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PubMed1996

Estimated gain in life expectancy. A simple tool to select optimal reperfusion treatment in individual patients with evolving myocardial infarction.

Currently several modes of reperfusion therapy for acute myocardial infarction are available. Streptokinase, accelerated alteplase and direct angioplasty are the most frequently used. These options are increasingly effective, but are also increasingly complex and costly. Since, unfortunately, physicians are often restricted by budget limitations, choices must be made in clinical practice to provide optimal therapy to individual patients. In order to guide such decision making, we developed a model to predict the expected benefit of therapy in terms of gain in life expectancy. Patients' life expectancy will decrease after infarction. Part of this loss can be prevented by early reperfusion therapy. The clinical benefit of therapy ranges from negligible gain in patients with small infarcts treated relatively late to an expected gain of more than 2 years in patients with extensive infarction treated within 3 h of onset of symptoms. The expected benefits are presented in a set of tables and depend on age, previous infarction, estimated infarct size, treatment delay and intracranial bleeding risk. With the help of these table, resources will be allocated in such a manner that patients who will benefit the most will receive the most effective therapy. Patients with similar expected treatment benefit will be offered the same mode of therapy. Future life years were discounted at 5% per year. The arbitrary thresholds currently applied for decision making at the Thoraxcenter are: no reperfusion therapy when the estimated gain in discounted life expectancy was < 1 month, streptokinase for 1-4 months and accelerated alteplase for a gain > or = 5 months. Direct angioplasty is recommended in patients with an estimated gain > or = 12 months, and in patients with an increased risk of intracranial bleeding. In this way, approximately 80% of our patients will be treated with thrombolytics (40% streptokinase and 40% accelerated alteplase), while in 10% direct angioplasty will be initiated. Patients with small infarcts presenting late will not receive reperfusion therapy. These threshold values have been chosen arbitrarily, and different thresholds may be selected in other centres. However, the developed model would guarantee that treatment decisions are made in a consistent manner, to provide optimal therapy for patients with evolving myocardial infarction, in spite of limited resources.

Adolescent↗
PubMed1990

Mn K-edge XANES spectroscopy of a photosynthetic O2-evolving complex. High-quality pre-edge features and distinct fine structures in the S1- and S2-states.

High-resolution XANES (X-ray Absorption Near Edge Structure) spectroscopy for Mn in the S1 and S2 states of the spinach photosynthetic O2-evolving complex revealed distinct features in K-edge spectra, when a high signal-to-noise (S/N) ratio of ca. 80 with a low and constant background-to-signal (B/S) ratio of 0.15 to 0.18 was attained. Six features resolved in each S-state spectrum involve a pre-edge feature due to 1s----3d transitions, a main-edge feature possibly due to 1s----4s transitions and four fine structures superimposed on the principal absorption bands due to 1s----4p* transitions. The high-quality pre-edge features were analyzed according to a parametric ligand-field theory in comparison with those of some typical authentic Mn complexes. It was deduced that i) all of the four Mn ions in the S1-state are octahedrally coordinated and two of them constitute a di-mu-oxo bridged Mn(III, III) dimeric subunit; ii) the bridged Mn(III) ions are further bridged by a deprotonated water dimer, (HOHOH)-, and coordinated by imidazole-N and carboxylate-O- on the opposite side of the Mn atom from the di-mu-oxo bridge; iii) the other two Mn ions exist in the form of Mn(III) monomeric subunits; and iv) upon the S1----S2 transition, only the bridged Mn(III,III) is oxidized to Mn(III,IV). The distinct change in the principal absorption band shape upon the S1----S2 transition is briefly discussed to obtain the XANES evidence for a tetrameric Mn-cluster.

Cell Membrane↗
PubMed2001

The yeast protein interaction network evolves rapidly and contains few redundant duplicate genes.

