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71.
The binding thermodynamics of the HIV-1 protease inhibitor acetyl pepstatin and the substrate Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-Gln, corresponding to one of the cleavage sites in the gag, gag-pol polyproteins, have been measured by direct microcalorimetric analysis. The results indicate that the binding of the peptide substrate or peptide inhibitor is entropically driven; i.e., it is characterized by an unfavorable enthalpy and a favorable entropy change, in agreement with a structure-based thermodynamic analysis based upon an empirical parameterization of the energetics. Dissection of the binding enthalpy indicates that the intrinsic interactions are favorable and that the unfavorable enthalpy originates from the energy cost of rearranging the flap region in the protease molecule. In addition, the binding is coupled to a negative heat capacity change. The dominant binding force is the increase in solvent entropy that accompanies the burial of a significant hydrophobic surface. Comparison of the binding energetics obtained for the substrate with that obtained for synthetic nonpeptide inhibitors indicates that the major difference is in the magnitude of the conformational entropy change. In solution, the peptide substrate has a higher flexibility than the synthetic inhibitors and therefore suffers a higher conformational entropy loss upon binding. This higher entropy loss accounts for the lower binding affinity of the substrate. On the other hand, due to its higher flexibility, the peptide substrate is more amenable to adapt to backbone rearrangements or subtle conformational changes induced by mutations in the protease. The synthetic inhibitors are less flexible, and their capacity to adapt is more restricted. The expected result is a more pronounced effect of mutations on the binding affinity of the synthetic inhibitors. On the basis of the thermodynamic differences in the mode of binding of substrate and synthetic inhibitors, it appears that a key factor to understanding resistance is given by the relative balance of the different forces that contribute to the binding free energy and, in particular, the balance between conformational and solvation entropy.  相似文献   
72.
Infants with congenital diaphragmatic hernia (DH) and profound pulmonary hypoplasia are currently unsalvageable. The authors previously demonstrated that tracheal ligation (TL) accelerates fetal lung growth and reverses the pulmonary hypoplasia of fetal nephrectomy. The purpose of this study was to determine if the pulmonary hypoplasia of experimental DH could be similarly reversed and, if so, whether the resulting lungs would show better function than those of their DH counterparts. Eighteen fetal lambs were divided into three experimental groups of six animals each. In group 1, DH was created at 90 days' gestation. In group 2, DH was created at 90 days' gestation and TL performed during the same operation. Group 3 consisted of sham-operated controls. These animals were delivered near full-term, and their lungs analyzed by standard morphometric techniques. Ten additional fetal lambs were divided into two experimental groups of five animals each. In group 4, DH was created at 90 days' gestation. In group 5, DH was created at 90 days' gestation and TL performed 20 days later, at 110 days' gestation. These animals were pressure-ventilated via tracheostomy over a 2-hour period in which PaO2, PaCO2, and compliance were measured. Intratracheal pressure (ITP) was measured at the time of delivery in all groups. Upon retrieval, DH animals had abdominal viscera in the chest and small lungs; in contrast, DH/TL animals had the herniated viscera reduced from the chest by enlarged lungs. DH/TL lungs showed markedly increased growth, with significant increases in lung volume:body weight ratio (LV:BW; P = .0001), alveolar surface area (ALV.SA; P = .0001), and alveolar number (ALV#) (P = .0001) when compared with those of the DH or control group. This growth was associated with a normal maturation pattern based on histological appearance, normal airspace fraction, and normal alveolar numerical density. ITP in the DH/TL group was increased when compared with that of DH and control animals (P = .0001). Total lung DNA and protein were both elevated in the DH/TL animals (P = .0001). However, the DNA:protein ratio remained normal, suggesting lung growth had occurred through cell proliferation, not by hypertrophy. When ventilated over a range of settings, DH/TL lungs were more compliant (P = .0001) and achieved higher PaO2s (P < .003) and lower PaCO2s (P = .0001) than their DH counterparts. From these data, the authors conclude: (1) Experimental fetal DH produces hypoplastic lungs that are not capable of adequate gas exchange with conventional ventilation.(ABSTRACT TRUNCATED AT 400 WORDS)  相似文献   
73.
A false left ventricular aneurysm and coronary artery aneurysm were discovered in a 29 year old patient with Beh?et's syndrome. The operation under cardiopulmonary bypass consisted of closing the neck of the false aneurysm by an endo-aneurysmal approach with a Gore-Tex patch. The coronary artery aneurysms were respected. There were no postoperative complications. Cardiac involvement is rare in Beh?et's syndrome (6%). The originality of this case is the association of two aneurysmal pathologies: the coronary and ventricular aneurysms due to the angiitis and the myocardial fragility induced by ischaemia.  相似文献   
74.
The plasma membrane (PM) H(+)-ATPase has been proposed to play important transport and regulatory roles in plant physiology, including its participation in auxin-induced acidification in coleoptile segments. This enzyme is encoded by a family of genes differing in tissue distribution, regulation, and expression level. A major expressed isoform of the maize PM H(+)-ATPase (MHA2) has been characterized. RNA gel blot analysis indicated that MHA2 is expressed in all maize organs, with highest levels being in the roots. In situ hybridization of sections from maize seedlings indicated enriched expression of MHA2 in stomatal guard cells, phloem cells, and root epidermal cells. MHA2 mRNA was induced threefold when nonvascular parts of the coleoptile segments were treated with auxin. This induction correlates with auxin-triggered proton extrusion by the same part of the segments. The PM H(+)-ATPase in the vascular bundies does not contribute significantly to auxin-induced acidification, is not regulated by auxin, and masks the auxin effect in extracts of whole coleoptile segments. We conclude that auxin-induced acidification in coleoptile segments most often occurs in the nonvascular tissue and is mediated, at least in part, by increased levels of MHA2.  相似文献   
75.
