or above-normal levels in rIL-2 treated mice. Natural killer cell activity was also moderately stimulated by rIL-2 treatment. Significant amounts of interferon were not detected in the sera of treated mice. Weight gain and survival rates were similar for both toxicity and normal controls indicating that rIL-2 treatments had no toxic effect.

Animals↗
PubMed1991

Affective and behavioral responses of gay and bisexual men to HIV antibody testing.

Fifty-six gay and bisexual men were tested for antibody to the human immunodeficiency virus. Twenty-two subjects who tested positive, 22 subjects who tested negative, and 12 subjects who chose not to learn the test results were surveyed by questionnaire after one week and after about six months after testing. Subjects who tested positive and those who tested negative were also compared two weeks after learning results. Subjects who tested positive experienced an increase in anxiety, depression, and AIDS anxiety, and subjects who tested negative experienced a decrease in these feelings after learning results. Subjects who did not learn the results of their tests experienced no change in these feelings. All three groups altered their sexual behavior. Subjects were more likely to tell test results to lovers and to regular sexual partners than to casual sexual partners. Implications for social work practice are discussed.

AIDS Serodiagnosis↗
PubMed1990

Preventing HIV infection in gay and bisexual men: experimental evaluation of attitude change from two risk reduction interventions.

In the course of learning their HIV serostatus, gay and bisexual men participated in small discussion groups aimed at increasing their practice of safer sex. Small discussion groups were randomly assigned to receive one of two interventions: a lecture/discussion by a gay health educator, or an intervention that included the lecture/discussion followed by a small group process aimed at increasing social skills for safer sex and at increasing peer support for safer sex. Men completed questionnaires relating to their knowledge about HIV and AIDS, attitudes toward sexual behavior change, and self-reported sexual behavior. At second follow-up, one year post-intervention, men who had received skills training and peer support endorsed significantly stronger attitudes in favor of safer sex than did men receiving lecture/discussion only. In particular, skills training and peer support caused greater reduction of the value placed on ejaculation inside the partner, stronger endorsement of plans to use condoms, and greater reduction of negative attitudes about condoms, than did lecture/discussion only. These results are helpful to design interventions for men who continue to engage in riskful behavior.

Adolescent↗
PubMed1989

Factors related to seroconversion among homo- and bisexual men after attending a risk-reduction educational session.

Thirteen homosexual men, volunteers in a study of the natural history of HIV, who seroconverted to HIV after participating in an educational program on HIV prevention, were interviewed about the circumstances leading to their seroconversion. Six men had participated in unprotected anal intercourse with at least one partner whom they believed was HIV-negative. Four men attributed their conversion to mental health problems or to drug and alcohol use. Two men's seroconversions could not be ascertained and one man attributed seroconversion to a condom break. Most men who had learned how to avoid infection, and had successfully done so for a time, had knowingly engaged in unsafe behaviors because of strong emotional responses to certain partners or because of mental health or drug and alcohol-related problems. Skills training for dealing with partners who pressure men to behave unsafely is needed, as is mental health and drug and alcohol counseling for men at risk for HIV infection.

Acquired Immunodeficiency Syndrome↗