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Biomedical subjects

L Smith

Publications and source records attributed to L Smith.

At least 163 records · Page 9Linked to original sources
PubMed1999

Analysis of radiographic measurements as prognostic indicators of treatment success in patients with developmental dysplasia of the hip.

Measurements were taken and statistically analyzed from the initial radiographs, the 1-year follow-up radiographs, and the most recent radiographs of 81 patients (103 hips) to determine which measurements could predict the success of treatment. The average follow-up was 49 months (range, 12-139 months), and the average age of the patients at the last follow-up was 65 months (range, 15-190 months). Analysis of the data showed that the measurement with statistically significant predictive value was the Tonnis grade of dislocation determined from the initial radiograph. A single unit increase in the Tonnis grade was associated with a doubling of the odds of failure in patients treated with a Pavlik harness (P < 0.04, odds ratio = 2.2) or a closed reduction (odds ratio = 2.0).

Adolescent↗
PubMed1998

The p53 codon 249 mutational hotspot in hepatocellular carcinoma is not related to selective formation or persistence of aflatoxin B1 adducts.

Sequence-dependent formation and lack of repair of polycyclic aromatic hydrocarbon-induced DNA adducts correlates well with the positions of p53 mutational hotspots in smoking-related lung cancers (Denissenko et al, 1996, 1998). The mycotoxin aflatoxin B1 (AFB1) is considered to be a major causative agent in hepatocellular carcinoma (HCC) in regions with presumed high food contamination by AFB1. A unique mutational hotspot, a G to T transversion at the third base of codon 249 of the p53 gene is observed in these tumors. To test whether a selectivity of AFB1 adduct formation is related to this peculiar mutational spectrum, we have mapped AFB1-DNA adducts at nucleotide resolution using ligation-mediated PCR and terminal transferase-dependent PCR. Human HepG2 cells were exposed to AFB1 metabolically activated in the presence of rat liver microsomes. Significant adduct formation was seen at the third base of codon 249. However, this was not the major site of AFB1 adducts and strong adduction was also observed at codons 226, 243, 244, 245 and 248 in exon 7 of the p53 gene and at several codons in exon 8. The damage at codon 249 does not consist of a unique abasic site or ring-opened aflatoxin B1 adduct but rather is consistent with the principal N7-guanine adduct of AFB1. Time course experiments indicate that, under the conditions used, AFB1 adducts are not removed in a strand-selective manner and adduct removal from the third base of codon 249 proceeds at a relatively fast rate (50% in 7 h). The incomplete correspondence between sites of persistent AFB1 damage and the specific codon 249 mutation suggests that AFB1 may not be involved in mutation of this site or that additional mechanisms such as parallel infection with hepatitis B virus may be required for selection of codon 249 mutants in HCC.

Aflatoxin B1↗
PubMed1998

Death in springtime.

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Adaptation, Psychological↗
PubMed1998

AIDS: the new drug war.

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Acquired Immunodeficiency Syndrome↗
PubMed1998

Proliferation signaling and activation of Shc, p21Ras, and Myc via tyrosine 764 of human granulocyte colony-stimulating factor receptor.

The membrane-distal region of the cytoplasmic domain of human granulocyte colony-stimulating factor receptor (G-CSF-R) contains four conserved tyrosine residues: Y704, Y729, Y744, and Y764. Three of these (Y729, Y744, and Y764) are located in the C-terminal part of G-CSF-R, previously shown to be essential for induction of neutrophilic differentiation. To determine the role of the tyrosines in G-CSF-mediated responses, we constructed tyrosine-to-phenylalanine (Y-to-F) substitution mutants and expressed these in a differentiation competent subclone of 32D cells that lacks endogenous G-CSF-R. We show that all tyrosines can be substituted essentially without affecting the differentiation signaling properties of G-CSF-R. However, substitution of one specific tyrosine, ie, Y764, markedly influenced proliferation signaling as well as the timing of differentiation. 32D cells expressing wild-type (WT) G-CSF-R (or mutants Y704F, Y729F, or Y744F) proliferated in G-CSF-containing cultures until day 8 and then developed into mature neutrophils. In contrast, 32D/Y764F cells arrested in the G1 phase of the cell cycle within 24 hours and showed complete neutrophilic differentiation after 3 days of culture. This resulted in an average 30-fold reduction of neutrophil production as compared with the 32D/WT controls. Importantly, G-CSF-mediated activation of Shc, p21Ras and the induction of c-myc were severely reduced by substitution of Y764. These findings indicate that Y764 of G-CSF-R is crucial for maintaining the proliferation/differentiation balance during G-CSF-driven neutrophil development and suggest a role for multiple signaling mechanisms in maintaining this balance.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Genetically transmitted cholinergic hyperresponsiveness predisposes to experimental asthma.

