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P Hoffman

Publications and source records attributed to P Hoffman.

At least 55 records · Page 3Linked to original sources
PubMed1996

A comparison of the performance in vitro of precision cut tissue slices and suspensions of human spleen with special reference to immunoglobulin and cytokine production.

During the past decade our knowledge of the cellular and molecular events associated with key immunological responses has been greatly advanced by the use of isolated subpopulations of immunocompetent cells, cloned cell lines and recombinant derived cytokines. Valuable as these studies have been they do not truly reflect the complex integrative events which take place in both primary and secondary lymphoid tissue both in vivo and in vitro. In order to address this problem we have developed a tissue culture procedure which is a modification of that previously used by others to study T cell maturation in the thymus. This involves culturing precision cut slices of human lymphoid tissue in a sponge culture system. Using this technique we have observed marked differences in both immunoglobulin and cytokine secretion between slices and suspensions of human spleen. In brief, cultured slices (mitogen stimulated or otherwise) consistently secrete higher levels of immunoglobulin, IL-1 beta, IL-6, IL-8 and IL-11 and exhibit much lower proliferation than suspensions of the same tissue. Mitogen stimulated suspensions on the other hand secrete higher levels of IL-2, IL-4, IL-10 and TNF alpha than do slices. These differences are also observed at the intracellular cytokine level. Additional studies reveal that the immunoglobulin and cytokine secretion observed is largely due to the de novo synthesis of these molecules and not as a result of spontaneous secretion of preformed products. Furthermore immunoglobulin secretion in both slices and suspensions can be inhibited by the addition of specific antibodies to IL-1 beta, IL-6 and TNF alpha while IL-6 production can be differentially modulated by a variety of substances. Preliminary studies indicate that close interaction between B cells and stromal cells within explants accounts for some of the observed differences. This review article describes the basic technique, summarises the results we have obtained in this system and outlines the possible basis of the observed differences.

B-Lymphocytes↗
PubMed1995

Monoamine oxidases and alcoholism. I. Studies in unrelated alcoholics and normal controls.

Low platelet MAO activity has been associated with alcoholism. In order to evaluate the role of MAO genes in susceptibility to alcoholism, we have taken a biochemical and molecular genetic approach. The sample consisted of 133 alcoholic probands who were classified by subtypes of alcoholism and 92 normal controls. For those subjects typed for platelet MAO activity, alcoholics (N = 74) were found not to differ from the non-alcoholics controls (N = 34). Neither was there a significant difference between type I and type II alcoholics or between either subtype and normal controls. However, we do find significant differences between male and female alcoholics, but not between male and female controls. The allele frequency distribution for the MAO-A and MAO-B dinucleotide repeats is different between the alcoholic sample (N = 133) and the normal control sample (N = 92). In a two-way analysis of variance of MAO-B activity as a function of the allelic variation of each marker locus and diagnosis, there is no evidence for mean differences in activity levels for the different alleles. Our findings do not rule out a role for the MAO-B gene in controlling the enzyme activity because the dinucleotide repeats are located in introns.

Adult↗
PubMed1995

Health care network communications infrastructure: an engineering design for the Military Health Service System.

The Military Health Service System (MHSS) provides health care for the Department of Defense (DOD). This system operates on an annual budget of $15 Billion, supports 127 medical treatment facilities (MTFs) and 500 clinics, and provides support to 8.7 million beneficiaries worldwide. To support these facilities and their patients, the MHSS uses more than 125 different networked automated medical systems. These systems rely on a heterogeneous telecommunications infrastructure for data communications. With the support of the Defense Medical Information Management (DMIM) Program Office, our goal was to identify the network requirements for DMIM migration and target systems and design a communications infrastructure to support all systems with an integrated network. This work used tools from Business Process Reengineering (BPR) and applied it to communications infrastructure design for the first time. The methodology and results are applicable to any health care enterprise, military or civilian.

Computer Communication Networks↗
PubMed1994

Adenovirus E3 protein causes constitutively internalized epidermal growth factor receptors to accumulate in a prelysosomal compartment, resulting in enhanced degradation.

