Membranes in ARF: a procrustean hypothesis or scientific advance?
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Acute Kidney Injury↗
Biomedical subjects
S M Lang
Publications and source records attributed to S M Lang.
Detection of Ki-ras mutations by PCR and differential hybridization and of p53 mutations by SSCP analysis in endoscopically obtained lavage solution from patients with long-standing ulcerative colitis.
OBJECTIVES: The goal of this study was the early detection of malignant transformation in patients with long-standing ulcerative colitis; therefore, mutations of the Ki-ras and p53 gene were analyzed in lavage solution and biopsies obtained at surveillance colonoscopy. METHODS: DNA was isolated from 14 patients (nine female, five male) with a history of pancolitis for more than 10 yr. Exon 1 of the Ki-ras gene and exons 5-8 of the p53 gene were amplified via polymerase chain reaction. Mutations of the p53 gene were detected via single-strand conformation polymorphism analysis; point mutations of the Ki-ras gene were hybridized on dot blots with oligonucleotides marked with digoxigenin. RESULTS: Wild-type Ki-ras and wild-type p53 were detected in all cases of ulcerative colitis and in four of seven control patients. In two ulcerative colitis patients, a mutation was found in the Ki-ras gene (Gly --> Asp 12 and Gly --> Val 12), and in one patient, a mutation in exon 5 of the p53 gene. Mutations were found only in the lavage fluid, whereas random biopsies were negative. CONCLUSIONS: From colonic lavage fluid, it is possible to extract DNA of sufficient quantity and quality for polymerase chain reaction-based amplification and subsequent analysis via single-strand conformation polymorphism or hybridization. Mutations were found in three of 14 patients with long-standing ulcerative colitis but were not found in controls. The method may be useful for the screening of such patients.
Aspartic Acid↗
Relative importance and functional role of genetic elements targeted for a live attenuated AIDS vaccine.
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AIDS Vaccines↗
[Clinical aspects of biocompatibility].
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Artificial Organs↗
Identification of Lck-binding elements in tip of herpesvirus saimiri.
A protein called Tip (tyrosine kinase interacting protein) of herpesvirus saimiri associates with Lck in virus-transformed human T cells and is an in vitro substrate for Lck kinase. Mutational analyses of a GST-Tip fusion protein revealed that binding to Lck requires putative SH3 binding sequences and a sequence homologous to the carboxyl terminus of Src-related kinases. These sequences are referred to as SH3-Binding (SH3B) and C-terminal Src-related Kinase Homology (CSKH) elements. Peptide fragments as short as 37 amino acids containing both SH3B and CSKH elements were sufficient to form a stable complex with Lck in vitro. Furthermore, these same sequences of Tip were necessary for in vivo association with Lck when Tip and Lck were expressed transiently in COS-1 cells or stably in Rat-1 cell lines. These results demonstrate that the CSKH element of Tip participates in the binding of sequences within Lck. Tip of herpesvirus saimiri has apparently acquired such CSKH and SH3B elements for the purpose of targeting cellular protein kinases. The interaction of Tip with Lck may influence Lck kinase activity or its binding to other cellular proteins and thereby alter Lck function in T cells infected by h. saimiri.
Amino Acid Sequence↗
Identification of a nef allele that causes lymphocyte activation and acute disease in macaque monkeys.
Residues 17 and 18 in nef of SIVmac239 were changed from RQ to YE to create a translated sequence of SRPSGDLYERLLRARGETYGRLLGEVEDGYSQSP from residues 10-43. The YXXL motifs in this context match very well with consensus sequences for SH2 binding domains and are similar to ones present in nef of the acutely lethal pathogen SIVpbj14. The YE variant of SIVmac239, unlike SIVmac239 but like SIVpbj14, replicated well in resting peripheral blood mononuclear cell cultures, caused extensive T lymphocyte activation, and produced an acute disease in rhesus and pigtailed monkeys characterized by severe diarrhea, rash, and extensive lymphoid proliferation in the gastrointestinal tract. The YEnef gene transformed NIH 3T3 cells in culture. Both 239nef and YEnef were found to associate with src in cotransfected COS cells, and both 60 kDa src and 34 kDa nef were phosphorylated at tyrosine in these cells. The extent of tyrosine phosphorylation of 239nef was considerably less than that of YEnef in these assays. These findings identify an important determinant of the SIVpbj14 phenotype, and they provide evidence of a role for nef in signal transduction and cellular activation.
3T3 Cells↗
[Vaso-occlusive crises in sickle-cell anemia].