A deletion mutant of the catalytic RNA component of Escherichia coli RNase P missing residues 87-241 retains the ability to interact with the protein component to form a functional catalyst. The deletion of this phylogenetically conserved region significantly increases the Km, indicating that the deleted structures may be important for binding to the precursor tRNA substrate but not for the cleavage reaction. Under some reaction conditions, this RNase P deletion mutant can become a relatively non-specific nuclease, indicating that this RNA's catalytic center may be more exposed. The catalytic core of the RNase P is formed by less than one third of the 377 residues of the RNase P RNA.  相似文献   
76.
Scattered radiation from within the treatment head can contribute significant dose to all parts of a radiotherapy treatment field. A multileaf collimator may be used to create an arbitrarily shaped field, and may also be used, under dynamic control, to modulate the beam intensity over the field. This method of intensity modulation is effectively a superposition of a large number of fields which have the same beam direction, but different shapes, and some of these shapes may have unusually small dimensions, particularly in the direction of the leaf movement. Two models for predicting the head scatter under these conditions have been investigated. These are a first-order Compton scatter approximation from the flattening filter, and an empirical fit to measured data using an exponential function. The first model only considers scatter from the flattening filter and has been applied to field sizes between 2 cm by 2 cm and 10 cm by 10 cm, where agreements are all within 1%. However it is not satisfactory at larger field sizes where small scatter contributions, from scattering sources other than the flattening filter, are integrated over large areas. The second model uses measured data between 4 cm by 4 cm and 30 cm by 30 cm to optimize the exponential function and is used to calculate the head scatter contribution for all field sizes. In this case good agreement is achieved over the full field size range, and hence this is a more generally applicable model. Results are presented for static irregularly shaped fields and intensity modulated beams created using a Philips multileaf collimator.  相似文献   
77.
BACKGROUND: The goal of this study was to compare patterns of recurrence and long-term outcome after sphincter-saving procedures (SSPs) and abdominoperineal resection (APR) in patients with tumors located in the lower third of the rectum. METHODS: We reviewed the charts of 1001 patients operated on for primary rectal adenocarcinoma between 1980 and 1991. All patients with tumors located between 5 and 7 cm from the anal verge and treated with curative intent were included. RESULTS: Of the 261 patients who met our criteria, 162 had undergone SSP and 99 had undergone APR. The local recurrence rates for SSP and APR were 8% and 11%, respectively (p = 0.41), and the distant metastases rates were 23% and 28%, respectively (p = 0.35). Recurrence and distant metastases rates for SSP and APR, respectively, did not differ by TNM classification: state I, 10% versus 9% (p = 0.9); stage II, 25% versus 43% (p = 0.13); and stage III, 56% versus 57% (p = 0.92). Five-year disease-free survival rates for SSP and APR patients were 70.5% and 62.3%, respectively (p = 0.2). CONCLUSIONS: Tumors in the lower third of the rectum can be treated with sphincter-saving procedures without compromising the chance of cure.  相似文献   
78.
The purpose of this study was to determine the long-term results of allogeneic bone marrow transplantation for chronic myeloid leukemia. A retrospective analysis was carried out of the outcome of 373 consecutive transplants performed at 38 European institutions between 1980 and 1988 and reported to the registry of the European Group for Blood and Marrow Transplantation. All transplants were carried out for first chronic phase of chronic myelogenous leukemia using unmanipulated marow cells from HLA-identical sibling donors. The probability of survival and leukemia-free survival at 8 years were 54% (95% CI: 49-59) and 47% (95% CI: 41-52) respectively. The probabilities of developing acute GVHD (II-IV) at 100 days and chronic GVHD at 4 years after transplant were 47% (95% CI: 41-53) and 52% (95% CI: 46-58) respectively. The probabilities of transplant-related mortality and leukemic relapse 8 years after BMT were 41% (95% CI: 36-48) and 19% (95% CI: 14-25), respectively. Transplant within 12 months of diagnosis was associated with reduced transplant-related mortality (34 vs 45%, P = 0.013) and resulted in improved leukemia-free survival (52 vs 44%, P = 0.03). The probability of relapse was significantly reduced in patients who developed chronic GVHD (RR = 0.33, P = 0.004). The probability of relapse occurring more than 2 years after transplant was increased more than five-fold in patients transplanted from a male donor (RR = 5.5, P = 0.006). Sixty-seven patients in hematologic remission were studied for residual disease by two-step RT/PCR for BCR-ABL mRNA and 61 (91%) tested negative. We conclude that bone marrow transplantation can induce long-term survival in approximately one-half of CML patients; the majority of survivors have no evidence of residual leukemia cells when studied by molecular techniques. The probability of late relapse is increased with use of a male donor.  相似文献   
79.
BACKGROUND: In a series of 229 patients infected with mycobacterial organisms, we noted a specific female phenotype that involves isolated infections of the middle lobe and lingula. METHODS: Thirteen patients were found to have infections of the middle lobe, lingula, or both. All of them were infected with Mycobacterium other then Mycobacterium tuberculosis, all were women, 12 of the 13 were slender, and most had variable combinations of skeletal abnormalities. All underwent resection of the middle lobe, lingula, or both. RESULTS: There were no operative deaths. Only 2 patients have had reactivation requiring additional antibiotic therapy. All patients have had a decreased number of pulmonary infections in the postoperative period. Anatomic findings at operation included a complete major fissure and at least a partially complete minor fissure with middle lobe resections or an elongated lingula. CONCLUSIONS: Mycobacterial infection of the middle lobe and lingula is primarily a disease of asthenic women and is often associated with skeletal abnormalities and complete fissures or an elongated lingula. We recommend that surgical intervention be performed early once the condition is identified.  相似文献   
80.
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