We have previously identified and characterized an integral membrane protein coded for by the early transcription region 3 (E3) of human group C adenoviruses that down-regulates the epidermal growth factor receptor (EGFR). The goal of this study was to characterize the early receptor trafficking events leading to enhanced EGFR degradation in adenovirus-infected cells. Specifically, we wished to determine whether adenovirus increases the rate of EGFR internalization or alters the subcellular compartmentalization of internalized EGFRs. Once the optimal time for measuring early trafficking events was determined, surface EGFRs were labeled with a cleavable biotin reagent to measure internalization rates and with a receptor-specific monoclonal antibody (MAb) conjugated to colloidal gold for intracellular localization studies. We first showed that the rate of EGFR internalization in adenovirus-infected cells is indistinguishable from the constitutive internalization rate for unoccupied EGFRs. The possibility that the E3 protein can affect trafficking of EGFRs internalized at a low constitutive rate was further supported by studies showing that adenovirus-mediated down-regulation occurs independently of EGFR oligomerization and intrinsic EGFR tyrosine kinase activity, which are required for efficient ligand-induced internalization. Other tyrosine kinases inhibited by genistein are also not required for adenovirus-induced down-regulation. When the intracellular localization of EGFRs during adenovirus-mediated down-regulation was examined by electron microscopy, there was a threefold increase in the number of EGFRs localized to multivesicular bodies. The multivesicular body has been proposed to be important for regulating intracellular membrane protein sorting, since trafficking patterns for receptors that recycle and receptors that are degraded diverge in this organelle. These data therefore suggest that adenovirus may enhance EGFR degradation by causing constitutively internalized EGFRs to accumulate in a prelysosomal compartment. This is the first example of a mechanism that efficiently down-regulates EGFR without significantly increasing the rate of internalization or that does not require EGFR tyrosine kinase activity. Since viral proteins often mimic or modify a host counterpart, this suggests that there are normal physiological conditions when receptor destruction without tyrosine signalling is beneficial.

Adenovirus E3 Proteins↗
PubMed1994

[Value of biplane transesophageal echocardiography in congenital abnormalities of the heart atrium and venous-atrial connection].

BACKGROUND: Transesophageal echocardiography with transversal planes offers many advantages in the evaluation of patients with congenital anomalies of atrium, allowing visualization of obscure areas, not visualized with traditional echocardiography, as appendages, venous connections, upper interatrial defects. The aim of this paper is to check what advantages the transesophageal imaging in longitudinal plane, recently insert in biplane probes, might confer over transversal plane imaging in the evaluation of patients with congenital heart disease of atrium and venous connections. METHODS: We carried out a prospective study on 70 patients (49 adults and 22 children) with congenital heart diseases of this area. Fifty-six studies out of 71 were preoperative diagnostic, 15 were carried out in the late postoperative period. Twenty-two studies were performed under general anaesthesia during concomitant cardiac catheterisation, 49 were carried out in outpatient clinic. All the transesophageal diagnoses were subsequently confirmed at either catheterization or surgery. Lesions studied included 36 atrial septal defects (ASD) ostium secundum, 6 interatrial septal aneurysms, 1 ASD coronary sinus, 5 ASD venous sinus, 5 partial and 2 complete atrioventricular septal defects, 1 double outlet right ventricle; in operated patients 2 ASD ostium secundum, 2 ASD sinus venosus, 11 post Mustard or Senning in TGA. RESULTS: Anomalies either better defined or that obtained important additional informations by long axis scanning (vs transverse scanning) included: ASD ostium secundum 36/36, ASD multiple 1/3, caval obstruction in Mustard or Senning 4/5, anterior mitral valve cleft 2/5, left superior vena cava to coronary sinus 3/3. Features visualized by longitudinal plane alone were: ASD coronary sinus 1/1, caval obstruction in sinus venosus operated 1/1, multiple ASD 2/3, coronary artery fistula to right atrium 1/1; for associated features anterior bringing leaflets 2/2, left ventricular outflow tract obstruction 2/2, right ventricular outflow tract obstruction 1/1. Anomalies better characterized by transversal plane versus longitudinal plane were: ASD ostium primum 2/7, ASD sinus venosus sinus 3/5; for associated anomalies VSD inlet 1/1. Features visualized by transversal plane alone were: right upper pulmonary vein in superior vena cava 4/4, right upper pulmonary vein to right atrium 1/1, DIA ostium primum 5/7, ASD sinus venosus 2/5, superior vena cava obstruction in Mustard 1/5, left juxtaposition of the atrial appendages 1/1. The transversal plane alone provided the correct morphologic and hemodynamic diagnosis in 74/88 (84%) (in this group longitudinal plane gave 68% additional informations), the longitudinal planes in 69/88 (78%). However in 11% of cases longitudinal plane was the only means for identifying the congenital lesion and transversal plane in 16%. It was the combination of longitudinal and transverse scanning which gave in 97% the correct complete morphologic diagnosis. CONCLUSIONS: Thus we conclude that both planes are required for optimal transesophageal evaluation of congenital disease of atrium and venous connection.

