Pseudomonas septicaemia associated with HIV.

Between July 1985 and January 1990, pseudomonas scepticaemia occurred in 19 out of 584 patients with AIDS attending the Westminster and St Stephen's AIDS Unit, London, UK. Ten of these 19 were being treated for active cytomegalovirus infection. Fourteen of the 19 patients had a central venous catheter in situ, which was the source of infection in 11. Seven patients died. Mortality was significantly greater in those patients infected with Pseudomonas aeruginosa, in those patients whose source of infection was not the central venous line, and in those patients whose central line was not removed.     

Testing patients for HIV before surgery: The views of doctors performing surgery

The aim of this study was to investigate the attitudes of doctors performing surgery to the HIV antibody testing of surgical patients. Fifty of eighty (62.5%) doctors performing surgery who are working in two London teaching hospitals returned completed anonymous postal questionnaires. Sixty-six per cent of the sample would like some form of compulsory testing of pre-operative patients, although most of them feel that this is only necessary for patients considered to be in 'high-risk groups'. Eighty-four per cent believe that this would ensure their safety from infection during surgery. Forty-eight per cent agreed with testing patients without their consent. Results suggest that most of the doctors performing surgery in this study agree with compulsory HIV antibody testing of pre-operative patients in the belief that this would protect them from infection during surgery. The problems associated with compulsory testing and relying on such testing in order to protect doctors from infection during surgery are discussed.     

The common heat shock protein receptor CD91 is up-regulated on monocytes of advanced melanoma slow progressors

Despite advances in our understanding of tumour immunology there is no therapy of proven survival benefit for advanced melanoma. Nevertheless, disease progression is slow in a small proportion of patients with metastatic melanoma, suggesting a contribution to outcome from host factors. Recent data have indicated the importance of the heat shock protein receptor CD91 in immune responses to, and progression of, infectious disease. Here we investigate the relationship between CD91 expression and outcome in malignancy. Rare melanoma patients were recruited with advanced disease that was progressing unusually slowly. CD91 expression on their monocytes was compared with control patients with more typical rapidly advancing metastatic disease. Th1 and Th2 cytokines, as well as innate and adaptive immune subsets, were also measured in the two groups. A significant increase in median CD91 expression levels was observed in slow progressors (P = 0.006). There were no differences in other immune subset markers or inflammatory cytokines. The ability of CD91 to internalize and cross-present tumour antigens through the major histocompatibility complex class I pathway may maintain CD8-positive cytotoxic T cell responses and contribute to slow progression of advanced melanoma.     

Reconstitution of CD4+ T cell responses in HIV-1 infected individuals initiating highly active antiretroviral therapy (HAART) is associated with renewed interleukin-2 production and responsiveness

Reconstitution of functional CD4(+) T cell responsiveness to in vitro stimuli is associated with continuous highly active antiretroviral therapy (HAART). Thirty-six antiretroviral naive patients received HAART over 16 weeks. Antigen-specific, mitogen and interleukin (IL)-2 induced lymphocyte proliferative responses and specific IL-2 and IL-4 production were assessed at each time-point, together with quantification of HIV-1 RNA load and lymphocyte populations. Reconstitution of recall responses was limited largely to persistent antigens such as Herpes simplex virus and Candida, rather than to HIV-1 or neo-antigens. Recall antigens, mitogens and IL-2-induced renewed responses were associated with in-vitro production of IL-2, but not IL-4. Differential responsiveness to low versus high concentration IL-2 stimulus increases in a stepwise manner, suggesting normalization of IL-2 receptor expression and improved functionality. These increases in in-vitro proliferative responses thus probably reflect short lived effector clones, driven by ongoing antigenic stimulus associated with persisting long-term organisms. In this context non-responsiveness to HIV-1 antigens suggests ongoing HIV-1 specific clonal T cell anergy.     

Mutation of the gene encoding fibrillin-2 results in syndactyly in mice

Fibrillins are large, cysteine-rich glycoproteins that form microfibrils and play a central role in elastic fibrillogenesis. Fibrillin-1 and fibrillin-2, encoded by FBN1 on chromosome 15q21.1 and FBN2 on chromosome 5q23-q31, are highly similar proteins. The finding of mutations in FBN1 and FBN2 in the autosomal dominant microfibrillopathies Marfan syndrome (MFS) and congenital contractural arachnodactyly (CCA), respectively, has highlighted their essential role in the development and homeostasis of elastic fibres. MFS is characterized by cardiovascular, skeletal and ocular abnormalities, and CCA by long, thin, flexed digits, crumpled ears and mild joint contractures. Although mutations arise throughout FBN1, those clustering within exons 24-32 are associated with the most severe form of MFS, so-called neonatal MFS. All the mutations described in CCA occur in the "neonatal region" of FBN2. Both MFS and CCA are thought to arise via a dominant negative mechanism. The analysis of mouse mutations has demonstrated that fibrillin-1 microfibrils are mainly engaged in tissue homeostasis rather than elastic matrix assembly. In the current investigation, we have analysed the classical mouse mutant shaker-with-syndactylism using a positional candidate approach and demonstrated that loss-of-function mutations outside the "neonatal region" of Fbn2 cause syndactyly in mice. These results suggest that phenotypes distinct from CCA may result in man as a consequence of mutations outside the "neonatal region" of FBN2.     

