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J Hammer

Publications and source records attributed to J Hammer.

At least 127 records · Page 7Linked to original sources
PubMed1995

Peptide binding specificity of HLA-DR4 molecules: correlation with rheumatoid arthritis association.

We have investigated whether sequence 67 to 74 shared by beta chains of rheumatoid arthritis (RA)-associated HLA-DR molecules imparts a specific pattern of peptide binding. The peptide binding specificity of the RA-associated molecules, DRB1*0401, DRB1*0404, and the closely related, RA nonassociated DRB1*0402 was, therefore, determined using designer peptide libraries. The effect of single key residues was tested with site-directed mutants of DRB1*0401. The results have demonstrated striking differences between RA-linked and unlinked DR allotypes in selecting the portion of peptides that interacts with the 67-74 area. Most differences were associated with a single amino acid exchange at position 71 of the DR beta chain, and affected the charge of residues potentially contacting position 71. The observed binding patterns permitted an accurate prediction of natural protein derived peptide sequences that bind selectively to RA-associated DR molecules. Thus, the 67-74 region, in particular position 71, induces changes of binding specificity that correlate with the genetic linkage of RA susceptibility. These findings should facilitate the identification of autoantigenic peptides involved in the pathogenesis of RA.

Amino Acid Sequence↗
PubMed1995

Validation of the phase angle technique as an objective measure of upper airway obstruction.

Thoraco-abdominal asynchrony (TAA) during upper airway obstruction (UAO) in small children can be documented by phase angle analysis of the Lissajous figure from the output of a noncalibrated respiratory inductance plethysmograph. Phase angle measurements have not been related to levels of inspiratory resistance, nor to the effect of breathing a 79% helium-21% oxygen mixture (heliox) during inspiratory resistance. We examined the effects of graded inspiratory loading (5-1000 cm H2O/L/sec) on TAA as measured by phase angle in 10 male, anesthetized, and intubated Rhesus monkeys, breathing room air and heliox. Phase angles increased with inspiratory loading from a baseline value of 22 +/- 3 degrees to 165 +/- 8 degrees at 1,000 cm H2O/L/sec resistance and correlated significantly with the level of inspiratory loading (r = 0.82). End-tidal carbon dioxide PETCO2 increased from 39 +/- 1 to 49 +/- 3 mm Hg at the highest load, but correlated only weakly with phase angle measurements (r = 0.60) and the level of inspiratory loading (r = 0.56). By changing to heliox breathing at the highest tolerated resistance, PETCO2 dropped significantly from 49 +/- 3 to 40.5 +/- 4 mmHg (P < 0.001) with no significant change in phase angles: 169 +/- 13 degrees and 165 +/- 8 degrees, respectively (P > 0.05). We conclude that heliox therapy for acute alveolar hypoventilation during UAO improves ventilation, but does not decrease TAA at high inspiratory resistance. Continuous monitoring of the relative changes in phase angles is useful to observe the severity of UAO in the early stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Obstruction↗
PubMed1995

Infant lung function testing in the intensive care unit.

As a result of the previous shortage of tools to assess objectively the overall physiological status of the respiratory system in infants and young children, it has been difficult to measure the degree of physiological disorder or the response to therapy in respiratory diseases such as BPD, the pediatric version of ARDS, bronchiolitis, pneumonia, asthma and croup in this patient population. The newborn- four-year old child is particularly difficult to study because of their lack of cooperation and size. The recent progress in computer technology made pulmonary function testing available for this age range and opened up new possibilities for monitoring changes in disease processes affecting the respiratory system. This may improve medical management of infants and children with lung and heart diseases in particular. In 1989, Shannon [49] proposed in this Journal that the minimum physiological information needed for the intelligent use of mechanical ventilation (particularly if lower airway and/or pulmonary parenchymal disease was apparent) required the measurement of at least 4 variables: i) arterial partial pressure of carbon dioxide; ii) arterial oxygen saturation; iii) the mechanical time constant of the lung and iv) FRC. In many circumstances, arterial CO2 is approximated by alveolar (end-tidal) CO2 and the arterial oxygen saturation is obtained from pulse oximetry accurately if perfusion is adequate. The mechanical time constant and FRC are easily measured by the techniques described above and together provide important information concerning appropriate ventilator settings for a given disease. The described techniques bring new insights and awareness, but also new responsibilities in the management of infants and children with respiratory compromise. Not all of these techniques need to be applied to all infants in the ICU. Not all the assumptions upon which some of the techniques we have described are based will prove true. Any such methods which do not withstand solid scientific testing must be quickly discarded and replaced with better and (hopefully) easier methods.