In this paper, the structure and evolution of the protein interaction network of the yeast Saccharomyces cerevisiae is analyzed. The network is viewed as a graph whose nodes correspond to proteins. Two proteins are connected by an edge if they interact. The network resembles a random graph in that it consists of many small subnets (groups of proteins that interact with each other but do not interact with any other protein) and one large connected subnet comprising more than half of all interacting proteins. The number of interactions per protein appears to follow a power law distribution. Within approximately 200 Myr after a duplication, the products of duplicate genes become almost equally likely to (1) have common protein interaction partners and (2) be part of the same subnetwork as two proteins chosen at random from within the network. This indicates that the persistence of redundant interaction partners is the exception rather than the rule. After gene duplication, the likelihood that an interaction gets lost exceeds 2.2 x 10(-3)/Myr. New interactions are estimated to evolve at a rate that is approximately three orders of magnitude smaller. Every 300 Myr, as many as half of all interactions may be replaced by new interactions.

Evolution, Molecular↗
PubMed2001

Fungal Zuotin proteins evolved from MIDA1-like factors by lineage-specific loss of MYB domains.

Proteins are often characterized by the presence of multiple domains, which make specific contributions to their cellular function. While the gain of domains in proteins by duplication and shuffling is well established, domain loss is poorly documented. Here, we provide evidence that domain loss has played an important role in the evolution of protein architecture and function by demonstrating that fungal Zuotin proteins evolved from MIDA1-like proteins, present in animals and plants, by complete loss of the carboxyl-terminal MYB domains. Phylogenetic analyses of the DnaJ motif (the J domain) present in both Zuotin and MIDA1 proteins were complicated by the limited length and profound differences in evolutionary rates exhibited by this domain. To rigorously examine J domain phylogeny, we combined the nonparametric bootstrap with Monte Carlo simulation. This method, which we have designated the resampled parametric bootstrap, allowed us to assess type I and type II error associated with these analyses. These results revealed significant support for domain loss rather than domain gain or gene loss involving paralogs. The absence of sequences related to the MIDA1 MYB domains in Saccharomyces cerevisiae further indicates that the domains have been completely lost, consistent with known functional differences between Zuotin and MIDA1 proteins. These analyses suggest that the description of additional examples of complete domain loss may provide a method to identify orthologous proteins exhibiting functional differences using genomic sequence data.

Amino Acid Sequence↗
PubMed2002

Mammalian sperm proteins are rapidly evolving: evidence of positive selection in functionally diverse genes.

A growing number of genes involved in sex and reproduction have been demonstrated to be rapidly evolving. Here, we show that genes expressed solely in spermatozoa represent a highly diverged subset among mouse and human tissue-specific orthologs. The average rate of nonsynonymous substitutions per site (K(a)) is significantly higher in sperm proteins (mean K(a) = 0.18; N = 35) than in proteins expressed specifically in all other tissues (mean K(a) = 0.074; N = 473). No differences, however, are found in the synonymous substitution rate (K(s)) between tissues, suggesting that selective forces, and not mutation rate, explain the high rate of replacement substitutions in sperm proteins. Four out of 19 sperm-specific genes with characterized function demonstrated evidence of strong positive Darwinian selection, including a protein involved in gene regulation, Protamine-1 (PRM1), a protein involved in glycolysis, GAPDS, and two egg-binding proteins, Adam-2 precursor (ADAM2) and sperm-adhesion molecule-1 (SAM1). These results demonstrate the rapid evolution of sperm-specific genes and highlight the molecular action of sexual selection on a variety of characters involved in mammalian sperm function.

Amino Acid Substitution↗
PubMed1996

Noncoding sequences from the slowly evolving chloroplast inverted repeat in addition to rbcL data do not support gnetalean affinities of angiosperms.

