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PubMed1993

Hematopoietic stem cells engraft in untreated transplant recipients.

We investigated the engraftment of hematopoietic stem cells in completely untreated transplant recipients to further study hematopoietic cell regulation and for possible inclusion in gene therapy protocols. Untreated female Balb/c recipients received a single infusion of male Balb/c marrow cells. Donor origin of the hematopoietic cells was determined by polymerase chain reaction (PCR), Southern and in situ hybridization analyses with Y-chromosome-specific probes. We found that up to 47% day 12 CFU-S (26.2 +/- 12.6%, mean +/- SD, range 13.3 to 46.7%), 7.3 +/- 5.5% CFU-GM and from 2.5 to approximately 10% nucleated marrow cells were of donor-origin at 8 weeks after marrow infusion. Our results indicate that hematopoietic stem cells can stably engraft in completely unconditioned recipients but, during the interval analyzed, have a low tendency to differentiate. Moreover, the data suggest that under steady-state conditions, niches for primitive hematopoietic cells present in the marrow microenvironment are not saturated, and are readily available. We conclude that the untreated-recipient transplant model, in conjunction with sensitive techniques for the detection of donor cells, provides a valuable means for studying hematopoietic stem cell regulation and indicates a need to reassess our understanding of the interactions between stem cells and the hematopoietic microenvironment.

Animals↗

PubMed2002

Identifying native-like protein structures using physics-based potentials.

As the field of structural genomics matures, new methods will be required that can accurately and rapidly distinguish reliable structure predictions from those that are more dubious. We present a method based on the CHARMM gas phase implicit hydrogen force field in conjunction with a generalized Born implicit solvation term that allows one to make such discrimination. We begin by analyzing pairs of threaded structures from the EMBL database, and find that it is possible to identify the misfolded structures with over 90% accuracy. Further, we find that misfolded states are generally favored by the solvation term due to the mispairing of favorable intramolecular ionic contacts. We also examine 29 sets of 29 misfolded globin sequences from Levitt's "Decoys 'R' Us" database generated using a sequence homology-based method. Again, we find that discrimination is possible with approximately 90% accuracy. Also, even in these less distorted structures, mispairing of ionic contacts results in a more favorable solvation energy for misfolded states. This is also found to be the case for collapsed, partially folded conformations of CspA and protein G taken from folding free energy calculations. We also find that the inclusion of the generalized Born solvation term, in postprocess energy evaluation, improves the correlation between structural similarity and energy in the globin database. This significantly improves the reliability of the hypothesis that more energetically favorable structures are also more similar to the native conformation. Additionally, we examine seven extensive collections of misfolded structures created by Park and Levitt using a four-state reduced model also contained in the "Decoys 'R' Us" database. Results from these large databases confirm those obtained in the EMBL and misfolded globin databases concerning predictive accuracy, the energetic advantage of misfolded proteins regarding the solvation component, and the improved correlation between energy and structural similarity due to implicit solvation. Z-scores computed for these databases are improved by including the generalized Born implicit solvation term, and are found to be comparable to trained and knowledge-based scoring functions. Finally, we briefly explore the dynamic behavior of a misfolded protein relative to properly folded conformations. We demonstrate that the misfolded conformation diverges quickly from its initial structure while the properly folded states remain stable. Proteins in this study are shown to be more stable than their misfolded counterparts and readily identified based on energetic as well as dynamic criteria. In summary, we demonstrate the utility of physics-based force fields in identifying native-like conformations in a variety of preconstructed structural databases. The details of this discrimination are shown to be dependent on the construction of the structural database.

Algorithms↗

PubMed2005

Molecular cloning of TRPC3a, an N-terminally extended, store-operated variant of the human C3 transient receptor potential channel.