Child, Preschool↗
PubMed1995

Elevated levels of serum carbohydrate deficient transferrin are not specific for alcohol abuse in patients with liver disease.

BACKGROUND: Serum carbohydrate deficient transferrin is a marker of chronic alcohol consumption; it increases above normal in healthy individuals after a daily alcohol intake of more than 60 g/d for more than 2 weeks. The influence of liver disease itself on carbohydrate deficient transferrin levels has not been sufficiently established. METHODS: We investigated serum levels of carbohydrate deficient transferrin in 196 consecutive patients admitted to our Gastroenterology and Hepatology Unit and correlated this parameter with the patients' statements about alcohol intake during the previous 2 weeks and with other markers of chronic alcohol consumption. RESULTS: In our patient population, carbohydrate deficient transferrin had the best overall performance with respect to sensitivity (88%), specificity (82%), and negative predictive value (98%), as compared to other markers, although specificity was much lower than previously reported in patients without liver disease. In the group of patients with liver disease, sensitivity and specificity were 90% and 73%, respectively, and in patients without liver disease, 80% and 88%. The negative predictive value was excellent (96% for patients with liver disease and 99% for patients without liver disease). CONCLUSIONS: Thus, in a patient with a negative interview for chronic alcohol abuse and normal carbohydrate deficient transferrin level, alcohol is unlikely to be the cause of liver disease, and further investigations to establish the etiology of liver disease are warranted. An increased carbohydrate deficient transferrin level, however, cannot be regarded as reliable evidence for chronic alcohol abuse in patients with liver disease.

Adolescent↗
PubMed1995

New methods to predict MHC-binding sequences within protein antigens.

The identification and analysis of MHC-binding sequences within protein antigens, and ultimately the ability to predict them, is central to immunology. Recent advances have revealed increasingly complex MHC-binding motifs and allows prediction of sequences that bind to both classes of MHC molecules. The systematic characterization of binding motifs for all human MHC alleles is now possible and will facilitate the design of peptides for therapeutic intervention.

Amino Acid Sequence↗
PubMed1995

Albuterol responsiveness in infants with respiratory failure caused by respiratory syncytial virus infection.

OBJECTIVE: To assess the bronchodilator effect of inhaled albuterol in the acute stage of severe respiratory syncytial virus (RSV) infection. DESIGN: Prospective, nonrandomized study of previously healthy infants who underwent intubation and whose lungs were ventilated because of respiratory failure caused by RSV infection. Ten infants with an endotracheal tube in place and without lung disease were matched for age and weight and served as normal control subjects. METHODS: Lung function tests, including respiratory mechanics by single-breath occlusion, small airway function by forced deflation, and lung volumes by nitrogen washout, were performed before and after inhalation of 900 micrograms albuterol by metered dose inhaler. Bronchodilator response was defined as a change of more than twice the coefficient of variation of repeated baseline measurements. RESULTS: Twenty-three infants (mean +/- SE age = 4.2 +/- 1.1 months) were studied, of whom 20 (87%) had obstructive small airway disease, and 3 (13%) had exclusively restrictive lung function profiles. Ten of the infants with obstructive disease (50%) did not benefit from albuterol, and 9 (45%) had small but significant improvements in lung function. Deterioration of lung function was documented in 1 patient after albuterol inhalation. CONCLUSION: Inhaled albuterol is of limited value as a bronchodilator in infants with RSV-induced respiratory failure and should be discontinued if a beneficial response cannot be observed.

Acute Disease↗
PubMed1995

HBV and HCV genome in peripheral blood mononuclear cells in patients undergoing chronic hemodialysis.

