Mike Grace speaks to Jacqui Smith.
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Dental Hygienists↗
Biomedical subjects
J Smith
Publications and source records attributed to J Smith.
Gene therapy for hemophilia A: production of therapeutic levels of human factor VIII in vivo in mice.
Continuous delivery of factor VIII (FVIII) protein in hemophiliacs by gene therapy will represent a major clinical advance over the current practice of infrequent administration of purified FVIII. Conceptually, retroviral vectors that can permanently insert the FVIII gene into the DNA of the host cell appear the most suitable vehicles for this specific purpose. However, most retroviral vector systems have shown a poor performance in the production of FVIII from primary cells in vitro and in vivo. Here we report the retroviral-mediated gene delivery of a B-domain-deleted human FVIII by using the MFG vector system. This vector permitted efficient transduction of the majority of the primary cells in culture without the use of a selectable marker. High levels of FVIII were produced by various transduced primary cells in vitro. Upon transplantation of primary fibroblasts into mice, therapeutic levels of FVIII in the circulation were obtained for > 1 week. The capacity of primary cells to deliver the FVIII into the circulation was strongly dependent on the site of implantation. These results represent a major step forward in development of gene therapy for treating hemophilia A.
3T3 Cells↗
A phase III study of accelerated radiotherapy with and without carboplatin in nonsmall cell lung cancer: an interim toxicity analysis of the first 100 patients.
PURPOSE: In 1989 we initiated a multicenter randomized trial to determine if accelerated radiotherapy with or without concurrent carboplatin improves local control and survival in patients with limited nonsmall cell lung cancer. This interim analysis was performed on the first 100 patients to determine whether the toxicity of the four treatment arms is acceptable. METHODS AND MATERIALS: One hundred patients with limited nonsmall cell lung cancer have been randomized to receive one of four treatments: arm I, radiotherapy 60 Gray (Gy) in 30 fractions in 6 weeks; arm II, accelerated radiotherapy 60 Gy in 30 fractions in 3 weeks; arm III, radiotherapy as in arm I plus carboplatin 350 mg/m2 during weeks 1 and 5 of radiotherapy; arm IV, radiotherapy as in arm II plus carboplatin 350 mg/m2 during week 1. Survival was measured for the group as a whole and treatment-related toxicities in the four arms were compared. RESULTS: The estimated median survival for all 100 patients was 17.1 months with 33% estimated survival at 2 years. The major toxicities were hematologic and esophageal. Patients receiving carboplatin had more neutropenia (p < 0.0001) and thrombocytopenia (p = 0.002) than patients receiving radiotherapy alone, and this was most marked in patients on arm III. Both carboplatin and accelerated radiotherapy separately caused more severe esophagitis when compared to conventional radiotherapy alone (p = 0.011 and p = 0.0017, respectively). Esophagitis was more prolonged in patients having accelerated radiotherapy (p < 0.0001, median duration 3.2 months compared with 1.4 months for patients receiving conventional fractionation). Six patients (23%) treated on arm II have required dilatation of esophageal stricture, one dying with a laryngo-esophageal fistula. CONCLUSION: In patients receiving radiotherapy for unresectable lung cancer, overall treatment time can be halved and carboplatin administered concurrently with increased but acceptable esophageal and hematologic toxicity.
Adult↗
n-pentyl N-acetylprolinate. A new skin penetration enhancer.
The activity of n-pentyl N-acetylprolinate (PNAP) as a transdermal penetration enhancer was investigated. PNAP was synthesized from L-proline by acetylation with acetic anhydride, followed by acid-catalyzed esterification with 1-pentanol. Structure confirmation was accomplished by IR and NMR spectroscopy and elemental analysis. Benzoic acid (BA) was used as a model drug, and the effect of PNAP on the flux of BA through human cadaver skin was evaluated. The central nervous system (CNS) toxicity of PNAP was evaluated by comparing the effects of intraperitoneal administration of PNAP to mice with those of laurocapram (Azone), a known penetration enhancer. Based on preliminary studies, PNAP appears to be an effective transdermal penetration enhancer, is nontoxic at low doses, and exhibits dose-related CNS toxicity at higher doses.
Administration, Cutaneous↗
Role of glutathione in macrophage activation: effect of cellular glutathione depletion on nitrite production and leishmanicidal activity.