AK032317 is the GenBank accession no. of a full-length RIKEN mouse cDNA. It encodes a putative variant of the C3-type TRPC (transient receptor potential channel) that differs from the previously cloned murine TRPC3 cDNA in that it has a 5' extension stemming from inclusion of an additional exon (exon 0). The extended cDNA adds 62 aa to the sequence of the murine TRPC3. Here, we report the cloning of a cDNA encoding the human homologue of this extended TRPC3 having a highly homologous 73-aa N-terminal extension, referred to as hTRPC3a. A query of the GenBank genomic database predicts the existence of a similar gene product also in rats. Transient expression of the longer TRPC3a in human embryonic kidney (HEK) cells showed that it mediates Ca2+ entry in response to stimulation of the Gq-phospholipase C beta pathway, which is similar to that mediated by the shorter hTRPC3. However, after isolation of HEK cells expressing hTRPC3 in stable form, TRPC3a gave rise to Ca2+-entry channels that are not only activated by the Gq-phospholipase C beta pathway (receptor-activated Ca entry) but also by thapsigargin triggered store depletion. In conjunction with findings from our and other laboratories that TRPC1, TRPC2, TRPC4, TRPC5, and TRPC7, can each mediate store-depletion-activated Ca2+ entry in mammalian cells, our findings with hTRC3a support our previous proposal that TRPCs form capacitative Ca-entry channels.

Amino Acid Sequence↗

PubMed1998

The intermediate filament protein, vimentin, in the lens is a target for cross-linking by transglutaminase.

Mere addition of Ca2+ to a lens cortical homogenate (bovine) generates a series of products composed of a variety of high molecular weight vimentin species. The Ca2+-induced cross-linking of this cytoskeletal element seems to be mediated by the intrinsic transglutaminase of lens, because the reaction could be blocked at the monomeric state of vimentin by the inclusion of small synthetic substrates of the enzyme dansylcadaverine or dansyl-epsilon-aminocaproyl-Gln-Gln-Ile-Val. These compounds are known to compete against the Gln or Lys functionalities of proteins that would participate in forming the Nepsilon(gamma-glutamyl)lysine protein-to-protein cross-links. The cytosolic transglutaminase-catalyzed reactions could be reproduced with purified bovine lens vimentin and also with recombinant human vimentin preparations. Employing the latter system, we have titrated the transglutaminase-reactive sites of vimentin and, by sequencing the dansyl-tracer-labeled segments of the protein, we have shown that residues Gln453 and Gln460 served as acceptor functionalities and Lys97, Lys104, Lys294, and Lys439 as electron donor functionalities in vimentin. The transglutaminase-dependent reaction of this intermediate filament protein might influence the shape and plasticity of the fiber cells, and the enzyme-catalyzed cross-linking of vimentin, in conjunction with other lens constituents, may contribute to the process of cataract formation.

Amino Acid Sequence↗

PubMedDate not supplied

Becoming 'indispensable': developing innovative community pharmacy practices.

OBJECTIVE: To describe common characteristics of successful innovative community pharmacy practices. DATA SOURCES: Four pharmacists who are successfully incorporating pharmaceutical care services into their pharmacy practices were identified for inclusion by key informants. Sites considered for inclusion were within 300 miles of the University of Minnesota College of Pharmacy. The four innovative community pharmacy practices were located in Maquoketa, Iowa, and in Bemidji, Anoka, and Minneapolis, Minn. Published articles identified through a Medline search-using the terms pharmaceutical care, Medicaid, Medicare, pharmacist, pharmacy, and collaborative practice-provided information to prepare for pharmacist interviews. STUDY SELECTION: By the authors. DATA EXTRACTION: Previsit telephone interviews with each pharmacist, combined with literature selected by the authors, were used to identify common characteristics of successful practices. Structured, on-site empirical observation was then performed to devise a tool for pharmacists to use for the development of innovative community pharmacy practices. The tool was then validated by two additional practitioners. DATA SYNTHESIS: Components of successful innovative community pharmacy practices include philosophy of practice, patient care process, management system, and clinical knowledge. A checklist tool is presented to be used in conjunction with the narrative description of the four components. CONCLUSION: Advanced pharmacy services delivered within pharmaceutical care practices can be a successful business opportunity for community pharmacists. Community pharmacists motivated to develop an innovative practice and provide pharmaceutical care services can use the checklist tool during practice implementation.

