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L Hoffman

Publications and source records attributed to L Hoffman.

At least 55 records · Page 3Linked to original sources
PubMed1997

SP-A enhances uptake of bacillus Calmette-Guérin by macrophages through a specific SP-A receptor.

Surfactant-associated protein A (SP-A) is a C-type lectin that is involved in surfactant metabolism as well as host defense functions in the lung. We have recently identified a receptor on macrophages [specific 210-kDa SP-A receptor (SPR210)] that binds SP-A. In the current study we have investigated the role of SP-A in mediating uptake of bacillus Calmette-Guérin (BCG) by rat macrophages and human monocytes and have examined the role of the macrophage SPR210 in this process. 125I-labeled SP-A bound BCG in a Ca(2+)-, carbohydrate-, and dose-dependent manner. To examine association of SP-A-BCG complexes with macrophages, BCG were opsonized with SP-A and were incubated with rat bone marrow-derived macrophages (RBMM), rat alveolar macrophages (RAM), or human monocytes at a 1-to-1 ratio for 4 h. The cells were washed, fixed in formalin, and stained with auramine-rhodamine. Cell-associated organisms were enumerated by fluorescent microscopy. The percentage of cells with one or more associated BCG was increased by SP-A from 27% of RBMM with BCG alone to 54% with SP-A-BCG complexes; 1-16% in RAM; and 39-67% in human monocytes. This enhanced uptake was dependent on the dose of SP-A, with maximal increases seen with 10 micrograms/ml. Electron microscopic analysis supported the conclusion that organisms were ingested by and not simply bound to the macrophages. Inclusion of SPR210 antibodies blocked association of SP-A-BCG complexes, suggesting a role for SPR210 in mediating the interaction of SP-A-BCG with the macrophages. This was further supported by the finding that modulation of SPR210 activity resulted in altered SP-A-BCG uptake. These results demonstrate that SP-A binds to BCG and that uptake of these SP-A-BCG complexes is mediated in part by the SPR210 on rat macrophages and human monocytes.

Animals↗
PubMed1997

Two families with an autosomal dominant inheritance pattern for papillary carcinoma of the thyroid.

BACKGROUND: Papillary carcinoma of the thyroid (PTC) is the most prevalent malignancy of the thyroid gland. Although the majority of lesions are sporadic tumors, an established relationship exists between familial adenomatous polyposis (FAP) and PTC. Moreover, some authors postulate the existence of familial PTC as a distinct entity. Evidence for this is limited, however, there being few well characterized descriptions of pedigrees with high prevalence of PTC. AIMS: The objective of the present study was to examine an apparent heritable predisposition to PTC occurring in two Tasmanian families in which PTC occurs commonly. METHODS: Pedigree charts were constructed for both families and the medical records of the members reviewed. RESULTS: In Pedigree I, 7 of 25 members had PTC (6 of these had coexisting multinodular goiter (MNG), and 11 others had MNG. In Pedigree II, identical male twins and their daughters had PTC. CONCLUSIONS: In both families there is evidence of autosomal dominant inheritance of PTC. The association of PTC with MNG suggests a possible role for MNG in tumor pathogenesis in hereditary PTC. The majority of the patients were diagnosed with PTC before commencement of prospective screening, indicating clinically relevant disease in the families described.

Adult↗
PubMed1996

Nucleotidase activities of the 26 S proteasome and its regulatory complex.

The 26 S proteasome can be assembled from the multicatalytic protease (or 20 S proteasome) and a large multisubunit regulatory complex in an ATP-dependent reaction. The 26 S proteasome and its regulatory complex were purified from rabbit reticulocytes for characterization of their nucleotidase properties. Both particles hydrolyze ATP, CTP, GTP, and UTP to the corresponding nucleoside diphosphate and inorganic phosphate. The Km values for hydrolysis of specific nucleotides by the 26 S proteasome are 15 microM for ATP and CTP, 50 microM for GTP, and 100 microM for UTP; Km values for nucleotide hydrolysis by the regulatory complex are 2-4-fold higher for each nucleotide. Several ATPase inhibitors (erythro-9-[3-(2-hydroxynonyl)]adenine, oligomycin, ouabain, and thapsigargin) had no effect on ATP hydrolysis by either complex whereas known inhibitors of proteolysis by the 26 S enzyme (hemin, N-ethylmaleimide (NEM), and vanadate) significantly reduced ATP hydrolysis by both particles. Hydrolysis of all nucleotides was inhibited by 5 mM NEM but only GTP and UTP hydrolysis was significantly reduced at 50 microM NEM. The 15 microM Km for ATP hydrolysis by the 26 S proteasome is virtually identical to the observed Km of 12 microM ATP for Ub-conjugate degradation. Although nucleotide hydrolysis is required for protein degradation by the 26 S proteasome, nucleotide hydrolysis and peptide bond cleavage are not strictly coupled. Substrate specificity constants (kcat/Km) are similar for hydrolysis of each nucleotide, yet GTP and UTP barely supported Ub-conjugate degradation. Further evidence that nucleotide hydrolysis is not coupled to peptide bond cleavage was obtained using N-acetyl-leucyl-leucyl-norleucinal (LLnL). This compound inhibited peptide hydrolysis by the multicatalytic protease and Ub-conjugate degradation by the 26 S proteasome, but it had little effect on ATP or UTP hydrolysis by the 26 S enzyme.