We have examined the effects of two agents depleting the intracellular pool of glutathione (GSH) on macrophage activation induced by IFN-gamma + LPS, as measured by nitrite production and leishmanicidal activity. Diethylmaleate (DEM), which depletes intracellular GSH by conjugation via a reaction catalyzed by the GSH-S-transferase, strongly inhibited nitrite secretion and leishmanicidal activity when added before or at the time of addition of IFN-gamma + LPS; this inhibition was progressively lost when addition of DEM was delayed up to 10 hr. A close correlation was observed between levels of intracellular soluble GSH during activation and nitrite secretion. Inhibition was partially reversed by the addition of glutathione ethyl ester (GSH-Et). Buthionine sulfoximine (BSO), a specific inhibitor of gamma-glutamylcysteine synthetase, also inhibited macrophage activation, although to a lesser extent than DEM despite a more pronounced soluble GSH depletion. This inhibition was completely reversed by the addition of GSH-Et. DEM and BSO did not alter cell viability or PMA-triggered O2- production by activated macrophages, suggesting that the inhibitory effects observed on nitrite secretion and leishmanicidal activity were not related to a general impairment of macrophage function. DEM and BSO treatment reduced iNOS specific activity and iNOS protein in cytosolic extracts. DEM also decreased iNOS mRNA expression while BSO had no effect. Although commonly used as a GSH-depleting agent, DEM may have additional effects because it can also act as a sulhydryl reagent; BSO, on the other hand, which depletes GSH by enzymatic inhibition, has no effect on protein-bound GSH. Our results suggest that both soluble and protein-bound GSH may be important for the induction of NO synthase in IFN-gamma + LPS-activated macrophages.
Amino Acid Oxidoreductases↗
Natural killer cell lymphoproliferative disorder of granular lymphocytes presenting as hemolytic anemia: case report and review of the literature.
Lymphoproliferative disorders of granular lymphocytes (LDGLs) have recently been hypothetically defined based on their immunophenotype, function, and clonality. The majority (129/161) of LDGLs are of the T-cell subset, which is typically associated with neutropenia and occasionally with anemia. The remainder (32/161) are of natural killer cell origin. This subset is associated with neutropenia (52% of cases) and anemia (60% of cases). The anemia most often has no immediately apparent cause. The Coombs test was negative in all cases reported. There is only one reported case of an associated Coombs-negative hemolytic anemia. We report an unusual case of natural killer cell LDGL, defined by morphology and immunophenotypic analysis, presenting as a de novo Coombs-negative hemolytic anemia. The anemia was resistant to steroid therapy. Therapeutic splenectomy resulted in a temporary resolution of the hemolytic process. The splenic pathology is also described.
Aged↗
Linear aggregations of stomata and epidermal cells in Tradescantia leaves: evidence for their group patterning as a function of the cell cycle.
We tested Charlton's hypothesis (1990) that stomata are present and patterned in linear cell aggregations using the monocot Tradescantia. We examined the following features of the leaf epidermis in support of this theory: linear groups (strings) of stomatal complexes and of epidermal cells were sought in immature and mature regions of entire leaves; the lengths (in cell number) and incidences (numerical occurrence) of both string types were determined; the uniformity and progression of stomatal differentiation within strings were studied; physical characteristics of differentiating strings within cell files were measured. Undifferentiated epidermal cells from the leaf base were stained with DAPI to reveal precursors of stomatal strings immediately proximal to the stomatal initial region. The results indicated that the Tradescantia epidermis in the leaf blade consists of linear groups of stomata and epidermal cells, which did not change in cell number nor incidence during development. The incidence of stomata by length was nonrandom. Although incidence decreased with string length, the decline was not linear nor exponential. Stomatal strings show cell cycle synchrony in DAPI staining of stomatal precursors and synchrony of stomatal differentiation within a string. The irregularity in the length of the stomatal development region, and each differentiation stage in it, by cell file was consistent with the variation in string length and unity in string development. The evidence supports Charlton's hypothesis that cells are patterned based on their position in the cell cycle and that linear groups of stomata reflect cell lineages, which maintain a degree of cell cycle synchrony.
Cell Aggregation↗
Natural helping functions of lay health advisors in breast cancer education.