Attitude of Health Personnel↗

PubMed1996

Rifabutin as salvage therapy for cases of chronic multidrug-resistant pulmonary tuberculosis in Taiwan.

This study was aimed at assessing the efficacy and tolerability of rifabutin for the re-treatment of cases of chronic, multidrug-resistant pulmonary tuberculosis. The study design was self-controlled, single center. Rifabutin was administered as part of an individual-tailored multidrug regimen. In-patients suffering from pulmonary tuberculosis, infected with Mycobacterium tuberculosis bacilli resistant to isoniazid, rifampicin and other drugs with progressive disease unresponsive to prior courses with standard anti-tuberculosis medications were treated. Overall, 43 patients were enrolled and treated with rifabutin at 300 or 450mg/day according to body weight in conjunction with available anti-tuberculous drugs for a mean time of 353 days (range 42-678). Of these, 36 met all eligibility criteria (i.e. positive baseline culture of sputum with bacilli resistant to rifampicin at least) and were retained for the analysis of efficacy. Seventeen patients (47%) achieved a sustained conversion to a negative culture of sputum in a mean time of 47.7 days with a range of 14-120 days. Treatment prevented deterioration in most patients and resulted in clinical and radiological cure or marked improvement in more than half of cases. No correlation was found between treatment outcome and use of medication concomitant to rifabutin or susceptibility of bacilli to the drugs used. Four deaths occurred due to disease progression, in no case being related to study drugs. Ten patients reported a total of 18 adverse events that led to treatment discontinuation in 5 cases. Rifabutin should be considered for inclusion in regimens for cases of pulmonary multidrug-resistant tuberculosis which fail to respond to previous therapy.

Adolescent↗

PubMed2004

Extensive lesions of monkeypox in a prairie dog (Cynomys sp).

Monkeypox with extensive lesions was diagnosed in a prairie dog that was involved in a recent human outbreak of monkeypox in the Midwestern United States. Gross lesions included oral ulcers, pulmonary consolidation, enlarged cervical and thoracic lymph nodes, and multifocal, small, white umbilicated plaques in the gastrointestinal wall. Microscopic lesions were extensive in the lungs and consisted of fibrinonecrotic bronchopneumonia with vasculitis and poorly defined eosinophilic intracytoplasmic inclusion bodies in cells thought to be alveolar epithelial cells, histiocytes, and fibroblasts. Multifocal necrotizing lesions, often accompanied by myxedema, were also present in most of the other examined organs. Aggregates of pox viral particles were observed within lesions by transmission electron microscopy. Monkeypox virus infection was confirmed by real-time polymerase chain reaction and virus culture at the Centers for Disease Control and Prevention. This report highlights the difficulties of rapid diagnosis of exotic or emerging diseases and further substantiates the prairie dog as an animal model of monkeypox.

Animals↗

PubMed1993

Efficacy of flexion and extension treatments incorporating braces for low-back pain patients with retrodisplacement, spondylolisthesis, or normal sagittal translation.

Radiographic instability seemingly enjoys the status of a well-defined clinical syndrome. The concept is widely used, and specific treatments, usually spinal fusion, are routinely performed based on the diagnosis. The minimum standards necessary to establish radiographic instability as a legitimate clinical syndrome have not been established, however. The primary purpose of this study was to determine if treatment involving bracing, exercise, and education controlling either flexion or extension postures, would result in a distinctive pattern of favorable or unfavorable results, depending on the type of radiographic instability (retrodisplacement or spondylolisthesis). Fifty-six patients meeting strict study inclusion and radiographic evaluation criteria were assigned signed to a bracing treatment (flexion, extension, placebo-control) according to a randomization scheme, designed to ensure equal representation of translation categories (retro, normal, spondy) across treatment groups, and assessed at admission and 1-month follow-up. The sample was relatively evenly divided between men (46%) and women (54%), and by age. Translation classification was related to both gender and age, with men more likely classified as retro and women more likely spondy and patients in their 20s having lower incidence of spondy and higher incidence of normal translation. Translation classification was not related to selected indices of low-back pain history. Brace treatments were not shown to reduce patient range of motion or lessen trunk strength. A significant treatment by time interaction for the modified pain interference (VAS) scale indicated improvement for patients in extension compared with patients in flexion and control-placebo treatments. In conjunction with no significant three-way interaction between treatment, translation classification, and time, it was hypothesized that radiographic instability might more appropriately be considered a corroborative sign of advanced discogenic problems. Improvement in extension treatment, regardless of the type of radiographic abnormality, suggests that the treating clinician might consider extension treatment for chronic low-back pain patients. Causes and implications for the failure of this study to provide support for considering radiographic instability as a clinical syndrome are considered and future directions for this area of research suggested.

