ASGT - Third Meeting. Recent advances in clinical gene therapy.
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Journal Article↗
Biomedical subjects
K Palmer
Publications and source records attributed to K Palmer.
Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma.
We vaccinated metastatic melanoma patients with irradiated, autologous melanoma cells genetically engineered to secrete interleukin 2 (IL-2) to investigate whether an anti-tumor immune response would be induced. Melanoma cell cultures were established from surgical specimens and were engineered to secrete IL-2 by infection with recombinant retrovirus. Twelve patients were vaccinated subcutaneously one, two, or three times with approximately 10(7) irradiated, autologous, IL-2-secreting tumor cells. Treatment was well tolerated, with local reactions at 11 of 24 injection sites and minor systemic symptoms of fever and headache after 6 injections. One patient developed anti-tumor DTH after the first vaccination and showed an increased response after the second vaccination. Anti-autologous tumor CTLs could be detected prevaccination in the peripheral blood of seven patients and their activity increased after vaccination in four patients. No UICC-defined clinical responses were seen, but three patients had stable disease for 7-15 months, one of whom has not yet progressed (15+ months). Thus, patient vaccination with autologous, genetically engineered tumor cells is feasible and safe. Anti-tumor DTH and CTLs can be induced in some patients with such a vaccine.
Adult↗
Safety and immunogenicity of recombinant Bacille Calmette-Guérin (rBCG) expressing Borrelia burgdorferi outer surface protein A (OspA) lipoprotein in adult volunteers: a candidate Lyme disease vaccine.
This phase I clinical trial was designed to determine the feasibility of using rBCG as a live bacterial vaccine vector for the outer surface protein A (OspA) of Borrelia burgdorferi and as model for other vaccines based on a rBCG vector. To construct the vaccine, a signal peptide derived from a mycobacterial lipoprotein was used to direct the export, and membrane-associated surface expression, of OspA in a standard strain of BCG (Connaught). The rBCG OspA vaccine was safe and immunogenic in several animal species, and protective in a mouse model of Lyme borreliosis. An intradermal injection (0.1 ml) of rBCG OspA was administered to 24 healthy adult volunteers sequentially at one of four dose levels, ranging from 2.0 x 10(4) CFU to 2 x 10(7) CFU, using a dose-escalation design. All volunteers were initially PPD-skin test and OspA antibody negative, and they were monitored for 2 years after immunization. Three volunteers had mild flu-like reactions 1-2 days after vaccination. Local ulceration and drainage at the site of injection, which occurred in 50% and 83% of volunteers in the two highest dose groups, persisted for 1-70 days before the ulcers healed. Most of the drainage samples yielded rBCG colonies that contained the OspA plasmid. Thirteen of 24 vaccinees, principally in the two highest dose groups, converted their PPD skin tests from negative to positive. None of the 24 volunteers developed OspA antibody. In conclusion, the current rBCG vaccine construct, the first such construct tested in humans, had a safety profile comparable to that of licensed BCG, but it did not elicit primary humoral responses to the vectored antigen.
Adolescent↗
Frequency and impact of regional musculoskeletal disorders.
Regional musculoskeletal disorders are a major cause of morbidity both in the community and in the workplace. They comprise a heterogeneous group of conditions that are, for the most part, poorly characterized. Consequently, agreed diagnostic criteria have not existed for many of these disorders, and epidemiological investigations have used varied or ill-defined approaches to case definition. This chapter describes our current understanding of the epidemiology of regional pain disorders and details the strengths and weaknesses of the available data. Pain syndromes can be divided anatomically into those which cause generalized pain, such as fibromyalgia syndrome and myofascial pain syndromes, and those which are confined to one regional anatomical area. The latter group comprise those of the neck, shoulder, elbow, wrist/hand, hip, knee and ankle/foot. Current information is considered on the known risk factors for disorders at these sites, in addition to their impact upon both the individual and society.
Carpal Tunnel Syndrome↗
Transient gene transfer of non-ELR chemokines to rodent lung induces mononuclear cell accumulation and activation.