The Save Our Sisters Project builds on the roles of 95 "natural helpers" to increase mammography screening among older African American women in a NC county. Natural helpers are lay people to whom others naturally turn for advice, emotional support, and tangible aid. Findings from 14 focus group interviews showed that older women seek out these individuals when they have a female-specific concern, rather than or before seeking help from professionals. The characteristics of natural helpers, revealed in the findings, were used to identify and recruit them to become trained lay health advisors in breast cancer education. Through the SOS Project, natural helpers provide a community-based system of care and social support that complements the more specialized role of health professionals; linking them to women through places and ways that no health professional could begin to acquire. The three roles of lay health advisors are: (1) to assist individuals in their social networks with needs that are difficult for professionals to address; (2) to negotiate with professionals for support for the health system; and (3) to mobilize the resources of associations in their community to sustain support from the health system.
Black or African American↗
Chest radiographs of neonates with respiratory failure caused by congenital syphilis.
Congenital syphilis still occurs in newborn babies and the prevalence has increased in recent years, especially in developing countries. This has led to an increase in the number of babies with congenital syphilis requiring intensive care for respiratory failure. The early recognition of this disease could lead to the institution of timely and appropriate treatment. In this study the radiological picture of syphilitic pneumonitis is described in 20 neonates admitted to our neonatal intensive care unit requiring ventilation for respiratory failure. The radiological picture of the babies with syphilis was compared to 20 babies with other causes of respiratory distress. The radiological picture in 17 babies demonstrated a coarse nodular pattern in addition to band-like opacities radiating from the hilar regions. The nodular opacities became confluent on follow-up radiographs. In 13 cases, the proximal humeri showed changes typical of congenital syphilis. Two of the three babies with syphilis who did not have the typical chest radiological picture had bony involvement visible on the chest radiograph. Both the sensitivity and specificity of radiographic diagnosis were 75% with a positive and negative predictive value of 75%. The diagnosis of congenital syphilitic pneumonitis can therefore be suspected on chest radiographs and should be included in the differential diagnosis of any baby who presents with an interstitial pattern on chest radiography.
Case-Control Studies↗
Ethical awareness among first year medical, dental and nursing students.
Ethics is increasingly being included in the training curriculum for health-care professionals. However, debate continues around the appropriate content of ethics courses for such students and the most relevant teaching approaches which will enable students to apply their ethical knowledge in clinical settings. At a time when health-care professionals are starting to collaborate more closely in multidisciplinary teams, it is appropriate to explore the ethical values held by different groups of health professionals. This study sought to ascertain the ethical views and knowledge which medical, dental and nursing students have at the commencement of their training, to establish their opinions on the most important areas of ethical debate in contemporary health care and to examine their ethical reasoning in response to a series of vignettes. Students gave detailed answers to the questionnaire and the data they provided furnishes useful material for those designing and teaching ethics courses.
Adult↗
Isolation of nucleic acid from paraffin embedded tissue for PCR amplification and sequencing of TcR V beta genes.
PCR analysis of DNA and RNA from fresh and frozen tissue is now a routine practice in most laboratories. Furthermore DNA extracted from paraffin embedded tissue is routinely used for clonality studies and for HLA typing. However the use of RNA from paraffin embedded tissue is more problematical due to degradation and only short sequences are suitable for amplification. In this report we examine the suitability of extracted nucleic acid from paraffin embedded tissue for the PCR amplification of TcR V beta genes and sequencing of resultant PCR products.
Amino Acid Sequence↗
Patterns of Cryptosporidium antigen and oocyst excretion in calves studied by reverse passive haemagglutination and light microscopy.
A reverse passive haemagglutination (RPH) assay incorporating a monoclonal antibody against Cryptosporidium parvum oocysts was used to follow Cryptosporidium coproantigen excretion by calves. RPH detected soluble antigen that passed 0.22 micron filters. Non-specific reactions that occurred in some samples were markedly reduced by heat treatment of the faecal specimens and were abolished by filtration after heat treatment. Results were compared with oocyst counts performed by microscopy of modified Ziehl-Neelsen (MZN) stained faecal smears. Five hundred and thirty-two daily specimens were examined from 30 calves. The mean age at which positive results for both oocysts and antigen was detected was 9 days (range 5-15 days), and excretion lasted for 5-11 days with some cycling of positive reactions in some calves. The occasional cycling to a negative reaction demonstrates a need to take samples from consecutive days to ensure diagnosis. Two hundred and ninety-one (54.7%) specimens were negative in both tests, 178 (33.5%) were positive in both, 14 (2.6%) were positive only by microscopy, and 49 (9.2%) were positive only by RPH. By these criteria the kappa coefficient of agreement between the tests was good (0.753). Compared with MZN, the sensitivity of RPH is 92.7%, specificity 85.6%, positive predictive value 78.4% and negative predictive value 95.4%. The method is simple, objective, has ease of quality control, and either single samples or batches can be processed.