Adolescent↗
PubMed1994

Monoamine oxidases and alcoholism: studies in unrelated alcoholics, normal controls and alcoholic families.

Monoamine oxidases (A and B) are of great interest in connection with alcoholism. Low MAO activity has been found in the brains and the platelets of alcoholics and their relatives supporting the hypothesis that low MAO activity is a biological marker for vulnerability to misuse. In order to determine the role of the MAO genes in alcoholism we have measured MAO-B activity and typed two simple sequence repeats (one in the MAO-A gene and one in the MAO-B gene) in a sample of 133 unrelated alcoholics, 300 subjects from 30 two- and three-generation pedigrees ascertained through an alcoholic proband, and 92 normal controls. The unrelated alcoholic group did not differ in MAO-B activity from normal controls nor were there significant differences between subtypes. We did, however, find significant differences between alcoholic males and females (t = 2.836, p = .005), a difference that was not present in controls. A two-way analysis of variance of MAO-B activity as a function of the allelic variation of each marker locus and diagnosis among male subjects was performed. There was no evidence for mean differences in activity levels for different alleles. The distribution of MAO-A and MAO-B "alleles" in the alcoholic sample differed from that of the control sample. Affected sib pair linkage analysis of MAO genes and alcoholism showed no evidence for an excess of concordant affected sib pairs suggesting that this region of the X-chromosome does not harbor a susceptibility locus.

Adult↗
PubMed1993

Nosocomial Legionnaires' disease: aspiration as a primary mode of disease acquisition.

PURPOSE: Nosocomial Legionnaires' disease remains a significant problem with many unresolved questions regarding transmission of legionella organisms to patients. We performed a case-control and environmental study to identify risk factors and modes of transmission of Legionella infection during an outbreak of nosocomial Legionnaires' disease in a military medical center. PATIENTS AND METHODS: During the calendar year 1989, 14 cases of nosocomial Legionnaires' disease were identified by active surveillance following the discovery of 2 culture-proven cases among organ transplant recipients. Four control patients were matched to each case by age, sex, and date of admission. Cases and controls were compared with respect to past medical history and hospital exposure variables. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for matched variables. Environmental culturing of air and water supplies in and around the medical center was also performed. RESULTS: The case-control study revealed the following significant risk factors for the acquisition of nosocomial Legionnaires' disease: immunosuppressive therapy (OR = 32.7, CI = 4.5 to 302.6), nasogastric tube use (OR = 18.4, CI = 2.6 to 166.2), bedbathing (OR = 10.7, CI = 2.2 to 59.0), and antibiotic therapy (OR = 14.6, CI = 2.9 to 84.4). Shower use (OR = 0.1, CI = 0 to 0.4) appeared to be a negative risk factor. Water cultures revealed Legionella pneumophila serogroup 1, monoclonal antibody subtype Philadelphia (identical to all patient isolates) in the ground-water supply to the hospital, 1 hot-water tank, and 15% of 85 potable water sites tested. Air sampling of cooling towers, hospital air intakes, and medical air and oxygen supplies were negative for Legionella organisms. CONCLUSIONS: This study confirms the importance of potable water in transmitting nosocomial Legionnaires' disease and suggests that the organism gains access to the hospital via external water supplies. The risk factors identified in this case-control study provide evidence that Legionnaires' disease may act as a superinfection in a nosocomial setting and is likely acquired by aspiration, similar to other nosocomial pneumonias.