Adult↗

PubMed2003

Seeking the optimal target range for insulin-like growth factor I during the treatment of adult growth hormone disorders.

Impaired GH activity at target tissues, occurring when GH action is blocked or during suboptimal GH replacement therapy, may result in a pathological state associated with lowering of IGF-I, but not GH levels. Such a state represents functional but not necessarily actual GH deficiency (GHD). The aim of this study was to identify a range of IGF-I values commensurate with GHD, which could be used to determine the risk of functional GHD during the treatment of adult GH disorders. Centrally measured baseline IGF-I data from the Kabi International Metabolic Study European GHD database were analyzed. Inclusion criteria were adult-onset GHD and two or more additional anterior pituitary hormone deficits. Adults with childhood-onset GHD and cured acromegaly were excluded. The cohort was stratified into six gender-based age ranges. Baseline IGF-I measurements from 376 females (median age, 48 yr; range, 21-77 yr) and 434 males (median age 52 yr; range 21-80 yr) were analyzed. Data were not normally distributed and are presented as medians (quartiles). The median serum IGF-I and IGF-I SDS in males were 94.0 microg/liter (64 and 141) and -1.52 (-2.53 and -0.456; n = 434). Both were significantly greater than the equivalent values of females, which were 73 microg/liter (46 and 103.5) and -2.30 (-3.28 and -1.328; n = 376; P < 0.0001 for both). Age and gender-related 90th and 95th percentiles for IGF-I SDS were determined to generate risk estimates for functional GHD, which, in conjunction with the clinical status of the patient, may be used to aid dose titration during treatment of GH disorders in adulthood.

Adult↗

PubMed1997

FLT3 ligand preserves the ability of human CD34+ progenitors to sustain long-term hematopoiesis in immune-deficient mice after ex vivo retroviral-mediated transduction.

Stromal support is required during retroviral-mediated transduction of human bone marrow-derived CD34+ cells to maintain the clonogenicity of the primitive progenitors. We hypothesized that the cytokine FLT3 ligand (FL) might be able to replace the maintenance role provided by the stroma. CD34+ progenitors from human bone marrow were transduced by the retroviral vector LN with the cytokines interleukin-3 (IL-3), IL-6, and stem cell factor (SCF) present in all cultures. Transductions were performed with or without stromal support and with or without the inclusion of 100 U/mL FL. No significant increase in gene transfer into colony-forming cells was obtained by the addition of FL to the cultures. Transduction and survival of more primitive human hematopoietic cells was determined by growth in immune-deficient mice for 7 to 8 months. Human myeloid cells, T lymphocytes, and colony-forming progenitors were recovered from the marrow of mice that had received human cells transduced on stroma or in suspension culture with IL-3, IL-6, SCF, and FL, but not with IL-3, IL-6, and SCF alone. LN provirus was detected by polymerase chain reaction in the marrow recovered from 9 of 10 mice transplanted with human CD34+ cells transduced with stromal support, 5 of 11 mice that received human cells transduced in suspension culture with FL, but none of the 10 mice that received human cells transduced in suspension culture without FL We conclude that FLT3 ligand, in conjunction with IL-3, IL-6, and SCF, preserves the generative capacity of primitive human hematopoietic cells during in vitro transductions in suspension culture.

Animals↗

PubMed2000

Penetrating keratoplasty in eyes with keratoconus and vernal keratoconjunctivitis.