The excitatory innervation of the airway smooth muscle is primarily cholinergic in nature. However, the potential neural mechanism(s) underlying airway hyperresponsiveness, one of the hallmarks of asthma, is not fully understood. In this study, cholinergic hyperresponsive Flinders sensitive line (FSL) rats and their control counterparts, Flinders resistant line (FRL) rats, were repeatedly challenged with different doses of nebulized methacholine (0, 4, 16, 64, and 256 mg/ml) for 5 min. Airway responsiveness was assessed in spontaneously breathing, unrestrained animals by means of whole body plethysmography. Increased airway responsiveness of FSL rats was evidenced as a more pronounced increase in Penh value (enhanced pause, an index of bronchoconstriction) across different concentrations of methacholine. In subsequent experiments, FSL and FRL rats were sensitized to ovalbumin and challenged with nebulized antigen. Our results indicate that the genetically transmitted cholinergic hyperresponsiveness of the FSL rat is paralleled by an increased susceptibility to allergen-induced bronchoconstriction and inflammation of the airways. This study provides further evidence that neural factors can play an important role in determining airway responsiveness and thus may be relevant for the expression of asthma. In addition, the FSL rat may be a useful model for studies of airway hyperresponsiveness.

Airway Obstruction↗
PubMed1998

The practice of general internal medicine by subspecialists.

To determine the proportion of specialists in internal medicine at a university medical center practicing general internal medicine in addition to their specialty, full-time and voluntary faculty were asked to complete a questionnaire concerning their practice patterns. In addition, the directories of two of the largest managed-care groups in the area were reviewed to identify physicians who were also faculty members, to determine whether faculty in these directories self-identified as general internists. Excluding those with primary research appointments, 303 faculty in the Department of Medicine were asked to participate. Of these, 187 (62%) responded, of whom 86 (46%) were full-time and 101 (54%) voluntary faculty. Of the respondents, 183 (98%) were either board certified (152; 81%) or board eligible (31; 17%) in a subspecialty. Both general internal medicine and specialty medicine were practiced by 116 (65%), with full-time faculty being more likely to have solely subspecialty practices (P < .001). The majority of faculty (150; 80%) participated in managed care. A review of directories of two managed-care groups revealed that 100 (87%) of the 115 faculty with appointments within subspecialty divisions of the Department of Medicine were listed as general internists. Subspecialists in internal medicine already spend considerable time practicing general medicine and are increasingly willing to identify themselves as generalists. Unless this is recognized, the future need for generalists may be overestimated considerably.

Hospitals, University↗
PubMed1998

Industrial shift systems.

This technical report describes the identification of shift systems worked by industrial shiftworkers in England, Scotland and Wales. A diverse range of shift systems were reported to be in operation across 27 industrial sectors. Companies employed up to 14 different shift systems at a particular site. The numbers of shiftworkers on a given shift schedule ranged from 1 to 2977. Most systems employed fewer than 100 people. The majority of rotas were regular, rotating systems. The most common shift durations were 8 or 12 h. Compared to earlier surveys of shiftwork prevalence in certain industries there appeared to be a substantial increase over the past 3 decades in the proportion of the workforce who work shifts. Information about the average numbers of hours worked per week on major system types is given. In addition, data for the range of shifts per cycle, the distribution of shifts and distributions of their start and end times are presented.

Humans↗
PubMed1998

Shared learning for community based maternity care.

In order to ensure the best quality of maternity care midwives and doctors must work closely together but unfortunately the necessary interdisciplinary cooperation and respect has not always been present. This paper suggests that the benefits claimed for interprofessional education, which remain largely untested in maternity care, are being put forward as a panacea for earlier difficulties. It outlines some of the initiatives currently taking place. Material ripe for shared learning is identified and it is suggested that shared teaching in addition to shared learning for midwifery and medical students and for midwives and doctors should be the norm. Learners may then eventually provide shared care based on both their shared learning experiences and also on the role model of shared teaching. Such a major change would require considerable political will, including a shift in funding. There is some evidence that the necessary political will is developing and this may be given more emphasis by the need for teaching to follow care as the NHS becomes more primary-care led.

Community Health Nursing↗
PubMed1998

A phase I trial of vinorelbine in combination with mitoxantrone in patients with refractory solid tumors.

Vinorelbine (Navelbine) is a unique semi-synthetic vinca-alkaloid with a favorable safety profile that has demonstrated significant antitumor activity in patients with non-small cell lung cancer, advanced breast cancer, advanced ovarian cancer and Hodgkin's disease. The most common dose-limiting toxicity is neutropenia, while other reported toxicities are minimal. Mitoxantrone (Novantrone) is an anthracene derivative that has demonstrated antitumor activity in patients with breast cancer, ovarian cancer, acute leukemia, and lymphoma. Mitoxantrone also has a very favorable toxicity profile with significantly less nausea and vomiting, alopecia, and stomatitis as compared with anthracyclines. The dose-limiting toxicity for mitoxantrone is leukopenia. The study was designed to determine the safety and maximally tolerated dose of IV vinorelbine used in combination with a fixed dose of mitoxantrone for the treatment of patients with refractory solid tumors. Vinorelbine was administered on days 1 and 8 of the treatment regimen as a short IV infusion. The starting dose was 15 mg/m2. Mitoxantrone was administered as a 20-min infusion on day 1 only at a fixed dose of 10 mg/m2. Seventeen patients with solid malignancies were entered in the study. For personal reasons, one patient decided to discontinue the treatment after day 1 of cycle 1. Therefore, 16 patients were evaluable for toxicity. The main toxicity was myelosuppression which was dose-limiting and resulted in dose reductions and delays. The use of G-CSF had a minimal overall impact on this regimen. Stable disease was observed in three cases. In patients previously treated with chemotherapy, the maximally tolerated dose was defined as vinorelbine 20 mg/m2 on days 1 and 8 and mitoxantrone 10 mg/m2 on day 1 without growth factor support. These doses can be recommended for phase II study of the regimen as salvage treatment.