HISTORY AND FINDINGS: Severe pain suddenly occurred in the shaft of the right thigh in a 21-year-old patient of Turkish descent with known homozygotic sickle cell anaemia. He also had marked scleral jaundice and anaemia (haemoglobin 9.1 g/dl). An X-ray film of the lower leg pointed to a bone infarct. Type of pain, partial pressure of oxygen in blood (70 mm Hg), concentration of lactate dehydrogenase and the bilirubin level (4,5 mg/dl) as signs of haemolysis, as well as the fall in haemoglobin, indicated a vascular occlusive crisis in sickle cell anaemia. TREATMENT AND COURSE: The symptoms regressed within 8 days of the patient receiving fluids, analgesics and oxygenation by nasal tube. A few weeks later he developed a fever, productive cough and severe pain in joints and abdomen. Blood p02 was 54 mm Hg. Pneumonia in the right lung base was the cause of this renewed life-threatening crisis, which was again associated with haemolysis. Klebsiella having been found in sputum he was treated with cefotaxim (1 g twice daily intravenously) and oxygen insufflation via nasal tube (7 l/min). His condition quickly improved. CONCLUSIONS: In patients with sickle cell anaemia it is important (1) to regard crises as potentially life-threatening conditions, (2) to detect and treat infections as possible causes early and (3) to provide sufficient oxygen insufflation quickly, especially in pulmonary infections.
Acute Disease↗
Human vertebral cancellous bone surface distribution.
The three-dimensional distribution of bone surface and the bone volume fraction (BV/TV) of 110 human vertebral cancellous bone specimens from seven individuals were measured using a three-dimensional radiographic method (microcomputed tomography). The ratios of the three principal projections of bone surface per total volume were found to be relatively constant for specimens examined in this study. The constancy of the projected surface ratios means that the fraction of the total bone surface oriented in any direction does not change markedly with BV/TV. Bone volume fraction was a good predictor of bone surface per total volume (BS/TV) for a one-parameter nonlinear model (r2 = 0.92). The results of this pilot study suggest that the changes in surface distribution which occur during age-related bone loss are largely predetermined rather than adaptive. The results are also consistent with the idea that cancellous bone tends to maintain a constant ratio of trabecular number for the principal directions. If these inferences from the data are correct, the morphogenetic processes which create the initial adult trabecular pattern become of primary interest. A model was developed which explained the strong relationship between BS/TV and BV/TV. The model was used to demonstrate the importance of morphogenetic processes.
Aged↗
Downregulation of Lck-mediated signal transduction by tip of herpesvirus saimiri.
A protein, called tip, of herpesvirus saimiri associates with Lck in transformed T cells. To investigate the effects of complex formation on cellular signal transduction, we constructed human Jurkat-T-cell lines expressing tip. The expression of tip in Jurkat-T cells dramatically suppressed cellular tyrosine phosphorylation and surface expression of lymphocyte antigens. The expression of tip also blocked the induction of tyrosine phosphorylation by anti-CD3 stimulation. The expression of tip in fibroblast cells suppressed the transforming activity of oncogenic F505 Lck. Binding assays showed that the SH3 domain of Lck is sufficient to form a stable complex with tip in vitro. These results demonstrate that tip acts at an early stage of the T-cell signal transduction cascade by associating with Lck and downregulating Lck-mediated activation. Inhibition of Lck-mediated signal transduction by tip in T cells appears to be analogous to the inhibition of Lyn/Syk-mediated signal transduction in B cells by LMP2A of the B-cell-tropic Epstein-Barr virus.
Base Sequence↗
Progression to AIDS in the absence of a gene for vpr or vpx.
Rhesus monkeys (Macaca mulatta) were experimentally infected with strains of simian immunodeficiency virus (SIV) derived from SIVmac239 lacking vpr, vpx, or both vpr and vpx genes. These auxiliary genes are not required for virus replication in cultured cells but are consistently conserved within the SIVmac/human immunodeficiency virus type 2/SIVsm group of primate lentiviruses. All four rhesus monkeys infected with the vpr deletion mutant showed an early spike in plasma antigenemia, maintained high virus burdens, exhibited declines in CD4+ lymphocyte concentrations, and had significant changes in lymph node morphology, and two have died to date with AIDS. The behavior of the vpr deletion mutant was indistinguishable from that of the parental, wild-type virus. Rhesus monkeys infected with the vpx deletion mutant showed lower levels of plasma antigenemia, lower virus burdens, and delayed declines in CD4+ lymphocyte concentrations but nonetheless progressed with AIDS to a terminal stage. The vpr+vpx double mutant was severely attenuated, with much lower virus burdens and no evidence of disease progression. These and other results indicate that vpr provides only a slight facilitating advantage for wild-type SIVmac replication in vivo. Thus, progression to AIDS and death can occur in the absence of a gene for vpr or vpx.