PURPOSE: To determine the prognosis of penetrating keratoplasty in eyes with keratoconus and vernal keratoconjunctivitis. METHODS: The medical records of all patients with keratoconus and vernal keratoconjunctivitis who underwent penetrating keratoplasty at King Khaled Eye Specialist Hospital from January 1, 1986 to December 31, 1996 and for whom at least 24 months' follow-up is available were analyzed retrospectively. RESULTS: Of 85 (61 males, 24 females) patients, 90 eyes met the inclusion criteria. The mean follow-up was 44.7 (range, 26-144) months. At the most recent follow-up visit, 83 (92.2%) grafts were clear. The mean best corrected visual acuity was 20/40. Graft rejection episodes occurred in 12 (13.3%) eyes, with irreversible graft failure occurring in 4 (4.4%) eyes. Bacterial keratitis occurred in 6 (7.7%) eyes, 2 (2.2%) of which developed irreversible graft failure. Herpes simplex keratitis resulted in irreversible graft failure in 1 (1.1%) eye. CONCLUSION: Penetrating keratoplasty in eyes with keratoconus and vernal keratoconjunctivitis has an excellent visual outcome and a low complication rate.

Adolescent↗

PubMed1996

Adjuvant VHF therapy in locally recurrent and primary unresectable rectal cancer.

In a prospective randomized study, 434 mHz microwave therapy combined with external beam radiotherapy (VHF + RT) was compared with standard external beam radiotherapy (RT) in controlling locally recurrent or unresectable primary adenocarcinoma of the rectum. Independent assessors documented quality of life scores, performance status, toxicities, local response to treatment, and systemic disease progression before treatment and after treatment and every 8 weeks thereafter. Of 75 patients randomized, 73 were eligible for inclusion in the study. Forty-three of these patients had local pelvic tumour recurrence only and 21 also had distant metastases. In addition, nine patients had primary inoperable carcinomas, two of whom also had metastases. Thirty-seven patients were randomized to RT and 36 to VHF + RT. The median dose of radiation in the VHF+RT arm was 4275 cGy with a median fraction size of 150 cGy and median duration of therapy of 48.5 days versus 4500 cGy in the RT-only arm with a median fraction size of 180 cGy and median duration of therapy of 38 days. These doses are unlikely to be significantly different in biological effect. No significant difference between the two groups was observed in extent and duration of local control, measures of toxicity or quality of life scores. Additionally, survival and cumulative incidence of pelvic site of first progression did not differ significantly between the groups. We conclude that VHF microwave therapy in conjunction with radiotherapy produces no therapeutic advantage over conventional radiation therapy alone in the treatment of locally recurrent rectal carcinoma.

Adenocarcinoma↗

PubMed1975

Experimental investigations into the pathogenesis of endocarditis due to shock.

Generalized Shwartzman reaction (GSR) was induced in rabbits by two intravenous injections of endotoxin 24 hours apart. Consumption coagulopathy was found in all cases. Histological investigations showed an abacterial endocarditis (thrombotica or verruccosa simplex), comparable to the one seen in humans after shock, in 69% of the treated animals. Biopsies of mitral valve were investigated by electron microscopy. In the early stage of GSR the valvular alterations were characterized by an oedema of the entire valve, an increase in the number of microvesicles in the endothelial cytoplasm, and a marked enlargement of endothelial cell surface by numerous cytoplasmic projections. At a later stage autophagic vacuoles, often showing a destruction of their membranes, and degenerative changes in cytoplasmic organelles occurred in many cells of the valve. On the other hand there were cells in the endothelium, which presented a distinctly increased number of Golgi complexes and of cisternae of rough endoplasmic reticulum. In other regions ruptures of endothelial plasmalemma, as well as hemorrhages into the valvular stroma were observed. Thus predestined loci for thrombogenesis were formed. In conjunction with these structural changes three factors may be involved in the formation of endocarditis due to shock: 1. hypercoagulability in the course of consumption coagulopathy, leading to precipitation of fibrin and platelets in the circulating blood; 2. turbulences of the blood flow, which are produced by the closure of the heart valves, and favour thrombogenesis on valves: 3. direct changes of the endocardium during endotoxemia. Quantitative changes in the different compartments of intracytoplasmic organelles in many cells of the endothelium during the later stage of GSR are discussed.