Patients undergoing chronic hemodialysis are at risk for infection with hepatitis B virus (HBV) and hepatitis C virus (HCV). As peripheral blood mononuclear cells (PMNC) are known to be susceptible to infection of both HBV and HCV, assessment of viral genomes in those cells could uncover occult infections not detected by serologic methods or virus determination in serum. We investigated all 67 patients undergoing chronic hemodialysis at a single dialysis unit by PCR for the presence of HBV or HCV genomes in serum as well as in PMNC. None of the 67 patients was HBsAg positive or showed HBV-DNA in serum, but in 5 patients HBV-DNA in PMNC was detected as the only marker of HBV-infection; those patients were also anti-HBc negative. In 9 patients HCV-RNA was positive in serum; in 5 of those patients it was also found in PMNC. Three of these infected patients were negative for anti-HCV. One other patient had no anti-HCV or HCV-RNA in serum, but was positive for HCV-RNA in PMNC. Thus, in 6 patients (8.9%) undergoing chronic hemodialysis we found evidence of infection with HBV or HCV by detecting viral genomes in PMNC without the presence of viremia, antigenemia or specific viral antibodies in serum. The detection of viral genomes in PMNC could be useful in the positive identification of additional potentially infectious patients.

Adult↗
PubMed1995

DR alpha: E beta heterodimers in DRA transgenic mice hinder expression of E alpha: E beta molecules and are more efficient in antigen presentation.

HLA-DRA transgenic (tg) mice on H-2d background were constructed to study assembly, expression and function of DR alpha: E beta class II heterodimers when an alternate E alpha chain is available. Cytofluorimetric analysis and immunoprecipitation studies demonstrate that the majority (90%) of E beta d molecules on class II-positive splenocytes from DRA-tg mice are associated with DR alpha rather than E alpha chains. To characterize the functional role of the interspecies as compared with the wild-type I-E molecules, MHC restriction and T cell epitope immunodominance of synthetic peptides spanning the entire sequence of 65 kDa heat shock protein (hsp) from Mycobacterium tuberculosis were determined in hsp-primed DRA-tg and DBA/2 mice. A similar pattern of responsiveness was observed in both strains, but hsp epitopes recalled a higher response in DRA-tg as compared with DBA/2 mice. A panel of T cell hybridomas specific for two hsp peptides or a hen egg white lysozyme peptide presented by both DR alpha: E beta d and E alpha d: E beta d was studied in detail. Surprisingly, DR alpha: E beta d dimers present these peptides more efficiently than E alpha d: E beta d, even when the TCR was selected in mice expressing only E alpha d: E beta d molecules. The higher efficiency of antigen presentation by DR alpha: E beta d dimers does not appear to depend on increased binding affinity for peptides, as demonstrated by competition for antigen presentation, nor on increased efficiency in the interaction with CD4 molecules. Rather, the higher efficiency of antigen presentation could be explained by a more effective ligand-TCR interaction. This is consistent with molecular modeling based on the class II structure, indicating that 16 out of 17 substitutions between the first domain of E alpha d and DR alpha chains ile outside the peptide binding groove and are potentially available for interaction with the TCR.

Amino Acid Sequence↗
PubMed1995

Effect of lung volume on forced expiratory flows during rapid thoracoabdominal compression in infants.

The rapid thoracoabdominal compression (RTC) technique is commonly used in pulmonary function laboratories to assess flow-volume relationships in infants unable to produce a voluntary forced expiration maneuver. This technique produces forced expiratory flows over only a small lung volume segment (i.e., tidal volume). It has been argued that the RTC technique should be modified to measure flow-volume relationships over a larger portion of the vital capacity range to imitate the voluntary maximal forced expiratory maneuver obtained in older children and adults. We examined the effect of volume history on forced expiratory flows by generating forced expiratory flow-volume curves by RTC from well-defined inspiratory volumes delineated by inspiratory pressures of 10, 20, 30, and 40 cmH2O down to residual volume (i.e., the reference volume) in seven intubated and anesthetized infants with normal lungs [age 8.0 +/- 2.0 (SE) mo, weight 6.7 +/- 0.6 kg]. We compared maximal expiratory flows at isovolume points (25 and 10% of forced vital capacity) and found no significant differences in maximal isovolume flow rates measured from the different lung volumes. We conclude that there is no obvious need to initiate RTC from higher lung volumes if the technique is used for flow comparisons. However, compared with measurements of maximal flows at functional residual capacity by RTC from end-tidal inspiration, the initiation of RTC from a defined and reproducible inspiratory level appears to decrease the intrasubject variability of the maximal expiratory flows at low lung volumes.