We developed PCR primers against highly conserved regions of the rRNA operon located within the inverted repeat of the chloroplast genome and used these to amplify the region spanning from the 3' terminus of the 23S rRNA gene to the 5' terminus of the 5S rRNA gene. The sequence of this roughly 500-bp region, which includes the 4.5S rRNA gene and two chloroplast intergenic transcribed spacer regions (cpITS2 and cpITS3), was determined from 20 angiosperms, 7 gymnosperms, and 16 ferns (21,700 bp). Sequences for the large subunit of ribulose bisphosphate carboxylase/oxygenase (rbcL) from the same or confamilial genera were analyzed in both separate and combined data sets. Due to the low substitution rate in the inverted repeat region, noncoding sequences in the cpITS region are not saturated with substitutions, in contrast to synonymous sites in rbcL, which are shown to evolve roughly six times faster than noncoding cpITS sequences. Several length polymorphisms with very clear phylogenetic distributions were detected in the data set. Results of phylogenetic analyses provide very strong bootstrap support for monophyly of both spermatophytes and angiosperms. No support for a sister group relationship between Gnetales and angiosperms in either cpITS or rbcL data was found. Rather, weak bootstrap support for monophyly of gymnosperms studied and for a basal position for the aquatic angiosperm Nymphaea among angiosperms studied was observed. Noncoding sequences from the inverted repeat region of chloroplast DNA appear suitable for study of land plant evolution.

Base Sequence↗
PubMed1995

Functional constraints against variations on molecules from the tissue level: slowly evolving brain-specific genes demonstrated by protein kinase and immunoglobulin supergene families.

In the protein kinase family, the basic function of kinase domain is similar among members. According to the standard view of functional constraint, the molecular evolutionary rate depends on functional and structural features characteristic of individual molecules (local constraint). Thus the evolutionary rate of the kinase domain is expected to be similar for different members. Contrary to this expectation, a comparison of the evolutionary rates revealed a wide difference among members; it amounts to about 100 times difference between the maximum and minimum rates. A similar result was also found in members of the immunoglobulin (Ig) family. In addition, significant correlations in evolutionary rate were observed between the kinase domain and the Ig-like domain in the receptor protein tyrosine kinases and between the kinase domain and the SH domain in the nonreceptor-type kinases. Furthermore, the evolutionary rates of family members that are expressed tissue specifically differ widely, depending on their tissue distribution: members expressed in the brain evolve with significantly slower rates than those expressed in the immune system. These results strongly suggest the presence of an alternative constraint (global constraint) against changes on molecules derived from higher levels like tissues or organs.

Animals↗
PubMed1999

Highly purified thermo-stable oxygen-evolving photosystem II core complex from the thermophilic cyanobacterium Synechococcus elongatus having His-tagged CP43.

The carboxyl terminus of the CP43 subunit of photosystem II (PSII) in the thermophilic cyanobacterium, Synechococcus elongatus, was genetically tagged with six consecutive histidine residues to create a metal binding site on the PSII supramolecular complex. The histidine-tagging enabled rapid isolation of an intact cyanobacterial PSII core complex from dodecyl maltoside-solubilized thylakoids by a simple one-step Ni(2+)-affinity column chromatography. The isolated core complex was in a dimeric form with a molecular mass of about 580 kDa, consisting of five major intrinsic membrane proteins (CP47, CP43, D1, D2 and cytochrome b-559), three extrinsic proteins (33 kDa, 12 kDa, and cytochrome c-550), and a few low molecular mass membrane proteins, and evolved oxygen at a rate as high as 3,400 mumol (mg Chl)-1 h-1 at 45 degrees C with ferricyanide as an electron acceptor. The core complex emitted thermoluminescence B2-, B1- and Q-bands arising from S2QB-, S3QB- and S2QA- charge recombinations at respective emission temperatures of 45, 38 and 20 degrees C, all of which were higher by about 15 degrees C as compared with those in mesophilic spinach BBY membranes. These results indicated that the isolated core complex well retained the intact properties of thermoluminescence of thermophilic cyanobacterial cells, the deeper stabilization of PSII charge pairs. The isolated complex was extremely stable in terms of both protein composition and function, exhibiting no release of extrinsic proteins, no proteolytic degradation in any of its subunits, accompanied by only a slight (less than 10%) loss in oxygen evolution, after dark-incubation at 20 degrees C for 8 d. These properties of the thermophilic PSII core complex are highly useful for various types of studies on PSII.

Amino Acid Sequence↗
PubMed2000

Molecular characterization of cDNA encoding oxygen evolving enhancer protein 1 increased by salt treatment in the mangrove Bruguiera gymnorrhiza.