Animals↗

PubMedDate not supplied

QSAR models using a large diverse set of estrogens.

Endocrine disruptors (EDs) have a variety of adverse effects in humans and animals. About 58,000 chemicals, most having little safety data, must be tested in a group of tiered assays. As assays will take years, it is important to develop rapid methods to help in priority setting. For application to large data sets, we have developed an integrated system that contains sequential four phases to predict the ability of chemicals to bind to the estrogen receptor (ER), a prevalent mechanism for estrogenic EDs. Here we report the results of evaluating two types of QSAR models for inclusion in phase III to quantitatively predict chemical binding to the ER. Our data set for the relative binding affinities (RBAs) to the ER consists of 130 chemicals covering a wide range of structural diversity and a 6 orders of magnitude spread of RBAs. CoMFA and HQSAR models were constructed and compared for performance. The CoMFA model had a r2 = 0.91 and a q2LOO = 0.66. HQSAR showed reduced performance compared to CoMFA with r2 = 0.76 and q2LOO = 0.59. A number of parameters were examined to improve the CoMFA model. Of these, a phenol indicator increased the q2LOO to 0.71. When up to 50% of the chemicals were left out in the leave-N-out cross-validation, the q2 remained significant. Finally, the models were tested by using two test sets; the q2pred for these were 0.71 and 0.62, a significant result which demonstrates the utility of the CoMFA model for predicting the RBAs of chemicals not included in the training set. If used in conjunction with phases I and II, which reduced the size of the data set dramatically by eliminating most inactive chemicals, the current CoMFA model (phase III) can be used to predict the RBA of chemicals with sufficient accuracy and to provide quantitative information for priority setting.

Animals↗

PubMed1989

Evaluation of patients for the need of thrombolytic therapy in the prehospital setting.

Maximum benefit from thrombolytic therapy in acute myocardial infarction is obtained with early therapy. The earliest possible time to treat is during the initial evaluation of the patient in the home or ambulance, which requires accurate diagnosis of acute myocardial infarction in the prehospital setting. In our study, paramedics evaluated patients who had chest pain with a 12-lead ECG transmitted by cellular telephone and a checklist for inclusion and exclusion criteria for thrombolytic therapy. This information was transmitted to a hospital-based telemetry physician who diagnosed or excluded acute myocardial infarction and made a mock decision to withhold or administer a thrombolytic agent. Forty-eight patients with chest pain were evaluated. Six were diagnosed as having overt acute myocardial infarction by the hospital-based telemetry physician. All six patients had the diagnosis substantiated by both ECG and enzyme studies on hospital admission. Based on the data supplied by paramedics, two of these six patients were considered eligible for thrombolytic therapy by the physician. Hospital evaluation confirmed the prehospital decision to treat with a thrombolytic agent. In addition, all other patients were appropriately diagnosed as ineligible. Prehospital ECG diagnosis resulted in two patients going directly to the catheterization lab, thereby bypassing the emergency department. Overt acute myocardial infarction can be accurately identified by a prehospital-acquired 12-lead ECG transmitted to a hospital-based physician. Our study demonstrates that in conjunction with specially trained paramedics, the hospital physician can decide whether to administer thrombolytic therapy to such patients in the prehospital setting.

Adult↗

PubMed1979

Detection of herpes simplex virus infection of female genitalia by the peroxidase-antiperoxidase method alone or in conjunction with the Papanicolaou stain.