Aging↗
Deficits in lower extremity muscle and gait performance among renal transplant candidates.
This study was performed to determine the reliability and convergent validity of two lower extremity muscle performance (LEMP) measurements and to describe deficits in and determinants of LEMP and gait performance. Cross-sectional case series and criterion standard designs were used. The study took place at a tertiary care center. The subjects were referred from a volunteer sample of 110 renal transplant candidates. There were no interventions. The main outcome measures were knee extension strength measured by hand-held dynamometry and a sit-to-stand-to-sit (STSTS) test; gait independence on level surfaces and stairs; comfortable and maximum gait speed. Dynamometer measurements were reliable within (intraclass correlation coefficient (ICC) > or = .976) and between (ICC > or = .953) testers. Repeated STSTS measurements were also reliable (ICC > or = .843). The LEMP measures correlated significantly (p < .001) with one another (r > or = .406, R > or = .445). Compared with values predicted by regression equations derived from healthy individuals, transplant candidates showed significant deficits in knee extension force (33.2% to 34.6%) and gait speed (20.5% to 22.7%). Consistent as determinants of LEMP were sex, weight, and diabetic status. STSTS performance was the most consistent determinant of gait performance. The results of this study support the use of the STSTS test to characterize LEMP in kidney transplant candidates, particularly those who are diabetic or have deficits in gait performance.
Adolescent↗
Treatment with finasteride following radical prostatectomy for prostate cancer.
OBJECTIVES: The objective of this study was to evaluate the effect of finasteride (10 mg/d) or placebo on serum prostate-specific antigen (PSA) and recurrence rates in men with detectable PSA levels after radical prostatectomy. METHODS: A total of 120 men, 48 to 89 years old, previously treated with radical prostatectomy for prostate cancer within the past 10 years, with serum PSA levels between 0.6 and 10.0 ng/mL, with no evidence of skeletal metastasis on bone scan, and with no previous androgen deprivation therapy, were treated with 10 mg finasteride or placebo in a double-blind fashion for 12 months. After the first year, all patients were treated with finasteride for an additional 12 months. Primary endpoints were serum PSA levels and recurrence rates defined as positive bone scan or positive biopsy. RESULTS: Patients treated with finasteride had a delayed increase in serum PSA compared with placebo of approximately 9 months in the first year and 14 months by the end of the second year. Patients with baseline PSA levels less then 1.0 ng/mL had no significant increase in serum PSA during the 2 years of treatment. Fewer recurrences were observed in the finasteride group, but these differences were not statistically significant. Finasteride was well tolerated, and side effects were balanced between treatment groups. CONCLUSIONS: The results of this study indicate that treatment with finasteride delays but does not prevent the rise in serum PSA observed in untreated patients with detectable PSA levels after radical prostatectomy. The reduction in local and distant recurrences in the finasteride group suggests that the effect on PSA reflects a direct effect on tumor growth without affecting the initial response to subsequent hormonal therapy. These data require confirmation by studies that are longer and larger, focused on demonstrating significant differences in progression rates and survival before the use of finasteride can be considered as an option for men with detectable PSA levels after radical prostatectomy.
Aged↗
Effect of extended ibuprofen administration on the acute phase protein response in colorectal cancer patients.
The regulation of acute phase protein production and the relationship of the acute phase protein response to tumour growth was examined in colorectal cancer patients (n = 9). Ibuprofen (1200 mg/d) was administered for 8-11 days. Following ibuprofen administration there were reductions in circulating concentrations of C-reactive protein (P = 0.01), interleukin-6 (P = 0.06), cortisol (P = 0.04) and also in the platelet count (P = 0.01). There was no significant change in albumin, insulin and carcinoembryonic antigen. These results indicate that ibuprofen administered over a prolonged period substantially reduces acute protein production via its effect on interleukin-6 and cortisol. It remains to be determined whether ibuprofen is useful in moderating tumour growth in colorectal cancer patients.
Acute-Phase Proteins↗
The role of cancer registries.
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Databases, Factual↗
The archive of the Health Visitors' Association in the Contemporary Medical Archives Centre.
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Archives↗