Young plants of the common Okinawa mangrove species Bruguiera gymnorrhiza were transferred from freshwater to a medium with seawater salt level (500 mM NaCl). Two-dimensional gel electrophoresis revealed in the leaf extract of the plant a 33 kDa protein with pI 5.2, whose quantity increased as a result of NaCl treatment. The N-terminal amino acids sequence of this protein had a significant homology with mature region of oxygen evolving enhancer protein 1 (OEE1) precursor. The cloning of OEE1 precursor cDNA fragment was carried out by means of reverse transcription-PCR (RT-PCR) using degenerated primers. Both 3'- and 5'-regions were isolated by rapid amplification of cDNA ends (RACE) method. The deduced amino acid sequence consisted of 322 amino acids and was 87% identical to that of Nicotiana tabacum. In B. gymnorrhiza, the predicted amino acid sequence of the mature protein starts at the residue number 85 of the open reading frame. The first 84-amino acid residues correspond to a typical transit sequence for the signal directing OEE1 to its appropriate compartment of chloroplast. The expression of OEE1 was analyzed together with other OEE subunits and D1 protein of photosystem II. The transcript levels of all the three OEEs were enhanced by NaCl treatment, but the significant increase of D1 protein was not observed.

Algal Proteins↗
PubMed2004

Release and reactive-oxygen-mediated damage of the oxygen-evolving complex subunits of PSII during photoinhibition.

Under photoinhibitory illumination of spinach PSII membranes, the oxygen-evolving complex subunits, OEC33, 24 and 18, were released from PSII. The liberated OEC33 and also OEC24 to a lesser extent were subsequently damaged and then exhibited smeared bands in SDS/urea-PAGE. Once deteriorated, OEC33 could not bind to PSII. The effects of scavengers and chelating reagents on the damage indicated that hydroxyl radicals generated from superoxide in the presence of metal ions were responsible for the damage. These results suggest that, like the D1 protein of the PSII reaction center complex, OEC subunits suffer oxidative damage and turnover under illumination.

Cell Membrane↗
PubMed2005

Damage of cutaneous peripheral nervous system evolves differently according to the disease phase and subset of systemic sclerosis.

OBJECTIVE: Evidence shows that peripheral nervous system (PNS) is involved in systemic sclerosis (SSc), but few morphological studies have assessed the ultrastructural pathological modifications. The aim was to study ultrastructural modifications of skin PNS fibres in SSc according to subsets [limited SSc (lSSc) and diffuse SSc (dSSc)] and phases (early and advanced) of the disease. METHODS: Skin biopsies were taken from the forearms of 23 SSc patients (11 lSSc and 12 dSSc) and 10 controls. Each biopsy was processed for transmission electron microscopy (TEM). RESULTS: At TEM, observation in skin from early lSSc, signs of inflammation were evident, while PNS fibres were not damaged. The microvascular wall showed hypertrophic endothelial cells bulging into the lumen. In advanced lSSc, fibrosis prevailed on inflammation and slight ultrastructural alterations of PNS fibres were evident in the papillary derma. In early dSSc, ultrastructural alterations of PNS fibres, similar to those observed in the advanced phase of lSSc, were found together with signs of inflammation and fibrosis. In advanced dSSc, in the papillary and reticular dermis PNS fibres were reduced and showed relevant ultrastructural alterations. CONCLUSIONS: In SSc, PNS ultrastructure damage is linked to the progression and severity of skin involvement. The alterations evolve from the early to the advanced phase mainly in the diffuse subset. In particular, the severe PNS lesions found in advanced lSSc are already present and widely diffuse in early dSSc and the microvascular involvement in early lSSc seems to precede the modification of the PNS in the skin. Thus, an early therapeutic approach can be useful to reduce the progression of PNS and skin damage in SSc patients.

Adult↗
PubMed2003

Managed care and the evolving role of the clinical social worker in mental health.

This article discusses developments for practitioners in mental health care with the advent of managed care. With managed care's influence and new cost-containment strategies, the roles of clinical social workers, clinical psychologists, and psychiatrists are evolving, creating role conflict and competition. Along with changes in the utilization and definition of mental health practitioners' responsibilities, managed care has influenced issues such as private practice, mode of treatment, the use of outcome measurement and management, and the importance of case management. This article outlines the changes that have occurred and provides projections for the future.