The in vivo function of the CXC chemokines interferon-inducible protein-10 (IP-10) and monokine induced by gamma (MIG) was examined using replication-deficient adenoviral vectors expressing human IP-10 (AdIP-10) or murine MIG (AdMIG). Intratracheal and intranasal administration of AdIP-10 or AdMIG into rats and mice produced transient chemokine overexpression from the bronchial epithelium. IP-10 concentrations in the bronchoalveolar lavage fluid (BAL) of AdIP-10-treated animals showed peak expression (>2 ng/ml) 24-48 h after AdIP-10 administration. Dramatic transient increases in BAL cellularity (macrophages, monocytes, lymphocytes, and neutrophils) were observed in AdIP-10-treated and AdMIG-treated animals, and histologic examination of AdIP-10-treated lungs revealed transient infiltrations of mononuclear cells primarily localized around the bronchus and extending throughout the lung parenchyma. However, in immunocomprised SCID mice, only increases in natural killer cell populations were detected in BAL following AdIP-10 intranasal administration, indicating that monocyte/macrophage and neutrophil accumulation was likely the result of factors released from activated lymphocytes.
Adenoviridae↗
Repeatability and validity of an upper limb and neck discomfort questionnaire: the utility of the standardized Nordic questionnaire.
The repeatability and validity of a questionnaire for upper limb and neck complaints were assessed in a population of 105 hospital outpatients with a range of upper limb and neck disorders (including cervical spondylosis, adhesive capsulitis, lateral epicondylitis, carpal tunnel syndrome and Raynaud's phenomenon). Subjects were asked to complete a modified Nordic-style upper limb and neck discomfort questionnaire on two occasions closely spaced in time. The repeatability of their responses was assessed by calculating a kappa coefficient (kappa), and the sensitivity and specificity of component items in the questionnaire were determined for specific diagnostic categories of upper limb and neck disorder. Symptom reports for pain in the upper limb and neck, pain interfering with physical activities, neurological symptoms and blanching were all found to be highly repeatable (kappa = 0.63-0.90). A number of regional pain reports proved to be very sensitive in relation to specific upper limb disorders, but, with the exception of reported finger blanching in patients with Raynaud's phenomenon, none proved to have a good specificity (range = 0.33-0.38). We conclude that a modified Nordic-style questionnaire is repeatable and sensitive, and is likely to have a high utility in screening and surveillance. However a complementary examination schedule of adequate specificity and repeatability is essential to establish a clinical diagnosis.
Adult↗
Antidepressants, anxiolytics and antipsychotics in Japan. Summary and table.
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Anti-Anxiety Agents↗
Agents in development for dementia syndromes in Japan. Summary and table.
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Central Nervous System Agents↗
A world of opportunity... and need.
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Developing Countries↗
Frequency and impact of regional musculoskeletal disorders
Regional musculoskeletal disorders are a major cause of morbidity both in the community and in the workplace. They comprise a heterogeneous group of conditions that are, for the most part, poorly characterized. Consequently, agreed diagnostic criteria have not existed for many of these disorders, and epidemiological investigations have used varied or ill-defined approaches to case definition. This chapter describes our current understanding of the epidemiology of regional pain disorders and details the strengths and weaknesses of the available data. Pain syndromes can be divided anatomically into those which cause generalized pain, such as fibromyalgia syndrome and myofascial pain syndromes, and those which are confined to one regional anatomical area. The latter group comprise those of the neck, shoulder, elbow, wrist/hand, hip, knee and ankle/foot. Current information is considered on the known risk factors for disorders at these sites, in addition to their impact upon both the individual and society.
Journal Article↗
A highly sensitive, nested polymerase chain reaction based method using simple dna extraction to detect malaria sporozoites in mosquitos.
