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Biomedical subjects

I Cropley

Publications and source records attributed to I Cropley.

14 recordsLinked to original sources
PubMed2006

Adverse events and treatment interruption in tuberculosis patients with and without HIV co-infection.

BACKGROUND: Serious treatment associated adverse events are thought to occur more frequently in individuals with tuberculosis (TB) who are co-infected with HIV. A study was undertaken to assess the frequency of serious (grade III/IV) adverse events and interruption of anti-TB treatment in the era of effective antiretroviral therapy. METHODS: The incidence of serious adverse events was retrospectively compared in 312 individuals treated for TB, 156 of whom were co-infected with HIV. RESULTS: 111 HIV infected individuals (71%) received highly active antiretroviral therapy at the same time as anti-TB treatment. Serious adverse events were recorded in 40% HIV infected and 26% HIV uninfected individuals (p = 0.008). Peripheral neuropathy and persistent vomiting were more common in co-infected patients (p<0.001; p = 0.006), although all cause interruption of anti-TB treatment occurred with similar frequency in the two groups (13% in HIV infected patients and 15% in HIV uninfected patients; p = 0.74). In 85% of HIV infected patients and 87% of HIV uninfected individuals this was due to hepatotoxicity, which typically presented within 2 months of starting treatment. The median delay in restarting treatment was 4 weeks, so most individuals required full TB re-treatment. CONCLUSION: Despite a greater rate of serious (grade III/IV) adverse events among HIV infected individuals, discontinuation of anti-TB treatment occurred with a similar frequency in HIV infected and HIV uninfected individuals.

Adult↗
PubMed2006

Virological response to highly active antiretroviral therapy is unaffected by antituberculosis therapy.

We compared 156 human immunodeficiency virus (HIV)-infected patients who had tuberculosis with control populations of similar size. Of 111 patients with HIV infection and tuberculosis who received highly active antiretroviral therapy (HAART) and therapy for tuberculosis concurrently, 92 (83%) achieved or maintained virus loads of <50 copies/mL, and 99 (89%) achieved or maintained a >or=2 log10 reduction in virus load after 6 months. Virological response and changes in CD4 cell count were equivalent to those in 111 matched HIV-infected subjects without tuberculosis starting HAART. Tuberculosis recurrence rates were similar to those found in an HIV-uninfected population of 156 subjects (3% and 1%, respectively). Treatment for HIV and tuberculosis does not compromise outcomes for either disease.

AIDS-Related Opportunistic Infections↗
PubMed2000

Hepatitis C virus infection: co-infection with HIV and HBV.

Hepatitis C shares common routes of infection with hepatitis B (HBV) and the human immunodeficiency virus (HIV). It is, therefore, not surprising to find that some patients with HCV are co-infected with either HIV and/or HBV. Until recently, the effects of HIV on HCV infection have not been investigated--sadly patients with HIV died long before their liver disease became problematic. However, the development of successful therapies for HIV have led to dramatic improvements in life expectancy for patients infected with this virus and in these patients, with well controlled HIV, it is becoming clear that hepatitis C may lead to the early onset of advanced liver disease. The optimal treatment for these patients is unknown but it seems likely that combination antiviral therapy will be required. The effects of HBV on HCV are also beginning to be investigated and, again, it is clear that co-infection leads to more aggressive liver disease with the two viruses interacting in poorly defined ways to increase the rate of hepatic fibrosis. Management of combined HCV/HBV infection is still under investigation and will probably involve combination therapy.

Antiviral Agents↗
PubMed2000

Tuberculosis diagnosed during pregnancy: a prospective study from London.

