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Biomedical subjects

D L Miller

Publications and source records attributed to D L Miller.

At least 127 records · Page 7Linked to original sources
PubMed1998

Hospital service interventions and improving survival of AIDS patients St Mary's Hospital, London, 1982-1991.

The relationship between changes in hospital service interventions at St Mary's Hospital, London, reduced case fatality for patients with their first episode of Pneumocystis carinii pneumonia (PCP) and improved survival from diagnosis of AIDS was investigated for the period 1982-1991. Multivariate logistic regression models identified factors independently associated with episode survival; for those patients who survived their first episode of PCP, survival from time of diagnosis of AIDS was analysed using multivariate Cox's proportional hazards models. The case-fatality rate after 1987 was significantly lower for the 159 subjects. Median survival from diagnosis of AIDS increased significantly from 142 days to 554 days (P=0.01). Improved survival of first episode of PCP was associated with it being the index diagnosis and having a haemoglobin at diagnosis of PCP greater than 12 g/dl. The presence of a concurrent AIDS-defining condition in patients who presented with an A-a gradient equal to or greater than 40 mmHg was associated with reduced episode survival, especially before 1987. For the 126 individuals who survived their first episode of PCP, death rates were lowest in patients treated with primary or secondary PCP prophylaxis and those who received zidovudine since their first episode of PCP. Survival in patients with HIV disease is better in patients who receive appropriate antiretroviral treatment of HIV infection and timely treatment of opportunistic illnesses. Early diagnosis of HIV-1 infection with early diagnosis and treatment of first episode of PCP was associated with improved episode survival. Subsequent medical follow up combined with PCP prophylaxis and zidovudine were significantly associated with long-term survival.

AIDS-Related Opportunistic Infections↗
PubMed1998

Video-assisted thoracoscopic surgery for resection of lung metastases.

Resection of indeterminate pulmonary lesions in patients with a history of malignancy is indicated, as the presence of metastases will provide prognostic information and often dictate further therapy. Pulmonary metastasectomy also improves survival in select patients with favorable tumor histologies. We reported the results of video-assisted thoracoscopic surgery (VATS) resection of indeterminate lung nodules in 72 patients with a history of malignancy. All lesions identified on preoperative high-resolution CT scan were found at surgery with visual inspection, digital palpation, or (in 13 cases) CT-guided needle localization. All lesions were resected nonanatomically with a rim of normal parenchyma, as is done with open techniques; 63 patients were found to have metastases and 9 patients had benign disease. There was no mortality, minimal morbidity, and decreased hospital stays in patients undergoing VATS resection compared with historical control subjects. These data and other reports have led to the widespread use of VATS for patients undergoing resection to establish a diagnosis. The role of VATS in patients with favorable tumor histology and limited tumor burden for whom metastasectomy may result in a survival advantage remains controversial. Improved image resolution with spiral CT scans and digital palpation, combined with intraoperative ultrasound examination of the lung, may decrease or eliminate the number of lesions missed with a VATS approach. The role of therapeutic VATS metastasectomy remains to be defined. Thus, this procedure currently should be used only in clinical trials.

Endoscopy↗
PubMed1998

Flight controller alertness and performance during spaceflight shiftwork operations.

Decreased alertness and performance associated with fatigue, sleep loss, and circadian disruption are issues faced by a diverse range of shiftwork operations personnel. During Space Transportation System (STS) operations, Mission Operations Directorate (MOD) personnel provide 24-hr. coverage of critical tasks. A joint NASA Johnson Space Center and NASA Ames Research Center project was undertaken to examine these issues in flight controllers during MOD shiftwork operations. An initial operational test of procedures and measures was conducted during the STS-53 mission in December 1992. The study measures included a Background Questionnaire, a subjective daily logbook completed on a 24-hour basis (to report sleep patterns, work periods, etc.), and an 8 minute performance and mood test battery administered at the beginning, middle, and end of each shift period. Seventeen flight controllers representing the 3 Orbit shifts participated. The initial results clearly support the need for further data collection during other STS missions to document baseline levels of alertness and performance during MOD shiftwork operations. Countermeasure strategies specific to the MOD environment are being developed to minimize the adverse effects of fatigue, sleep loss, and circadian disruption engendered by shiftwork operations. These issues are especially pertinent for the night shift operations and the acute phase advance required for the transition of day shift personnel into the night for shuttle launch. Implementation and evaluation of the countermeasure strategies to maximize alertness and performance is planned. As STS missions extend to further EDO (extended duration orbiters), and timelines and planning for 24-hour Space Station operations continue, alertness and performance issues related to sleep and circadian disruption will remain highly relevant in the MOD environment.