Dried Anopheles farauti mosquitos caught in Solomon Islands in 1990 were examined for malaria sporozoites by ELISA and nested polymerase chain reaction (PCR). Only heads and thoraces were used. Plasmodium genus-specific nested PCR amplifications were carried out on all samples. Of the 402 pools of mosquitos that were processed, 30 were positive for malaria. Nest 1 products of positive samples were subjected to further PCR amplifications with species-specific primers for P. falciparum and P. vivax. Twenty pools were positive for P. vivax by PCR while only 7 were positive by ELISA. For P. falciparum 2 pools were positive by both ELISA and PCR, and one of these was a pool which was positive for P. vivax by PCR and ELISA. Thus the sensitivity of PCR for P. vivax was 100% while the specificity was 96.7%. For P. falciparum the sensitivity and specificity were 100%. The PCR technique is highly sensitive and can be used on dried mosquitos which makes it a valuable tool for determining sporozoite rates of mosquitos, even in remote areas.
Animals↗
Web alert. Viral methods of gene transfer.
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Animals↗
American Society of Gene Therapy--second annual meeting. 9-13 June 1999, Washington DC, USA.
Integrating viral vectors and new strategies for gene therapy were two of the major themes of this annual conference which was attended by over 2000 delegates. The conference was aimed at research scientists of all levels and participation was encouraged from graduate and professor alike. The conference was divided up into educational sessions, providing a review of topics and FDA legislation, scientific symposia concentrating on academic and mechanistic subjects, poster discussions, meet the investigator breakfast sessions and corporate symposia. A large number of pharmaceutical companies, medical publishers and clinical research organizations were represented in the exhibition hall.
Journal Article↗
Circulating, but not local lung, IL-5 is required for the development of antigen-induced airways eosinophilia.
IL-5 is induced locally in the lung and systemically in the circulation during allergic airways eosinophilic inflammation both in humans and experimental animals. However, the precise role of local and systemic IL-5 in the development of allergic airways eosinophilia remains to be elucidated. In our current study, we demonstrate that compared with their IL-5(+/+) counterparts, IL-5(-/-) mice lacked an IL-5 response both in the lung and peripheral blood, yet they released similar amounts of IL-4, eotaxin, and MIP-1alpha in the lung after ovalbumin (OVA) sensitization and challenge. At cellular levels, these mice failed to develop peripheral blood and airways eosinophilia while the responses of lymphocytes, neutrophils, and macrophages remained similar to those in IL-5(+/+) mice. To dissect the relative role of local and systemic IL-5 in this model, we constructed a gene transfer vector expressing murine IL-5. Intramuscular IL-5 gene transfer to OVA-sensitized IL-5(-/-) mice led to raised levels of IL-5 compartmentalized to the circulation and completely reconstituted airways eosinophilia upon OVA challenge, which was associated with reconstitution of eosinophilia in the bone marrow and peripheral blood. Significant airways eosinophilia was observed for at least 7 d in these mice. In contrast, intranasal IL-5 gene transfer, when rendered to give rise to a significant but compartmentalized level of transgene protein IL-5 in the lung, was unable to reconstitute airways eosinophilia in OVA-sensitized IL-5(-/-) mice upon OVA-challenge, which was associated with a lack of eosinophilic responses in bone marrow and peripheral blood. Our findings thus provide unequivocal evidence that circulating but not local lung IL-5 is critically required for the development of allergic airways eosinophilia. These findings also provide the rationale for developing strategies to target circulating IL-5 and/or its receptors in bone marrow to effectively control asthmatic airways eosinophilia.
Adenoviridae↗
Malaria epidemiology, glucose 6-phosphate dehydrogenase deficiency and human settlement in the Vanuatu Archipelago.