BACKGROUND: A study was undertaken to characterise the presentation of tuberculosis in pregnancy and the difficulties in diagnosis in an area of the UK with a high incidence of tuberculosis. METHODS: A prospective case series was investigated at Northwick Park Hospital, a university affiliated district general hospital in Brent and Harrow health authority in north-west London which incorporates a regional infectious diseases unit. Patients diagnosed with tuberculosis over the study period were included if the onset of symptoms occurred during pregnancy. RESULTS: Thirteen patients were diagnosed during a 30 month period from December 1995 to May 1998 during which 9069 mothers were delivered, a prevalence of 143.3/100 000 deliveries. Symptoms began at a median of 22 weeks gestation (range 9-40 weeks). All patients were recent immigrants of Indian subcontinent or Somali origin and their median duration of residence in the UK was 31 months (range 1-72). Prevalence broken down for racial origin of mothers was 466.3/100 000 for mothers of black African origin and 239.1/100 000 for mothers of Indian origin. Nine of the 13 patients had extrapulmonary tuberculosis. Four patients with widely disseminated disease had a negative Mantoux response and five with localised disease had a strongly positive Mantoux response. HIV co-infection was absent. The median delay between the onset of symptoms and diagnosis was seven weeks (range 2-30). The response to standard treatment was excellent and all patients were cured. CONCLUSIONS: Tuberculosis occurring in pregnancy is common in recent immigrants. Diagnosis during pregnancy is delayed because the disease is frequently extrapulmonary with few symptoms.

Antitubercular Agents↗
PubMed1995

Mutants of Escherichia coli heat-labile toxin lacking ADP-ribosyltransferase activity act as nontoxic, mucosal adjuvants.

A nontoxic mutant (LTK7) of the Escherichia coli heat-labile enterotoxin (LT) lacking ADP-ribosylating activity but retaining holotoxin formation was constructed. By using site-directed mutagenesis, the arginine at position 7 of the A subunit was replaced with lysine. This molecule, which was nontoxic in several assays, was able to bind to eukaryotic cells and acted as a mucosal adjuvant for co-administered proteins; BALB/c mice immunized intranasally with LTK7 and ovalbumin developed high levels of serum and local antibodies to ovalbumin and toxin. In addition, mice immunized intranasally with fragment C of tetanus toxin and LTK7 were protected against lethal challenge with tetanus toxin. Thus nontoxic mutants of heat-labile toxin can act as effective intranasal mucosal adjuvants.

Adjuvants, Immunologic↗
PubMed1995

Mucosal and systemic immunogenicity of a recombinant, non-ADP-ribosylating pertussis toxin: effects of formaldehyde treatment.

The effect of formaldehyde treatment on the mucosal and systemic immunogenicity of the genetically detoxified pertussis toxin (PT-9K/129G) was investigated. Groups of BALB/c were immunized intranasally (i.n.) or subcutaneously (s.c.) with untreated, lightly formaldehyde treated (LFT) or heavily formaldehyde treated (HFT) recombinant pertussis toxin (PT) mutant, PT-9K/129G. Intranasal immunization with native PT-9K/ 129G induced significant levels of anti-toxin antibodies in serum and IgA anti-toxin responses in nasal and lung lavages of these mice. Similar local and systemic responses were observed following intransal immunization with LFT toxin. However, i.n. immunization with HFT toxin failed to induce a local IgA response and elicited a much diminished anti-toxin response in the serum. In contrast, the total antibody response following s.c. immunization was not significantly affected. In addition, i.n. immunization with native PT-9K/129G induced low but detectable levels of toxin neutralizing antibodies in the serum. These results show that native PT-9K/129G protein acts as a mucosal immunogen in mice and that this activity is greatly diminished by HFT of the protein.

Administration, Intranasal↗
PubMed1995

A mutant pertussis toxin molecule that lacks ADP-ribosyltransferase activity, PT-9K/129G, is an effective mucosal adjuvant for intranasally delivered proteins.