Animals↗
vpr deletion mutant of simian immunodeficiency virus induces AIDS in rhesus monkeys.
In previous experiments, animals infected with SIVmac239 containing a point mutation in the vpr and nef genes developed AIDS-like symptoms after early reversion of the vpr and nef genes. Here we show that two animals in which the nef gene but not the vpr gene had reverted in the first few months did not develop disease during a 3-year observation period even after reversion to a functional vpr gene 70 weeks postinfection. To study the influence of a stable vpr mutation on virus load and pathogenesis, a 43-bp deletion was introduced into the vpr gene of SIVmac239on, a nef-open mutant of SIVmac239. Four rhesus monkeys were inoculated with the vpr deletion mutant (SIV delta vpr), and two control animals were infected with SIVmac239on. Both control animals had persistent antigenemia, high cell-associated virus loads, and elevated neopterin levels. They had to be euthanized 20 and 30 weeks postinfection because of AIDS-related symptoms. However, all four rhesus monkeys inoculated with SIV delta vpr showed only transiently detectable antigenemia. The cell-associated virus loads were high in three of the four animals. Two animals with AIDS-like symptoms had to be euthanized 71 and 73 weeks postinfection. The two remaining monkeys infected with SIV delta vpr were still alive 105 weeks postinfection. In contrast to the SIVmac239on-infected animals, SIV delta vpr-infected animals had strong humoral immune responses and intermittent cellular immune responses to SIV antigens. Our data show that a functional vpr gene is not necessary for pathogenesis. However, vpr-deficient SIVmac239 variants might be slightly attenuated, allowing some animals to resist progression to disease for an extended period of time.
Animals↗
Biocompatible membranes in acute renal failure: prospective case-controlled study.
The mortality of critically ill patients with acute renal failure has been halved through intervention by haemodialysis. However, several reports suggest that the course of the disorder may be prolonged by this procedure. Our prospective randomised study was done to see whether the generation of inflammatory mediators by bio-compatible membranes has an adverse effect on the outcome of acute renal failure. 52 patients, similar in age, severity of acute renal failure, general disease status (APACHE II), and management of acute renal failure or its related conditions, were divided into two groups. Haemodialysis was done with cuprophane or polyacrylonitrile membranes. Cuprophane membranes induced intense activation of the complement system (as judged by measurement of C3a) and lipooxygenase pathway (leukotriene B4) resulting in alterations of neutrophil kinetics and function. The cuprophane group had a lower survival rate (38 vs 65%), a higher proportion of patients dying from sepsis (71 vs 40%), required more haemodialysis sessions (12 vs 9), and demonstrated delayed resolution and recovery from acute renal failure than the polyacrylonitrile group. The difference in mortality regarding lethal sepsis as cause of death was statistically significant. Our observations indicate that the outcome of critically ill patients with acute renal failure may be influenced by bio-incompatibility reactions to the dialysis membrane. These results have direct implications for such patients on haemodialysis.
Acrylic Resins↗
Importance of vpr for infection of rhesus monkeys with simian immunodeficiency virus.
The importance of the vpr gene for simian immunodeficiency virus (SIV) replication, persistence, and disease progression was examined by using the infectious pathogenic molecular clone called SIVmac239. The ATG start codon of the vpr gene was converted to TTG by site-specific mutagenesis. The constructed Vpr- mutant virus is identical with the parental SIVmac239/nef-stop virus with the exception of this one nucleotide. These viruses replicated with similar kinetics and to similar extents in rhesus monkey lymphocyte cultures and in the human CEMX174 cell line. Five rhesus monkeys were inoculated with the Vpr- variant of SIVmac239/nef-stop, and two monkeys received SIVmac239/nef-stop as controls. Both controls showed reversion of the TAA stop signal in nef by 2 weeks postinfection, as has been observed previously. Reversion of the TAA stop codon in nef also occurred in the five monkeys that received the Vpr- variant, but reversion was delayed on average to about 4 weeks. Thus, the mutation in vpr appeared to delay the rapidity with which reversion occurred in the nef gene. Reversion of the TTG sequence in vpr to ATG was observed in three of the five test animals. Reversion in vpr was first observed in these three animals 4 to 8 weeks postinfection. No vpr revertants were found over the entire 66 weeks of observation in the other two test animals that received the vpr mutant. Antibodies to vpr developed in those three animals in which reversion of vpr was documented, but antibodies to vpr were not observed in the two animals in which reversion of vpr was not detected. Antibody responses to gag and to whole virus antigens were of similar strength in all seven animals. Both control animals and two of the test animals in which vpr reverted maintained high virus loads and developed progressive disease. Low virus burden and no disease have been observed in the two animals in which vpr did not revert and in the one animal in which vpr reversion was first detected only at 8 weeks. The reversion of vpr in three of the five test animals indicates that there is significant selective pressure for functional forms of vpr in vivo. Furthermore, the results suggest that both vpr and nef are important for maximal SIV replication and persistence in vivo and for disease progression.