The sensitive peroxidase-antiperoxidase (PXAPX) method individually and in conjunction with the Papanicolaou (PAP) stain was used to detect herpes simplex virus (HSV) in specimens from human female genitalia. Initial studies using a model system of HSV-1 or HSV-2-infected Vero cells established (i) acetone as the most effective fixative, (ii) optimal dilutions of preimmunization and anti-HSV serum for differentiation of infected from noninfected cells, (iii) optimal concentration of 3,3'-diaminobenzidine tetrahydrochloride and H2O2 for maximal staining of infected cells with minimal background reaction, and (iv) removal of endogenous peroxidase with absolute MeOH. These various parameters, once established, were utilized in the PXAPX or PXAPX-PAP on human specimens from the vulva or cervix. In these specimens, examined by standard light microscopy, PXAPX-positive cells were dark brown with a single nucleus or multiple nuclei. By coupling the PAP to the PXAPX, detailed nuclear observations of PXAPX-positive cells were possible and revealed nuclear changes consistent with HSV infection, including syncytium formation, chromatin condensation, and an occasional Cowdry type A inclusion. The PXAPX and PXAPX-PAP correlated (r = 0.742) over a period of 72 h with HSV isolation from these samples.

Adolescent↗

PubMed2006

Cost-effectiveness of extending cervical cancer screening intervals among women with prior normal pap tests.

OBJECTIVE: Annual cervical cancer screening in women with many prior normal Pap tests is common despite limited evidence on the cost-effectiveness of this strategy. We estimated the cost-effectiveness of screening women with 3 or more prior normal tests compared with screening those with no prior tests. METHODS: We used a validated cost-effectiveness model in conjunction with data on the prevalence of biopsy-proven cervical neoplasia in women enrolled in the Centers for Disease Control and Prevention National Breast and Cervical Cancer Early Detection Program. Women were grouped according to age at the final Program Pap test (aged < 30, 30-44, 45-59, and 60-65 years) and by screening history (0, 1, 2, and 3+ consecutive prior normal Program tests) to estimate cost per life-year and quality-adjusted life-year associated with annual, biennial, and triennial screening. RESULTS: For women aged 30-44 years with no prior tests, incremental cost-effectiveness ratios ranged from 20,533 US dollars for screening triennially (compared with no further screening) to 331,837 US dollars for screening annually (compared with biennially) per life-year saved. Among same-aged women with 3 or more prior normal Program tests, incremental cost-effectiveness ratios for the same measures ranged from 60,029 US dollars to 709,067 US dollars per life-year saved. Inclusion of the most conservative utility estimates resulted in incremental cost-effectiveness ratios in excess of 100,000 US dollars per quality-adjusted life-year saved associated with annual screening of same-aged women with 3 or more prior normal tests compared with biennial screening. CONCLUSION: As the number of prior normal Pap tests increases, the costs per life-year saved increase substantially. Resources should be prioritized for screening those never or rarely screened women. LEVEL OF EVIDENCE: II-2.

Adult↗

PubMed1999

Efficient transcription of the human angiotensin II type 2 receptor gene requires intronic sequence elements.

To investigate mechanisms of human angiotensin II type 2 receptor (hAT2) gene regulation we functionally characterized the promoter and downstream regions of the gene. 5'-Terminal deletion mutants from -1417/+100 to -46/+100 elicited significant but low functional activity in luciferase reporter gene assays with PC12W cells. Inclusion into the promoter constructs of intron 1 and the transcribed region of the hAT2 gene up to the translation start enhanced luciferase activity 6.7+/-1.6-fold and 11.6+/-1.7-fold (means+/-S.E.M.) respectively, whereas fusion of the promoter to the spliced 5' untranslated region of hAT2 cDNA did not, which indicated an enhancement caused by intronic sequence elements. Reverse transcriptase-mediated PCR confirmed that the chimaeric hAT2-luciferase mRNA was regularly spliced in PC12W cells. A Northern blot analysis of transfected cells showed levels of luciferase mRNA expression consistent with the respective enzyme activities. Mapping of intron 1 revealed that a 12 bp sequence in the centre of the intron was required for the increase in promoter activity, whereas the 5' adjacent intronic region mediated a decrease in luciferase activity. Mutation of the 12 bp region led to altered protein binding and markedly decreased luciferase activity. Cloned into a promoterless luciferase vector, a 123 bp intron 1 fragment was able to direct reporter gene expression to the same activity as occurred in conjunction with the 5' flanking region. These results indicate that sequence elements in intron 1 are necessary for efficient transcription of hAT2. In reporter gene assays, intron 1 might by itself function as a promoter and initiate transcription from an alternative start point.

5' Untranslated Regions↗