We examined the capacity of a genetically detoxified derivative of pertussis toxin (PTX), PT-9K/129G, to act as a mucosal adjuvant for an intranasally (i.n.) administered tetanus vaccine. Groups of mice were immunized i.n. with the nontoxic C-terminal 50-kDa portion of tetanus toxin (fragment C [Frg C]) either alone or mixed with PT-9K/129G, PTX, or cholera toxin (CT) or were immunized subcutaneously (s.c.) with an equivalent amount of Frg C adsorbed to alhydrogel. In response to a single immunization, mice receiving Frg C plus PT-9K/129G or CT i.n. and parenterally immunized mice developed high-titer (> 20,000) anti-Frg C antibodies, whereas mice immunized i.n. with Frg C plus PTX or with Frg C alone seroconverted only after being boosted. The serum anti-Frg C response was dominated by immunoglobulin G1 (IgG1) in mice immunized with Frg C plus PT-9K/129G, with Frg C plus PTX, or s.c. In contrast, IgG1, IgG2a, and IgG2b contributed almost equally to the Frg C response when CT was the adjuvant. Anti-Frg C IgE was detected only in the sera of mice immunized i.n. with Frg C plus PTX and immunized s.c. with Frg C plus alhydrogel. High levels of IgA antibodies were present in nasal lavage fluid from mice immunized i.n. with Frg C plus PT-9K/129G, PTX, or CT but not in that from mice given Frg C alone i.n. or parenterally. The mucosal adjuvanticity of PT-9K/129G was manifested in inbred as well as outbred mice. A single i.n. dose of Frg C plus either PT-9K/129G or PTX (with high specific activity) was sufficient to protect all immunized mice from tetanus toxin challenge, in contrast to the case for mice that received Frg C alone i.n. We conclude that the pertussis toxin analog PT-9K/129G, which is devoid of ADP-ribosyltransferase activity, is a potent mucosal adjuvant for vaccines delivered via the respiratory tract.

Adjuvants, Immunologic↗
PubMed1993

Protection of mice against respiratory Bordetella pertussis infection by intranasal immunization with P.69 and FHA.

Intranasal immunization of adult female Balb/c mice with the Bordetella pertussis antigens FHA or P.69, greatly enhanced their ability to clear B. pertussis from their lungs following aerosol challenge compared with ovalbumin-immunized controls. Low numbers of lymphocytes secreting antibodies (IgG, IgA and IgM) against the immunizing antigens could be isolated from the lungs of immunized mice. Following aerosol challenge with B. pertussis there was a large increase in the numbers of FHA or P.69-specific antibody-secreting cells in the lungs of mice immunized with these antigens. Intranasal immunization, particularly with FHA, also primed mice to develop a systemic serum anti-pertussis antibody response subsequent to challenge. However, pulmonary clearance of B. pertussis correlated most closely with the local antibody response. A strong anti-FHA response was demonstrated in the lungs of mice that received a booster dose of FHA 9 months after their previous exposure to FHA, demonstrating that long immunological memory can develop in the murine respiratory tract following direct application of pertussis antigens to the respiratory tract mucosa.

Adhesins, Bacterial↗
PubMed1993

The development of oral vaccines based on live attenuated Salmonella strains.

Safe, live attenuated Salmonella strains can be produced by introducing defined non-reverting mutations into the chromosome. Such rationally attenuated strains have proved to be excellent oral vaccines in several animal species and can therefore be considered as candidate vaccines against invasive salmonellosis in both animals and man. A panel of attenuating lesions is now available from which it is possible to tailor the level of attenuation and hence produce strains with different immunogenic properties. Because of the spectrum of immune responses produced by such Salmonella vaccine strains they have been utilised extensively as vectors for delivering heterologous antigens to the mammalian immune system. We have focussed on the development of a single dose oral tetanus vaccine based on attenuated Salmonella strains expressing a non-toxic, immunogenic protein derived from tetanus toxin (fragment C). Several different expression systems have been used for fragment C and candidate vaccine strains have been constructed that are capable of protecting orally immunised mice against a lethal challenge with tetanus toxin. An oral tetanus vaccine may help to reduce the mortality rate from tetanus in the developing world by overcoming the problems associated with the implementation of vaccine programmes using the current parenteral vaccine.

Administration, Oral↗