Case Management↗
PubMed2002

Integrin alpha(v)beta3 targeted therapy for Kaposi's sarcoma with an in vitro evolved antibody.

Here, we define integrin alpha(v)beta3 as a molecular target for antibody therapy for Kaposi's sarcoma (KS). We previously reported, using a new phage display strategy based on designed combinatorial V gene libraries, the humanization of mouse monoclonal antibody LM609 directed to human integrin alpha(v)beta3. In the present study, we describe the in vitro affinity maturation of humanized LM609 by using a phage display strategy for the sequential and parallel optimization of three complementarity determining regions of the antibody molecule. The evolved Fab had an affinity of 150 pM and was converted into IgG1 by use of a new mammalian expression vector. The resulting whole antibody, designated JC-7U IgG1, was found to selectively target human KS in a nude mouse model and inhibit tumor growth at a therapeutically relevant dose. Because of its high affinity and its high degree of humanization, JC-7U IgG1 is an excellent drug candidate for therapeutic applications that involve integrin alpha(v)beta3 as the molecular target. Of particular interest is therapy for KS, breast cancer, melanoma, and other cancers in which integrin alpha(v)beta3 is expressed on both angiogenic endothelial cells and tumor cells, which would allow a dual antiangiogenic and antitumor strike with a single drug.

Animals↗
PubMed1995

The evolving role of brachytherapy in breast cancer.

The role of brachytherapy in the treatment of carcinoma of the breast continues to evolve. Initially, brachytherapy was used alone; later it was used to boost external beam irradiation. In the 1980's, its role diminished. Low-energy radionuclides like iodine-125 and remote-controlled high-dose-rate brachytherapy have been used to reduce radiation exposure to medical care givers. The 1990's has seen renewed interest in the use of brachytherapy alone to the tumor for management of primary and recurrent breast cancer. Randomized, controlled clinical trials are needed to redefine the role of brachytherapy in breast cancer.

Brachytherapy↗
PubMed1976

Operative correction of pectus excavatum: an evolving perspective.

From 1949 to 1975, 220 children have undergone surgical reconstruction of pectus excavatum using a variety of operations on our Pediatric Surgical Service. The first 183 were previously reported and have had subsequent, careful followup evaluation. From 1970 to 1975, an identifiable group of 45 children had a standard operation, a modified Ravitch repair, with the addition of a three-point or tripod internal fixation technique for support of the sternum. These children have all obtained satisfactory reconstruction without prosthetic support of any kind. We have thus avoided the possible danger of foreign material within the chest and have obviated the need for another procedure to remove a supporting stent. The two groups have been analyzed and compared with respect to age distribution, postoperative complications and end results to see if we could detect any trends in the evolving management of children with this condition. The main indications for surgical correction remain cosmetic and postural. Specific trends which have emerged from our experience include an increased percentage of patients between 3 and 8 years of age (average 5.8 years); a decreased need for blood transfusion (10%); a near resolution of postoperative seromas with the use of substernal and subcutaneous suction drains; and in the last 45 children, a 100% excellent or acceptable result to date. We feel that age selection is an important factor in the improved operative result and in the emotional impact on these young patients. Eighty per cent of the children in the recent series were between 3 and 8 years of age at the time of repair. On the basis of this experience, we now feel confident in recommending our standardized operation for pectus excavatum at an elective age of 4 to 6 years.

Adolescent↗
PubMed1997

Implantable left ventricular assist devices: an evolving long-term cardiac replacement therapy.

