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Biomedical subjects

K Hillman

Publications and source records attributed to K Hillman.

At least 55 records · Page 3Linked to original sources
PubMed1992

Kinetics of soluble CD4 binding to cells expressing human immunodeficiency virus type 1 envelope glycoprotein.

The high-affinity interaction between the envelope glycoprotein (gp120-gp41) of the human immunodeficiency virus type 1 and its receptor, CD4, is important for viral entry into cells and therapeutical approaches based on the soluble form of CD4 (sCD4). Using flow cytometry, we studied the kinetics of binding of sCD4 to gp120-gp41 expressed on the cell surface. sCD4 binding was dependent on sCD4 concentration and temperature and exhibited bimolecular reaction kinetics. Binding was very slow at low sCD4 concentrations (below 0.2 micrograms/ml) and low temperatures (below 13 degrees C) but increased sharply with increasing temperature. The rate constant for association at 37 degrees C (1.5 x 10(5) M-1 s-1) was 14-fold higher than at 4 degrees C, but the affinity of sCD4 to membrane-bound gp120-gp41 was not significantly affected. The activation energy at higher temperatures (28 to 37 degrees C) was less than at lower temperatures (4 to 13 degrees C). After long periods of incubation, we observed a decrease of surface-bound sCD4 and gp120, even at low temperatures, which was attributed to sCD4-induced shedding of gp120. The rate of gp120 shedding was much lower than the rate of sCD4 binding and was dependent on sCD4 concentration and temperature. The finding that sCD4 binding is slow, especially at low sCD4 concentrations, can be of critical importance for efficient blocking of viral infection by sCD4 and should be considered when designing new protocols in the therapy of AIDS patients.

CD4 Antigens↗
PubMed1991

A polymer containing a repeating peptide sequence can stimulate T-cell-independent IgG antibody production in vivo.

The immunogenicity of a CD4 peptide sequence 303-315 (V4 domain) was determined for three forms of the peptide: (a) a polymer consisting of repeating peptide units, (b) a peptide linked to a large protein carrier, chicken serum albumin, and (c) unmodified free peptide. Two in vivo systems were used: a T-cell-competent BALB/c mouse and a T-cell-deficient nude mouse. In BALB/c mice the IgG antibody responses to the peptide-CSA conjugate were at least 100-fold greater than the response to the polymer, and the free peptide gave no response. However, in contrast to the normal BALB/c mice, in the nude mice the polymer produced the only significant response. Nude mice immunized with the polymer produced a predominantly IgG response with almost equal amounts of IgG1 and IgG 2a + 2b. This IgG subclass distribution was very similar to that obtained in the BALB/c for the peptide-CSA conjugate. Positive sera from both groups were able to react with immobilized CD4 molecule on Western blots, confirming the specificity of both the T-cell-independent as well as T-cell-dependent response. These results suggest that repeating epitopes on the same peptide polymer molecule may cause cross-linking of antigen-specific immunoglobin receptors on B-cells, and thus behave as a relatively T-cell-independent immunogen which can induce isotype switching.

Amino Acid Sequence↗
PubMed1991

A new continuous positive airway pressure (CPAP) device.

While continuous positive airway pressure (CPAP) is being increasingly employed for many forms of acute respiratory failure and postoperative hypoxaemia, most CPAP systems are either 'home made' or incorporated in sophisticated ventilators used in intensive care units. This paper describes the development of a continuous low flow CPAP system using a large latex reservoir bag and venturi generated positive end expiratory pressure (PEEP). The system has been successfully used for over twelve months in the general wards, the intensive care unit, accident and emergency department, the recovery ward and the coronary care unit.

Equipment Design↗
PubMed1990

Chemically induced CD4 mutants of a human T cell line. Evidence for dissociation between binding of HIV I envelope and susceptibility to HIV I infection and syncytia formation.

This study describes the derivation of a series of mutants from the human leukemic cell line CEM using the frame shift mutagen Ethyl-methanesulfonate followed by negative selection with multiple treatments of OKT4A + C, and sorting into CD4-, CD4-dull, and CD4-intermediate mutants. These mutants express reduced CD4 levels ranging from 0 to 60% of the parental line. The mutants were analyzed by staining with a battery of CD4-specific mAb, by assessing their ability to bind soluble gp120, and by their ability to form syncytia after infection with cell-free HIV I virus and a gp160-vaccinia vector. Two groups of particularly interesting mutants were identified: (1) CD4-dull mutants expressing only 5 to 10% of the wild type surface CD4 density, which nevertheless were infectable by HIV I and produced as many syncytia and reverse transcriptase activity as the parental line after infection with gp160-vaccinia or cell free HIV I. (2) CD4-intermediate mutants (30 to 60% of parental CD4 level), which express CD4-epitopes required for interaction with the HIV I envelope protein, yet are markedly deficient in their ability to form syncytia after gp160-vaccinia or HIV I infection. Two of these mutants did form syncytia after transient reconstitution with a wild type CD4 containing vaccinia vector. Inasmuch as they were found to bind soluble gp120 with the same avidity as other, functionally normal, CD4-intermediate mutants, these human T cell mutants may have a reduced susceptibility to HIV I infection due to the absence of a "fusogenic component" or to a structural alteration in a region of the CD4 molecule not required for binding of the HIV I envelope, but for the subsequent fusion and entry process.