Adult↗
PubMed1998

Bronchial foreign bodies simulating endobronchial malignancy.

Reported are two cases of benign endobronchial lesions with granulomatous reactions that led to complete airway obstruction. Combined with a long history of cigarette smoking and the appearance of a hilar mass, these lesions appeared clinically to be bronchogenic carcinomas. Both cases went to thoracotomy, but in each case the requirement that malignant tissue be identified, allowed recognition of a foreign body in one case, and broncholith in the second, avoiding pneumonectomy in both cases.

Aged↗
PubMed1998

Flight crew fatigue I: objectives and methods.

In 1980, NASA-Ames Research Center, Moffett Field, CA, initiated a program to assess flight crew fatigue, determine its potential operational consequences, and provide practical countermeasure suggestions. To assess the extent of the problem, crewmembers were monitored before, during, and after commercial short-haul (fixed-wing and helicopter aircraft), overnight cargo, and long-haul operations. A total of 197 volunteers were studied on 94 trip patterns with 1299 flight segments and 2046 h of flying time. The present paper outlines the program and describes the common methodology used in these studies, which are then presented in detail in the four subsequent papers. The sixth paper offers a synthesis of this work, reviewing the major causes of flight crew fatigue and making specific suggestions about ways to manage it in different operations.

Aviation↗
PubMed1998

Flight crew fatigue II: short-haul fixed-wing air transport operations.

We monitored 74 crewmembers before, during, and after 3-4-d commercial short-haul trips crossing no more than one time zone per 24 h. The average duty day lasted 10.6 duty hours, with 4.5 flight hours and 5.5 flights. On trips, crewmembers slept less, woke earlier, and reported having more difficulty falling asleep, with lighter, less restful sleep than pretrip. The consumption of caffeine, alcohol, and snacks increased on trip days, as did reports of headaches, congested nose, and back pain. The study suggests the following ways of reducing fatigue during these operations: base the duration of rest periods on duty hours as well as flight hours; avoid scheduling rest periods progressively earlier across a trip; minimize early duty report times; and inform crewmembers about strategic use of caffeine and alternatives to alcohol for relaxing before sleep.

Adult↗
PubMed1998

Flight crew fatigue IV: overnight cargo operations.

We monitored 34 B-727 crewmembers before, during, and after 8-d commercial overnight cargo trips crossing no more than one time zone per 24 h. Daytime sleep episodes were 41% shorter and were rated as poorer than nighttime sleep episodes. When the layover was long enough, crewmembers usually slept again in the evening before going back on night duty. Nevertheless, the total sleep per 24 h on duty days averaged 1.2 h less than pretrip. The circadian temperature rhythm did not adapt completely to night duty, delaying by about 3 h. Self-rated fatigue was highest around the time of the temperature minimum, which occurred near the end of the nighttime duty period. On trip days, crewmembers ate more snacks and there was a marked increase in reports of headaches, congested noses, and burning eyes. Comparisons with daytime short-haul operations confirm that a daytime rest period does not represent the same sleep opportunity as a nighttime rest period of the same duration. We examine regulatory and scheduling options, and personal countermeasure strategies, that could help to reduce sleep loss during overnight cargo operations.

Adult↗
PubMed1998

Flight crew fatigue V: long-haul air transport operations.

We monitored 32 flight crewmembers before, during, and after 4-9 d commercial long-haul trips crossing up to 8 time zones per 24 h. The average duty day lasted 9.8 h, and the average layover 24.8 h. Layover sleep episodes averaged 105 min shorter than pretrip sleep episodes. However, in two-thirds of layovers, crewmembers slept twice so that their total sleep per 24 h on trips averaged 49 min less than pretrip. Greater sleep loss was associated with nighttime flights than with daytime flights. The organization of layover sleep depended on prior flight direction, local time, and the circadian cycle. The circadian temperature rhythm did not synchronize to the erratic environmental time cues. Consequently, the circadian low point in alertness and performance sometimes occurred in flight. On trip days, by comparison with pretrip, crewmembers reported higher fatigue and lower activation; drank more caffeine; ate more snacks and fewer meals; and there were marked increases in reports of headaches, congested nose, and back pain. Scheduling strategies and countermeasures to improve layover sleep, cockpit alertness, and performance, are discussed.

Aviation↗
PubMed1998

Patient values: the guide to medical decision making.