Vanuatu is located at the southeast margin of the malarious band extending from southeast Asia to eastern Melanesia. We analysed the malaria situation on different islands of Vanuatu, using passive case detection and malariometric survey data from 1985 to 1992, i.e. after the DDT residual programme ceased and before the impregnated bed-nets programme started on a larger scale. Malaria was mainly hypo-mesoendemic but with hyperendemic spots in certain years and on some islands. The transmission was generally more intense in the northern islands than in the south. In the late 1980s, annual parasite incidence per one thousand population (API) was around 180. The overall parasite rate was 11.9% with Plasmodium falciparum, P. vivax and P. malariae rate of 5.2, 6.7, and 0.1%, respectively. There was a seasonal fluctuation of P. falciparum incidence, whereas the P. vivax incidence was rather stable. Vivax malaria was confined to children less than 10 years old, while the intense in the northern islands than in the south. In the late 1980s, annual parasite incidence per one thousand population (API) was around 180. The overall parasite rate was 11.9% with Plasmodium falciparum, P. vivax and P. malariae rate of 5.2, 6.7, and 0.1%, respectively. There was a seasonal fluctuation of P. falciparum incidence, whereas the P. vivax incidence prevalence of P. falciparum only changed moderately with age. The mean rate of glucose 6-phosphate dehydrogenase (G6PD) deficiency among male subjects was in 7.4% but with a wide variation of 0-14.3% on different islands. A positive rank-order correlation was found between malaria incidence and G6PD deficiency rate on the different islands. A reasonable hypothesis is that malaria was introduced to the islands with the first human settlement 4000 years ago, with a geographical malaria distribution similar to the present situation. Different malaria endemicities possibly then selected different prevalences of G6PD deficiency over many generations.
Adolescent↗
Work related upper limb disorders: getting down to specifics.
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Adult↗
Functional gastrointestinal disorders: psychological, social, and somatic features.
BACKGROUND: Psychological, social, and extraintestinal (somatic) disturbances are prominent features of functional gastrointestinal disorders (FGID); little attention, however, has been given to differences in the nature of these disturbances in the various FGID subgroups. AIMS: (1) To determine whether psychological, social, and extraintestinal factors are associated with specific FGID, and/or with the overall severity and extent of FGID disturbance (the number of coexistent FGID subgroups present in any individual); and (2) to determine whether chronic social stressors link gastrointestinal, extraintestinal, and emotional symptomatologies in FGID. PATIENTS: One hundred and eighty eight outpatients, fulfilling standard criteria for one or more functional gastroduodenal or functional bowel disorders. METHODS: Utilising detailed and objective interview and questionnaire methods, detailed gastrointestinal, extraintestinal, psychological, and social data were collected. RESULTS: Chronic stressors and extraintestinal and emotional symptomatologies were prominent features of functional dyspepsia (FD) and irritable bowel syndrome (IBS) alone. These particular features were, however, highly specific for particular FD and/or IBS subgroups. The chronic threat component of social stressors predicted the nature and extent of multisystem (gastrointestinal, extraintestinal, and emotional) symptomatology. CONCLUSIONS: Notable differences between the various FGID subgroups support the symptom based classification of FGID. Chronic stressor provoked psychological and extraintestinal disturbance is most specific for the FD-IBS group of syndromes.
Adaptation, Psychological↗
Dementia and occupational exposure to organic solvents.
OBJECTIVES: To investigate whether occupational exposure to organic solvents increases the risk of dementia. METHODS: Cases of dementia were identified from the computed tomography records of eight neuroradiology centres in England and Wales, and were compared with two sets of controls investigated at the same centres. The first set of controls were patients with brain cancer and the second set were patients with other disorders that were not chronically disabling. Lifetime occupational histories were obtained through a postal questionnaire completed by the subjects or their next of kin. Associations between dementia and occupation were examined by logistic regression. RESULTS: Usable questionnaires were returned for 204 (61%) of the cases, 225 (51%) of the controls with brain cancer, and 441 (61%) of the other controls. The findings with each of the two sets of controls were similar. In comparison with all controls combined, cases had less often worked ever as a painter or printer (odds ratio (OR) 0.6, 95% confidence interval (95% CI) 0.3 to 1.2), and were less likely to have worked for > 1 year as a printer, painter, or launderer or dry cleaner (OR 0.6, 95% CI 0.3 to 1.4). CONCLUSIONS: These findings provide no support for the hypothesis that occupational exposure to solvents is a cause of dementia. An excess risk in subsets of workers with extremes of exposure cannot be discounted, but the data indicate that any influence of exposure to solvents on the overall incidence of severe dementia in the general population of England and Wales is small.
Aged↗