Amino Acid Sequence↗
Comparison of the effects of moist and dry conditions on dermal repair.
The effects on dermal repair of moist conditions, achieved by covering excised wounds with the adhesive polyurethane dressing OPSITE, and dry conditions, achieved by exposure to air through dry gauze dressings, were compared in full thickness excised wounds on porcine skin during the period from 1 to 21 d after injury. Quantitative studies were made of changes in the populations of neutrophils, macrophages, fibroblasts, and endothelial cells. The number of inflammatory phase cells (neutrophils and macrophages) decreased more rapidly under moist conditions than under dry conditions. There was also a more rapid increase in the number of proliferative phase cells (fibroblasts and endothelial cells) in the moist wounds; by 5 d after injury 66% of the cells of the granulation tissue of the moist wounds were of this type, compared with only 48% of the cells of equivalent areas of the dry wounds. By 21 d after injury the number of fibroblasts in the granulation tissue of the moist wounds had fallen below that in the dry wounds, suggesting that progress from the proliferative into the remodelling phase of repair was more rapid in the moist wounds. It was concluded that there was an acceleration of the inflammatory and proliferative phases of dermal repair in wounds healing under moist conditions when compared with those healing under dry conditions.
Air↗
Correlation of mechanical properties of vertebral trabecular bone with equivalent mineral density as measured by computed tomography.
We tried to determine whether mineral-equivalent measurements that were obtained using computed tomography could be used to predict the mechanical properties of vertebral trabecular bone. Vertebral bodies that had been obtained during routine autopsy were evaluated by computed tomography. The mechanical properties of the vertebral trabecular bone were determined by subjecting cylindrical specimens to simple compression until failure occurred. The ultimate strength and elastic modulus were determined from load time curves, using constant displacement rate loading. Atomic absorption spectrophotometry was used to determine the weight per cent calcium of each specimen, and quantitative light microscopy was used to determine area fraction bone. Significant positive correlations were found between the observed mechanical properties of the trabecular bone and the equivalent mineral density as measured by computed tomography. Compressive strength (r = 0.720), elastic modulus (r = 0.574), trabecular calcium density (r = 0.780), and area fraction bone (r = 0.579) were all correlated with the equivalent mineral density.
Aged↗
Board-certified physicians in the United States: specialty distribution and policy implications of trends during the past decade.
Board certification is a universal ambition among graduates of American medical schools. It is a measure of postgraduate achievement and clinical ability that leads to staff appointments, promotions, clinical privileges, increased fees, and reduced malpractice premiums. The number of physicians receiving specialty-board diplomas each year has increased remarkably over the past 15 years. The annual mean for the years of 1976-1978 was 17,381--larger than the graduating medical class four years before. The number of board-certified physicians in medicine, surgery, and the clinical services increased from 106,300 in 1971 to 158,900 in 1978. The percentage of board-certified physicians in these fields has increased from 65 to 78 per cent. Board certification in family practice commenced in 1970 and is still increasing sharply (from 1523 [1970-1972] to 3444 [1976-1978]). The growth of internal medicine and its subjacent specialties is the most spectacular and has been more rapid than that of either surgery or the clinical services, in both which the board-certification rate and number of board-certified practitioners have stabilized since 1973. As board certification becomes a virtually universal criterion that carries the implication of de facto licensing, its social role should be reevaluated.
Certification↗
The evaluation of a haemoperfusion device in conscious dogs.
A newly designed charcoal haemoperfusion device was evaluated by repeated haemoperfusion of conscious dogs. The procedure was tolerated well and the incidence of side effects was low. Alterations to haematology were small with platelet drops of only 9% and only minor disturbances to plasma chemistry were seen.
Animals↗
Acetylpromazine administration: its effect on canine haematology.
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Acepromazine↗