Physicians are increasingly challenged by issues surrounding medical decision-making for hospitalized patients. Advance directives express a patient's preferences regarding end-of-life care; when available, they should be used to guide medical treatment. Patients who lack decision-making capacity require special consideration to ensure maximal patient participation with appropriate surrogate involvement. An ethics committee consultation may be especially helpful to resolve conflicts that may arise regarding medical treatments. Physicians play a vital role in promoting earlier patient-physician discussions about end-of-life care preferences, increased completion of advance directives, and ongoing education for physicians to improve communication skills.

Advance Care Planning↗
PubMed1997

The role of cysteinyl residues in the activity of bacterial elongation factor Ts, a guanosine nucleotide dissociation protein.

The modification of E.coli elongation factor Ts (EF-Ts) by NEM and other sulfhydryl reagents inactivates the protein's ability to bind EF-Tu.GDP and to catalyze GDP exchange. The reactive residue was found to be Cys-22. Replacement of Cys-22 by Ser or Gly only partially impairs the binding or catalytic properties of EF-Ts while it completely protects EF-Ts from the inactivation by NEM. Cys-22 of EF-Ts is not located at the EF-Ts.EF-Tu interface, yet it can be modified only when EF-Ts is not bound to EF-Tu. These results support the proposal that the conformation change around Cys-22 in the amino terminus of EF-Ts rather than Cys-22 itself is essential for binding EF-Tu. Apparently, modification of Cys-22 by NEM disrupts the conformation change and inactivates EF-Ts. The return of EF-Ts to its native conformation may provide the driving force for the rate-determining step in the catalytic cycle, the dissociation of EF-Ts from EF-Tu.GNP.

Amino Acid Substitution↗
PubMed1997

Characterization of beta-amyloid peptide precursor processing by the yeast Yap3 and Mkc7 proteases.

Two proteases, denoted beta- and gamma-secretase, process the beta-amyloid peptide precursor (APP) to yield the Abeta peptides involved in Alzheimer's disease. A third protein, alpha-secretase, cleaves APP near the middle of the Abeta sequence and thus prevents Abeta formation. These enzymes have defied identification. Because of its similarity to the systems of mammalian cells the yeast secretory system has provided important clues for finding mammalian processing enzymes. When expressed in Saccharomyces cerevisiae APP is processed by enzymes that possess the specificity of the alpha-secretases of multicellular organisms. APP processing by alpha-secretases occurred in sec1 and sec7 mutants, in which transport to the cell surface or to the vacuole is blocked, but not in sec17 or sec18 mutants, in which transport from the endoplasmic reticulum to the Golgi is blocked. Neutralization of the vacuole by NH4Cl did not block alpha-secretase action. The time course of processing of a pro-alpha-factor leader-APP chimera showed that processing by Kex2 protease, a Golgi protease that removes the leader, preceded processing by alpha-secretase. Deletions of the genes encoding the GPI-linked aspartyl proteases Yap3 and Mkc7 decreased alpha-secretase activity by 56 and 29%, respectively; whereas, the double deletion decreased the activity by 86%. An altered form of APP-695, in which glutamine replaced Lys-612 at the cleavage site, is cleaved by Yap3 at 5% the rate of the wild-type APP. Mkc7 protease cleaved APP (K612Q) at about 20% the rate of wild-type APP. The simplest interpretation of these results is that Yap3 and Mkc7 proteases are alpha-secretases which act on APP in the late Golgi. They suggest that GPI-linked aspartyl proteases should be investigated as candidate secretases in mammalian tissues.

Alzheimer Disease↗
PubMed1997

MCF-7 breast carcinoma cells overexpressing FGF-1 form vascularized, metastatic tumors in ovariectomized or tamoxifen-treated nude mice.

FGF-1 is expressed in a high proportion of breast tumors. While overexpression of FGF-4 in the MCF-7 breast carcinoma cell line confers the ability to form spontaneously metastasizing tumors in ovariectomized nude mice without estrogen supplementation and in mice that receive tamoxifen pellets, the response of a cell to individual FGFs can be controlled at multiple levels, and the significance of FGF-1 expression in human breast tumors is uncertain. To study the role of FGF-1, MCF-7 human breast cancer carcinoma cells, previously transfected with bacterial beta-galactosidase, were retransfected with FGF-1 expression vectors. FGF-1 transfectants formed large, vascularized tumors in ovariectomized nude mice without estrogen supplementation as well as in mice that received tamoxifen pellets. Lymphatic and pulmonary micrometastases were detected as deposits of X-gal-stained cells as early as 17 days after cell inoculation whereas no metastases were detected in estrogen-supplemented mice bearing similar-sized control tumors. When compared with controls, both clonal and polyclonal populations of FGF-1 overexpressing cells exhibited increased anchorage-independent growth and decreased population doubling times in estrogen-depleted or 4-hydroxytamoxifen containing medium. These results suggest that FGF signaling may be important in the transition of breast cancer cells from hormone-dependent to hormone-independent and from nonmetastatic to metastatic.