CD4 Antigens↗
PubMed1989

Common epitope in human immunodeficiency virus (HIV) I-GP41 and HLA class II elicits immunosuppressive autoantibodies capable of contributing to immune dysfunction in HIV I-infected individuals.

We previously reported the identification of highly conserved homologous regions located in the carboxy terminus of the HIV I gp41-envelope (aa 837-844), and the amino-terminal of the beta chain of all human HLA class II antigens (aa 19-25). Murine monoclonal antibodies, raised against synthetic peptides from these homologous regions, bound not only to the isolated peptides, but also to the native gp160 and class II molecules. In this study one-third of sera from HIV I-infected individuals, at different disease stages, were found to react with both the gp41 and class II-derived peptides. These sera also reacted with "native" HLA class II molecules. The potential affects of such autoantibodies on normal immune functions were examined. It was found that in the presence of class II-cross-reactive (but not control) sera, the proliferative responses of normal CD4+ T cells to tetanus toxoid and allogeneic stimuli were markedly decreased. In addition, these sera could eliminate class II-bearing cells by antibody dependent cellular cytotoxicity. Similar affects were seen with affinity-purified IgG antibodies from patients' sera. Thus, the "molecular mimicry" between HIV I and HLA class II antigens, may lead to the generation of autoantibodies in HIV I-infected individuals that may contribute to the early functional impairment of CD4+ T cell observed in many HIV I-infected individuals.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Production of antibodies against murine class II antigens using unconjugated synthetic peptides of the beta chain region 63-78.

synthetic peptides corresponding to residues 63-78 of the first domain of the beta chain of murine I-A/I-E class II antigens were used in the unconjugated rather than the traditional protein-conjugated form to immunize (129J X B6)F1 mice. The sequences made represented the four haplotypes; Ak beta, Ad beta, Abm-12 beta and Ed beta. These sequences were selected on the basis of computer algorithms used to predict surface accessibility and main-chain flexibility profiles, and by reported hypervariability and site-directed mutagenesis experiments of these regions. Factors such as the use of complete Freund's adjuvant, a continuous immunization regime, and the sex of the mice used were found to influence the amount of anti-peptide antibody produced when unconjugated peptide was used as the immunogen. Antibodies produced were shown by FACS analysis to react with I-A/I-E class II antigens expressed on the lymphocyte surface. These findings indicate that the use of unconjugated synthetic peptides representing sequences of proteins which are in close proximity to disulfide bonds may be an advantage over conventional methods of peptide conjugation to proteins.

Amino Acid Sequence↗
PubMed1988

Immunosuppression of collagen-induced arthritis in mice with an anti-IL-2 receptor antibody.

The use of an anti-IL-2R antibody, 7D4, was investigated in vivo in the suppression of collagen-induced arthritis in mice. 7D4 was shown to reduce the incidence of arthritis in a group of mice immunized with type II collagen as compared with a group similarly immunized with collagen and treated with a control isotype matched anti-Forsmann antibody. 7D4 was also shown to reduce the severity of arthritis in the treated mice as compared to the mice in the group treated with the control antibody. Anti-IL-2R antibodies may be useful in the treatment of autoimmune diseases by selectively suppressing activated T cells.

Animals↗
PubMed1988

Limitation of myocardial infarction by early infusion of recombinant tissue-type plasminogen activator.

In a double-blind randomized trial involving five Sydney hospitals and the city ambulance paramedical service, 145 patients with a first evolving myocardial infarction and with onset of pain less than 2.5 (mean 1.9 +/- 0.5 [SD]) hr previously were allocated to intravenous infusion of 100 mg recombinant tissue-type plasminogen activator (rt-PA) or placebo over 3 hr. The groups at entry were similar. At assessment 21 days later, left ventricular ejection fraction measured both by contrast and radionuclide ventriculography was higher in the rt-PA compared with the placebo group (61 +/- 13%, n = 64, vs 54 +/- 14%, n = 62, contrast, 2p = .006; 52 +/- 13%, n = 66, vs 48 +/- 13%, n = 62 isotope, 2p = .08). This indicates limitation of myocardial infarction by rt-PA.

Adult↗
PubMed1987

Fluid resuscitation in diabetic emergencies--a reappraisal.