Abdomen↗
PubMed1994

Precise prediction of major histocompatibility complex class II-peptide interaction based on peptide side chain scanning.

We describe here a new method for predicting class II major histocompatibility complex-binding peptides, based on the preferences observed in a systematic series of peptide binding experiments where each position in a "minimal" peptide was replaced individually by every amino acid. The DRB1*0401 peptide binding preferences were determined and incorporated into a computer program that looks through sequences for potential epitopes and assigns each a score. These scores correlate well with previously determined T cell epitopes of foreign antigens and endogenous peptides from self proteins. Our findings hold implications for the design of subunit vaccines and in the identification of autoantigenic peptide regions within self proteins.

Base Sequence↗
PubMed1994

High-affinity binding of short peptides to major histocompatibility complex class II molecules by anchor combinations.

We have previously identified four anchor positions in HLA-DRB1*0101-binding peptides, and three anchors involved in peptide binding to DRB1*0401 and DRB1*1101 molecules, by screening of an M13 peptide display library (approximately 20 million independent nonapeptides) for DR-binding activity. In this study, high stringency screening of the M13 library for DRB1*0401 binding has resulted in identification of three further anchor positions. Taken together, a peptide-binding motif has been obtained, in which six of seven positions show enrichment of certain residues. We have demonstrated an additive effect of anchors in two different ways: (i) the addition of more anchors is shown to compensate for progressive truncation of designer peptides; (ii) the incorporation of an increasing number of anchors into 6- or 7-residue-long designer peptides is shown to result in a gradual increase of binding affinity to the level of 13-residue-long high-affinity epitopes. The anchor at relative position 1 seems to be obligatory, in that its substitution abrogates binding completely, whereas the elimination of other anchors results only in partial loss of binding affinity. The spacing between anchors is critical, since their effect is lost by shifting them one position toward the N or C terminus. The information born out of this study has been successfully used to identify DR-binding sequences from natural proteins.

Amino Acid Sequence↗
PubMed1994

Effect of ranitidine on soluble interleukin 2 receptors and CD8 molecules in surgical patients.

The effect of perioperative immunomodulation with the H2-receptor antagonist ranitidine on postoperative changes in soluble interleukin (IL) 2 receptor and soluble CD8 levels was assessed in 24 patients undergoing major elective abdominal surgery. Eleven patients were randomized to receive intravenous ranitidine 100 mg twice daily for 4 days from skin incision, followed by oral ranitidine 150 mg twice daily for a further 5 days; 13 control patients received no ranitidine. Routine blood analysis, clinical data, duration of surgery, anaesthesia, antibiotic prophylaxis and perioperative blood transfusion were similar in the two groups. Serum concentrations of soluble IL-2 receptor and CD8 were measured before operation (day 0) and in the morning of postoperative days 1, 3 and 9 using commercial enzyme-linked immunosorbent assay kits. In patients treated with ranitidine, the serum level of soluble IL-2 receptor increased from day 0 to day 9 (P < 0.01); in control patients it decreased from day 0 to day 1, did not change significantly by day 3 and increased by day 9. The change from day 0 to day 1 was significantly different between the two groups (P < 0.01). Five of the 13 control patients developed postoperative infectious complications. No significant differences were shown in soluble CD8 concentration during the postoperative period. The postoperative change in soluble IL-2 receptor level may reflect lymphocyte activation status; ranitidine appears to promote activation of mainly CD4-positive lymphocytes since serum levels of CD8 were unchanged. Ranitidine may, therefore, improve immune function during major surgery.

Abdomen↗
PubMed1994

Defining rules for the peptide-MHC class II interaction.

Recent work has begun to clarify the molecular events governing peptide interaction with MHC class II proteins. The requirements for peptide binding to class I and class II molecules seem to be similar. Despite differences in peptide length, anchor residues defining allele-specific peptide motifs can also be found in class II binding peptides. The presence of conserved and allele-specific anchors appears to explain the promiscuity and the specificity of peptide recognition by DR molecules.

Alleles↗