Animals↗
PubMed1997

Elongation factor Ts of Chlamydia trachomatis: structure of the gene and properties of the protein.

A putative structural gene cluster containing four open reading frames (ORFs) located downstream of the omp1 gene of Chlamydia trachomatis mouse pneumonitis (MoPn) was cloned and sequenced. A GenBank survey indicated that the identified cluster is similar to the rpsB-tsf-pyrH(smbA)-frr region of Escherichia coli. The second ORF was 846 bp encoding a 282-amino-acid polypeptide with a calculated M(r) 30,824. Alignment of this deduced protein sequence and E. coli elongation factor Ts (EF-Ts, product of tsf) demonstrated 34% identity and an additional 14% similarity. The putative chlamydial tsf gene was expressed in E. coli as a nonfusion protein and as a 6x His-tagged fusion protein. By SDS-PAGE analysis, the molecular weights of the nonfusion recombinant protein and a protein of chlamydial elementary bodies (EBs), which was recognized by monoclonal antibodies derived from the nonfusion recombinant protein, are 34 kDa. The purified recombinant 6x His-tagged fusion protein increased the rate of GDP exchange with both Chlamydia and E. coli elongation factor Tu (EF-Tu). These data show that the second gene of the identified cluster is tsf. Unlike EF-Ts from any other species, its activity was comparable to that of E. coli EF-Ts in exchange reaction with E. coli EF-Tu.

Amino Acid Sequence↗
PubMed1997

Constitutive Raf-1 kinase activity in breast cancer cells induces both estrogen-independent growth and apoptosis.

Overexpression of many growth factor receptors, as well as growth factors, has been shown to confer varying degrees of estrogen-independent growth on estrogen receptor (ER) positive breast cancer cells. The proto-oncogene Raf-1 is a key intermediate in the signal transduction pathway of many of these growth factor receptors, and when constitutively activated in fibroblasts is transforming. To examine the effects of Raf-1 kinase activity on the estrogen-dependent growth of human breast cancer cells, ER + MCF-7 breast cancer cells were stably transfected with an expression construct directing the expression of an amino-truncated protein having constitutive kinase activity. Expression of constitutively activated Raf in MCF-7 cells is incompatible with growth in the presence of estrogen; that is, cells down-regulate expression of the transfected Raf. Constitutive Raf activity does allow for growth of the cells in the absence of estrogen, suggesting that activation of growth factor signaling pathways through Raf may confer a selective advantage for growth of breast cancer cells under estrogen-deprived conditions. In addition, the high levels of Raf activity induce apoptosis in cells grown under either condition. This is a novel activity for Raf, and may occur because the levels of the constitutive Raf are extremely high in these cells.

Apoptosis↗
PubMed1997

Reduction of histone cytotoxicity by the Alzheimer beta-amyloid peptide precursor.

In a search for Alzheimer beta-amyloid peptide precursor ligands, Potempska et al. (Arch. Biochem. Biophys. (1993) 304, 448) found that histones bind with high affinity and specificity to the secreted precursor. Because exogenous histones can be cytotoxic, we compared the effects of histones on the viability of cells which produce little beta-amyloid peptide precursor (U-937) to those on cells that produce twenty times as much precursor (COS-7). Addition of purified histones caused necrosis of U-937 cells (histone H4, LD50 = 1.5 microM). Extracellular A beta precursor in the submicromolar range prevented histone-induced U-937 cell necrosis. Cell-surface precursor also reduced histone toxicity: COS-7 cells were less sensitive to the toxic effects of histone H4 (LD50 = 5.4 microM). COS-7 cells in which the expression of an APP mRNA-directed ribozyme reduced the synthesis of the protein by up to 80% were more sensitive to histone H4 (LD50 = 3.2 microM) than cells that expressed the vector alone. Histone H4 binds to cell-associated A beta precursor. Cells expressing the A beta precursor-directed ribozyme bound less 125I-labeled histone H4 than those expressing the vector alone. In the limited extracellular space of tissues in vivo, both secreted and cell-surface A beta precursor protein may play significant roles in trapping chromatin or histones and removing them from the extracellular milieu.

Amyloid beta-Protein Precursor↗