Adult↗
PubMed1998

The impact of early and late shift changeovers on sleep, health, and well-being in 8- and 12-hour shift systems.

The effects on industrial shift workers of the timing of the changeover from the night to morning shift and of the length of the shift were examined. Two groups changed over at 6 a.m. and worked either 8-hr or 12-hr shift systems; the other 2 groups changed over at 7 a.m., working either 8- or 12-hr systems. Night sleeps between consecutive shifts that started at 6 a.m. were shorter and more disrupted than those starting at 7 a.m. Day sleeps following night shifts that finished at 6 a.m. were longer and less disrupted than those finishing at 7 a.m. Early starts were associated with poorer psychological and physical health. These effects of changeover time are considered in relation to the circadian rhythms in sleep duration and propensity. Although several measures favored 12-hr shifts, physical health indicators appeared to favor 8-hr systems, especially in combination with late changeovers. However, the observed effects of shift length on chronic outcome measures are somewhat inconsistent with previous research findings.

Adaptation, Psychological↗
PubMed1998

Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest.

Chromosome 3q alterations occur frequently in many types of tumours. In a genetic screen for loci present in rhabdomyosarcomas, we identified an isochromosome 3q [i(3q)], which inhibits muscle differentiation when transferred into myoblasts. The i(3q) inhibits MyoD function, resulting in a non-differentiating phenotype. Furthermore, the i(3q) induces a 'cut' phenotype, abnormal centrosome amplification, aneuploidy and loss of G1 arrest following gamma-irradiation. Testing candidate genes within this region reveals that forced expression of ataxia-telangiectasia and rad3-related (ATR) results in a phenocopy of the i(3q). Thus, genetic alteration of ATR leads to loss of differentiation as well as cell-cycle abnormalities.

Aneuploidy↗
PubMed1998

Novel ITGB4 mutations in lethal and nonlethal variants of epidermolysis bullosa with pyloric atresia: missense versus nonsense.

Epidermolysis bullosa with pyloric atresia (EB-PA), an autosomal recessive genodermatosis, manifests with neonatal cutaneous blistering associated with congenital pyloric atresia. The disease is frequently lethal, but nonlethal cases have also been reported. Expression of the alpha6 beta4 integrin is altered at the dermal-epidermal basement-membrane zone; recently, mutations in the corresponding genes (ITGA6 and ITGB4) have been disclosed in a limited number of patients, premature termination codons in both alleles being characteristic of lethal variants. In this study, we have examined the molecular basis of EB-PA in five families, two of them with lethal and three of them with nonlethal variants of the disease. Mutation analysis disclosed novel lesions in both ITGB4 alleles of each proband. One of the patients with lethal EB-PA was a compound heterozygote for premature termination-codon mutations (C738X/4791delCA), whereas the other patient with a lethal variant was homozygous for a missense mutation involving a cysteine residue (C61Y). The three nonlethal cases had missense mutations in both alleles (C562R/C562R, R1281W/R252C, and R1281W/R1281W). Immunofluorescence staining of skin in two of the nonlethal patients and in one of the lethal cases was positive, yet attenuated, for alpha6 and beta4 integrins. These results confirm that ITGB4 mutations underlie EB-PA and show that missense mutations may lead to nonlethal phenotypes.

Antigens, CD↗
PubMed1998

Operation Red Box: a pilot project of needle and syringe drop boxes for injection drug users in East Baltimore.

We assessed the acceptability and the use of a community-based needle and syringe disposal project designed to serve injection drug users. In June 1996, three surplus U.S. mail collection boxes were painted red and used as syringe and needle drop boxes in locations with high drug use in East Baltimore. Acceptance of the drop boxes was measured by focus groups of residents, drug users, and police, held before and after project implementation. Use was measured by weekly counts of needles recovered from the red boxes. A sample of all deposited needles was randomly chosen for needle washing and subsequent HIV antibody testing. Community impact was measured by systematic surveys of needles discarded on public sidewalks, in areas with and areas without drop boxes. Before implementation, members of focus groups expressed concerns that drop boxes could convey mixed messages to youth (e.g., seeming to condone drug use), might result in increased loitering, and could further community stigmatization. After project implementation, all focus groups expressed support of project expansion. In the first 10 months, 2971 needles were collected. Of 156 needles tested, 10.9% were positive for HIV antibody. Needle counts on the street showed no significant change in red box areas compared with control areas. In this pilot project, red boxes were accepted by the community and drug users. Police officers also used the boxes to dispose of confiscated needles. Although limited in the number of drop boxes and follow-up time, this pilot project shows promise as a community-based method of safe needle disposal.

Adolescent↗