A dog model of fulminant hepatic failure produced by paracetamol administration.

Oral administration of graded doses of paracetamol to dogs produced hepatic necrosis with some similarities to the clinical syndrome seen in man following a paracetamol overdose. Coma, with raised levels of arterial ammonia, was produced and the aspartate aminotransferase levels became markedly elevated in 2 animals who survived more than 24 h. However, the extent of the hepatic necrosis and the time of survival following paracetamol administration were too variable for this model to be of value for the testing of new methods of temporary liver support. When paracetamol was given by intraperitoneal injection many of the animals died of respiratory distress. Significant methaemoglobinaemia was detected, which was associated with a reduction in the arterial partial pressure of oxygen and was partly reversed by the administration of methylene blue.     

Management of pulmonary aspergillosis in AIDS: an emerging clinical problem.

AIMS--To review the clinical, radiographic, and therapeutic features of 11 cases of respiratory Aspergillus infection in patients with AIDS. METHODS--All induced sputum and bronchoalveolar lavage samples obtained from HIV seropositive patients between January 1985 and March 1993 were analysed for Aspergillus species. Additionally, where appropriate, bronchial or renal biopsy specimens, or both, were taken before treatment had started. RESULTS--In 11 patients Aspergillus fumigatus was identified in alveolar samples obtained by sputum induction. This was confirmed by bronchoalveolar lavage in eight. Three patients had Aspergillus plaques in the trachea and bronchus, while a fourth patient had an aspergilloma. Risk factors for Aspergillus infection were present in all patients, including corticosteroid treatment in three cases and neutropenia in four, three of whom had received chemotherapy for Kaposi's sarcoma. Four patients had concomitant cytomegalovirus infection. Ten patients had a CD4 count of less than 50 cells/mm3 while one patient had a disseminated T cell lymphoma with a CD4 count of 242 cells/mm3. Of the three patients with samples obtained by sputum induction who did not undergo bronchoscopy, two had a normal chest x ray picture and the third had a right lobar pneumonia complicating an aggressive lymphoma. All three were treated with itraconazole 200 mg twice a day without further investigation. Survival from the time of diagnosis of Aspergillus infection was short: seven patients died within six weeks, although only one death was directly attributed to pulmonary aspergillosis. At six monthly follow up, one patient, who initially had a positive Aspergillus culture from bronchial washings and a normal chest radiograph, developed a renal aspergilloma despite the disappearance of Aspergillus sp from the sputum. CONCLUSION--Pulmonary aspergillosis is an important clinical problem in patients with AIDS with a CD4 count of less than 50 cells/mm. Furthermore, patients with Aspergillus sp in sputum induction or bronchial washings may develop disseminated disease despite adequate treatment of the primary infection.     

Cytomegalovirus retinitis after the initiation of highly active antiretroviral therapy: a 2 year prospective study

BACKGROUND/AIMS: There have been several recent reports suggesting that the natural history of cytomegalovirus retinitis (CMVR) has been significantly modified with the development of highly active antiretroviral therapy (HAART). This 2 year prospective cohort study assesses the effect of HAART on the incidence and progression of CMV retinitis in patients with CD4 cell counts below 50 cells x10(6)/l. METHODS: 63 patients, with CD4 cell counts below 50 cells x10(6)/l, who were recruited to a 2 year prospective cohort study at the commencement of combination antiretroviral therapy including the use of the proteinase inhibitor, indinavir, were reported. The response to HAART was assessed in terms of a rise in the CD4 cell count and fall in HIV viral load. An experienced ophthalmologist performed dilated funduscopy at the time of recruitment and thereafter at 2 weekly intervals and retinal photography was performed at monthly intervals in patients with CMVR. The activity and progression of CMV retinitis was assessed on the basis of the characteristic clinical and photographic findings. RESULTS: 34 patients achieved at least 50 CD4 cells x10(6)/l at 3 months after initiation of therapy. New diagnoses of CMVR were seen only in the non-responder group (p=0. 085). Overall, the relative risk of a new retinitis event in this group was 3.52 (95% CI 1.16, 10.68) at 3 months compared with those patients who were responsive to HAART. 12 of the 63 patients had previous CMVR. Disease progression was associated with non-response to therapy (p=0.182 exact). In patients with CMVR the median time to first progression was 18 days (95% CI 8, 91) in non-responders and 121 days (95% CI 0.59, 3.65) in responders. By the end of the 2 year follow up period all surviving patients had >50 CD4 cells x10(6)/l. No CMV events were seen after 8 months of therapy in either group of patients. CONCLUSIONS: These findings suggest that significant clinical immunorestoration to CMV occurs in response to HAART in patients with CMVR after a lag time of 3-8 months. Initially, a rise in CD4 count is predictive of CMVR response but after the lag period all survivors appear to have developed a clinical immunorestoration to CMV. If HAART is commenced in at risk patients before the development of CMVR the incidence of new disease falls significantly.