OBJECTIVE: The authors' 8-year experience with both inpatient and outpatient left ventricular assist device (LVAD) support is presented to show the possibilities and limitations of long-term outpatient mechanical circulatory assistance. SUMMARY BACKGROUND DATA: The limitation of suitable cardiac donors has led to the use of LVADs as a temporizing measure for patients awaiting cardiac transplantation. The success of such devices in the short and medium term as a bridge to transplantation has led to their evaluation as a long-term destination therapy for end-stage heart disease. METHODS: Between August 1990 and February 1997, 85 patients with end-stage heart disease underwent insertion of implantable LVADs. Fifty-two patients underwent pneumatic device insertion and 32 patients received a vented electric device. RESULTS: Patients were supported for a mean of 109+/-13 days for an overall survival to transplant (54) or explant (3) of 73%. Nineteen patients were discharged from the hospital on a mean of postoperative day 41+/-4 (range, 17-68) for an outpatient support time of 108+/-30 days (range, 2-466). Of 12 patients supported after postcardiotomy cardiogenic shock, 10 (82%) survived to hospital discharge. Perioperative right ventricular failure was treated in most patients with inotropic agents and inhaled nitric oxide with only six patients requiring right ventricular assist device support. Thromboembolic rate was low (0.016 events/patient-month) despite minimal or no anticoagulation in all cases. CONCLUSIONS: Left ventricular assist device support has evolved to become an outpatient therapy with excellent survival rates and an acceptable morbidity. Accordingly, wearable LVADs should be studied as permanent treatment options for patients who are not transplant candidates.

Ambulatory Care↗
PubMed2002

Evolving techniques for mitral valve reconstruction.

OBJECTIVE: To analyze the effectiveness of new techniques of mitral valve reconstruction (MVR) that have evolved over the last decade, such as aggressive anterior leaflet repair and minimally invasive surgery using an endoaortic balloon occluder. SUMMARY BACKGROUND DATA: MVR via conventional sternotomy has been an established treatment for mitral insufficiency for over 20 years, primarily for the treatment of patients with posterior leaflet prolapse. METHODS: Between June 1980 and June 2001, 1,195 consecutive patients had MVR with ring annuloplasty. Conventional sternotomy was used in 843 patients, minimally invasive surgery in 352 (since June 1996). Anterior leaflet repair was performed in 374 patients, with increasing use over the last 10 years. Follow-up was 100% complete (mean 4.6 years, range 0.5-20.5). RESULTS: Hospital mortality was 4.7% overall and 1.4% for isolated MVR (1.1% for minimally invasive surgery vs. 1.6% for conventional sternotomy; =.4). Multivariate analysis showed the factors predictive of increased operative risk to be age, NYHA functional class, concomitant procedures, and previous cardiac surgery. The 5-year results for freedom from cardiac death, reoperation, and valve-related complications among the 782 patients with degenerative etiology are, respectively, as follows ( >.05 for all end points): for anterior leaflet repair, 93%, 94%, 90%; for no anterior leaflet repair, 91%, 92%, 91%; for minimally invasive surgery, 97%, 89%, 93%; and for conventional sternotomy, 93%, 94%, 90%. CONCLUSIONS: These findings indicate that late results of MVR after minimally invasive surgery and after anterior leaflet repair are equivalent to those achievable with conventional sternotomy and posterior leaflet repair. These options significantly expand the range of patients suitable for mitral valve repair surgery and give further evidence to support wider use of minimally invasive techniques.

Adult↗
PubMed2000

Quidne mortui vivos docent? The evolving purpose of human dissection in medical education.

The dissection experience has evolved over the past 500 years, following broader cutural trends in science and medicine. Through this time each period has recruited human gross anatomic dissection for characteristic purposes. Key variables have been: (1) the motivating philosophies of medicine and science, (2) how well clinical medicine and basic science have been integrated by anatomy, and (3) how explicity thoughts or feelings about death and dying have been addressed in the context of anatomy. The authors are especially interested in the third variable, and suggest that although anatomy is scientifically in decline, dissection is currently enjoying a revival as a vehicle for teaching humanist values in medical school. Changes in the culture of medicine have carried anatomy from a research science, to a training tool, nearly to a hazing ritual, to a vehicle for ethical and moral education. Physicians, scientists, and medical students, as well as observers such as sociologists and writers, have been only intermittently aware of these cultural shifts. Yet anatomic dissection has been remarkably persistent as a feature of medical education-indeed it stands out as the most universal and universally recognizable step in becoming a doctor. This paper attempts to explore and interpret in detail the history of anatomy education, drawing on both subjective commentary and objective data from each period.

Anatomy↗