The first objective in diabetic ketoacidosis is to restore the circulating volume and improve tissue perfusion. In any form of hypovolaemic shock the most efficient way of restoring circulating volume is to be use colloid solutions rather than crystalloids. At least three times the amount of crystalloid must be used to achieve the same effect. The historical reason for using isotonic saline in diabetic ketoacidosis is related not to its similarity to the fluid lost, but to its supposed efficiency in correcting the circulating volume. Excess crystalloid expands the interstitial space which results in pulmonary oedema, peripheral oedema and possibly cerebral oedema. Although currently difficult to define precisely in their more subtle forms, they all produce adverse pathophysiological effects. The fluid loss in diabetic ketoacidosis is equivalent to "half-normal" saline, a relatively hypotonic solution. As well as causing extensive oedema, resuscitation with isotonic saline can increase serum sodium and osmolarity while not providing free water to replace the intracellular losses.

Colloids↗
PubMed1987

Intrathoracic pressure fluctuations and periventricular haemorrhage in the newborn.

The incidence of periventricular intraventricular haemorrhage (PVH-IVH) in premature infants with respiratory distress syndrome (RDS) remains at about 40%. Although there are certain inherent anatomical and physiological features of a neonate which predisposes them to PVH-IVH, there is conflicting evidence about the precipitating cause. The most significant antecedents of PVH-IVH are mechanical ventilation and barotrauma. This report examines the hypothesis that the final common pathway in PVH-IVH is fluctuation in intrathoracic pressure, and then attempts to explain previous anomalies and conflicting results which have implicated other causes. Suggestions are offered as to how changes in current management could contribute to a decreased incidence of this serious and widespread complication in premature infants with RDS.

Airway Resistance↗
PubMed1986

A comparison of intermittent mandatory ventilation systems.

Many recent ventilators used in the ICU have a demand valve for intermittent gas flow. While demand systems conserve gas flow, they do not appear to be as well tolerated by patients as are continuous flow systems. Using a mechanical model to simulate a patient's spontaneous breathing efforts, we tested nine common ventilators in the intermittent mode. Their sensitivity varied from -2.0 to -0.2 cm H2O and the total delay time from 19 to 92 msec. The initial inspiratory resistance varied between 0.03 and 0.10 cm H2O/L X min and initial flow was between 2.5 and 12.3 L/min. These values were often not supplied or not the same as those in the manufacturer's specifications.

Equipment Design↗
PubMed1986

Pulmonary barotrauma during cardiopulmonary resuscitation.

Despite the large variety of ventilatory equipment and conditions under which CPR is performed, there have been few cases of pulmonary barotrauma, which is surprising since the transpulmonary pressures developed during CPR are relatively high. This report cites four cases demonstrating different mechanisms by which pulmonary barotrauma can be caused during CPR, and reviews their pathophysiologic consequences. The suggested levels of transpulmonary pressure needed for effective simultaneous chest compression and ventilation are even higher than those used for conventional CPR and are likely to contribute to the incidence of barotrauma during CPR.

Adult↗
PubMed1985

Continuous intragastric pH measurement in the critically ill and treatment with parenteral ranitidine.

Continuous measurement of gastric pH using a flexible pH electrode attached to a NG tube was performed in nineteen critically ill patients. The gastric pH readings correlated well with hourly intermittent pH values using indicator strips. Hypotension, physiotherapy and septicaemia was consistently associated with falls in gastric pH. A continuous infusion of Ranitidine, a H2-receptor antagonist, was titrated against the continuously measured gastric pH in an attempt to keep it above a pH of 4. This was successfully achieved in sixteen of the nineteen patients using widely variable doses of Ranitidine. The three patients whose gastric pH remained low all had severe septicaemia.

Electrodes↗
PubMed1985

Acute stress ulceration.

Stress ulceration is usually considered a mucosal abnormality of the oesophagus, stomach or duodenum in the critically ill. It is found to a varying degree in all such patients. Only about one-quarter of lesions are associated with blood loss and less than 5% need resuscitation and treatment. However, because treatment of established bleeding is unsatisfactory, and associated with a high mortality, prophylactic measures are usually employed. These include optimising gastric mucosal blood flow and oxygen delivery, correcting coagulation abnormalities and treating underlying infection. Enteral feeding should also be employed whenever possible. Other prophylactic measures currently used involve raising gastric pH above 4, with either antacids or H2 receptor antagonists. This is best achieved by measuring the gastric pH hourly and titrating it against an appropriate dose of either type of drug or a combination of both. Newer drugs, such as omeprazole, sucralfate and prostaglandins, are proving very successful in the treatment and prevention of gastric and duodenal ulcers and may prove even more effective than currently available agents.

Acute Disease↗
PubMed1983

Training in intensive care. A questionnaire to trainees.

A questionnaire was sent to senior registrars in General Medicine and Anaesthesia enquiring into the amount of training they received in Intensive Therapy and their attitudes to this in the light of their expectations for a consultant post. The results suggest that training is inadequate and that trainees are dissatisfied with the current situation.

Adult↗