Adult↗
PubMed1993

Additional value of biplane transoesophageal imaging in assessment of mitral valve prostheses.

OBJECTIVES: To determine whether biplane transoesophageal imaging offers advantages in the evaluation of mitral prostheses when compared with standard single transverse plane imaging or the precordial approach in suspected prosthetic dysfunction. DESIGN: Prospective mitral valve prosthesis in situ using precordial and biplane transoesophageal ultrasonography. SETTING: Tertiary cardiac referral centre. SUBJECTS: 67 consecutive patients with suspected dysfunction of a mitral valve prosthesis (16 had bioprostheses and 51 mechanical prostheses) who underwent precordial, transverse plane, and biplane transoesophageal echocardiography. Correlative invasive confirmation from surgery or angiography, or both, was available in 44 patients. MAIN OUTCOME MEASURES: Number, type, and site of leak according to the three means of scanning. RESULTS: Transverse plane transoesophageal imaging alone identified all 31 medial/lateral paravalvar leaks but only 24/30 of the anterior/posterior leaks. Combining the information from both imaging planes confirmed that biplane scanning identified all paravalvar leaks. Five of the six patients with prosthetic valve endocarditis, all three with valvar thrombus or obstruction, and all three with mitral annulus rupture were diagnosed from transverse plane imaging alone. Longitudinal plane imaging alone enabled diagnosis of the remaining case of prosthetic endocarditis and a further case of subvalvar pannus formation. CONCLUSIONS: Transverse plane transoesophageal imaging was superior to the longitudinal imaging in identifying medial and lateral lesions around the sewing ring of a mitral valve prosthesis. Longitudinal plane imaging was superior in identifying anterior and posterior lesions. Biplane imaging is therefore an important development in the study of mitral prosthesis function.

Adult↗
PubMed1993

[Focal epithelial hyperplasia. An unusual clinical aspect].

We report a case of focal epithelial hyperplasia in a child born in France of Algerian parents. The clinical appearance was unusual in that certain lesions were verrucous and pediculate. A virological study revealed the presence of papillomavirus 32, one of the two types of HPV specifically associated with this entity.

Africa, Northern↗
PubMed1992

Characterization of the adenovirus E3 protein that down-regulates the epidermal growth factor receptor. Evidence for intermolecular disulfide bonding and plasma membrane localization.

We have characterized the biosynthesis and processing of a 91 amino acid hydrophobic integral membrane protein encoded by human group C adenoviruses which down-regulates the EGF receptor (Carlin, C. R., Tollefson, A. E., Brady, H. A., Hoffman, B. L., and Wold, W. S. M. (1989) Cell 57, 135-144). Previous studies have shown that two immunologically related proteins are produced in vivo, a 13.7-kDa protein encoded by E3 message f and a 11.3-kDa protein derived from 13.7 kDa by proteolysis (Hoffman, B. L., Ullrich, A., Wold, W. S. M., and Carlin, C. R. (1990) Mol. Cell. Biol. 10, 5521-5524; Tollefson, A. E., Krajcsi, P., Yei, S., Carlin, C. R., and Wold, W. S. M. (1990) J. Virol. 64, 794-801). We report here that the 13.7- and 11.3-kDa proteins form intermolecular disulfide bonds cotranslationally at Cys-31 and tend to migrate as high molecular weight aggregates under nonreducing conditions. Both proteins are also present at the cell surface, as evidenced by specific immunoprecipitation from intact monolayers enzymatically labeled with 125I. Moreover, an antiserum specific for a putative extracellular epitope recognizes the same viral proteins as antibodies directed against a C-terminal synthetic 15-mer. The 13.7- and 11.3-kDa proteins are detected at early time points during pulse-chase radiolabeling of infected cells, do not undergo any further changes in molecular weight, and focus at their predicted isoelectric points (7.4 and 7.2, respectively). Identical results are obtained in stable transfectants constitutively expressing only 13.7 and 11.3 kDa, suggesting that biosynthesis and processing is not dependent on other viral proteins. These results have been incorporated into a computer-based model to predict the orientation of 13.7 and 11.3 kDa in the lipid bilayer. This model provides a basis for testing predictions regarding the topology of the viral proteins, as well as putative interactions with heterologous proteins in the microenvironment of the plasma membrane that cause down-regulation of the epidermal growth factor receptor.

Adenovirus Early Proteins↗
PubMed1992

Ligand-induced protein tyrosine kinase activity in living cells coexpressing intact EGF receptors and receptors with an extensive cytosolic deletion.

A population of stable NIH 3T3 transfectants with two molecular weight classes of membrane-bound EGF receptors encoded by a human EGF receptor cDNA has been identified and characterized. In addition to intact EGF receptors, these cells also express a molecule with an extensive cytosolic deletion. This deletion includes the ligand-activated intrinsic protein tyrosine kinase catalytic domain. Treatment with EGF caused dimerization of intact and truncated receptors, allowing us to assess protein tyrosine kinase activity in the heterodimer isolated from living cells. In contrast to homodimeric complexes with intact EGF receptor only, heterodimers were deficient in protein tyrosine kinase activity. Moreover, physical association between intact and truncated molecules suppressed receptor auto-phosphorylation by EGF receptor protein tyrosine kinase activated by antibody binding in vitro. Evidence presented here supports the idea that protein tyrosine kinase activation is facilitated by interaction between adjacent receptor molecules with intact catalytic domains. Furthermore, molecules with cytoplasmic deletions that are physically associated with kinase-active EGF receptors appear to behave as dominant negative mutations. The HerC cl cells used in this study were selected with methotrexate to amplify the EGF receptor cDNA, and in that sense may resemble certain tumor-derived cells characterized by overexpressed and rearranged EGF receptor genes.

Animals↗
PubMed1992

Lethal junctional epidermolysis bullosa with normal expression of BM 600 and antro-pyloric atresia: a new variant of junctional epidermolysis bullosa?

A newborn girl is described with a lethal junctional epidermolysis bullosa (Herlitz form) (JEB) associated with a congenital localized absence of skin, and a pyloric atresia (PA). The post-mortem examination of the digestive tract showed a widespread cleavage between the epithelium and the chorion. Immunohistological and electron microscopical examination showed a cleavage occurring through the lamina lucida of the digestive basement membrane, as for the skin blisters. Despite the lethal character of this form of JEB, the BM 600 glycoprotein was normally recognized at the dermo-epidermal junction by the monoclonal antibody GB3. This rare association of lethal JEB-PA-localized absence of skin, with a quite unusual GB3 positive immunophenotype could correspond to a new variant of JEB.

Antibodies, Monoclonal↗
PubMed1992

Malignant pancreatic oncocytoma. An unusual cause of organic hypoglycemia.

A case of malignant islet-cell tumor with oncocytic features occurring in a 54-year-old woman with symptoms of organic hypoglycemia is reported. The tumor was composed of ribbons of cells arranged in an endocrine pattern. The cytoplasm of these cells was eosinophilic and finely granular. Ultrastructurally, the cells contained numerous mitochondria and dense-core neurosecretory granules. Tumor cells were focally immunoreactive for neuron-specific enolase, insulin, glucagon and VIP. Capillaries invasion and metastases to lymph nodes argued in favor of malignancy but there was no subsequent malignant involvement during a 3-year follow-up after surgery. Such insulinomas with oncocytic features have not been previously described. Endocrine features in oncocytomas of the pancreas and of other locations are discussed.

Adenoma↗