Adenosine Triphosphatases↗
PubMed1996

The N terminus of antizyme promotes degradation of heterologous proteins.

Regulated degradation of ornithine decarboxylase (ODC) is mediated by its association with the inducible protein antizyme. The N terminus of antizyme (NAZ), although unneeded for the interaction with ODC, must be present to induce degradation. We report here that covalently grafting NAZ to ODC confers lability that normally results from the non-covalent association of native antizyme and ODC. To determine whether NAZ could act similarly as a modular functional domain when grafted to other proteins, we fused it to a region of cyclin B (amino acids 13-90) capable of undergoing degradation or to cyclin B (amino acids 13-59), which is not subject to degradation. The association with NAZ made both NAZ-cyclin B13-90 and NAZ-cyclin B13-59 unstable. Furthermore, NAZ and cyclin B 13-59 were together able to induce in vitro degradation of Trypanosoma brucei ODC, a stable protein. The ODC-antizyme complex bound to the 26 S protease but not the 20 S proteasome, consistent with the observation that ODC degradation is mediated by the 26 S protease. The association was shown to be independent of NAZ, suggesting that NAZ does not act as a recognition signal.

Animals↗
PubMed1996

Muscarinic acetylcholine receptor subtype mRNAs in the human and rat vestibular periphery.

The expression of the five muscarinic acetylcholine receptor (mAChR) subtypes (m1-m5) in the vestibular end-organs and in the primary afferent vestibular ganglia of the human and rat was studied using RT-PCR from the two tissue populations from both species. In the human, although all five mAChR subtypes were expressed in brain, only the m1, m2, and m5 mAChR subtypes were amplified from both the vestibular ganglia and the vestibular end-organs, while in the rat, all five mAChR subtypes were expressed. These data suggest that the efferent cholinergic axo-dendritic and axo-somatic synapses have a muscarinic component and that there are pharmacologic implications for patients with vestibular dysfunction.

Animals↗
PubMed1996

Somatotrophinomas in multiple endocrine neoplasia type 1: a review of clinical phenotype and insulin-like growth factor-1 levels in a large multiple endocrine neoplasia type 1 kindred.

PURPOSE: Within the spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN-1), widely disparate prevalence rates for somatotrophinomas have been described. Studies that combine multiple, small MEN-1 kindreds report pituitary disease in 60% to 65% of patients, somatotrophinomas accounting for 27% to 37% of total pituitary lesions. However, reports based on large MEN-1 family screening programs have produced lower prevalence rates for pituitary adenomas (9% to 40%), of which somatotrophinomas comprise up to 14%. We sought to determine the prevalence of both biochemical and clinically overt growth hormone (GH) hypersecretion in the largest reported MEN-1 genealogy, the Tasman 1 kindred. PATIENTS AND METHODS: The Tasman 1 MEN-1 kindred contains 165 members with established MEN-1. We reviewed the records of 124 MEN-1 patients for evidence of acromegaly or gigantism. To determine if clinical criteria underestimate the occurrence of biochemical GH hypersecretion, a subset of 33 patients was assessed for elevated levels of serum insulin-like growth factor-1 (IGF-1). RESULTS: No cases of acromegaly or gigantism were detected in the 124 patients reviewed. Of the 33 patients screened with IGF-1, 13 had previously diagnosed pituitary lesions--11 prolactinomas and 2 nonsecretory lesions. The IGF-1 levels were normal in all patients studied. There were no significant differences in mean IGF-1 values between patients with and without pituitary lesions. CONCLUSIONS: This report represents the largest study of growth hormone secretion patterns thus far described in MEN-1. The apparent absence of somatotrophinomas in a kindred of this size is unexpected. These results support the existence of kindred-specific MEN-1 phenotypes. We conclude that the pathogenesis of GH-secreting adenomas in MEN-1 is influenced by secondary factors acting in synergy with the well-documented primary MEN-1 gene defect on chromosome 11q13.

Adenoma↗
PubMed1996

Regulatory features of multicatalytic and 26S proteases.

It should be clear from the foregoing accounts that our understanding of MCP and 26S regulation is still rudimentary. Moreover, we have only recently identified about a dozen natural substrates of these two proteases. Those outside the field may view the situation with some dismay. Those who study the MCP and 26S enzymes are provided with rich opportunities to address fundamental questions of protein catabolism and metabolic regulation.

Adenosine Triphosphate↗
PubMed1996

Episodic paroxysmal laryngospasm: voice and pulmonary function assessment and management.

Episodic paroxysmal laryngospasm (EPL) is a sign of laryngeal dysfunction, often without a specific organic etiology, which can masquerade as asthma, vocal fold paralysis, or a functional voice disorder. The intermittent respiratory distress of EPL may precipitate an apparent upper airway obstructive emergency, resulting in unnecessary endotracheal intubation, cardiopulmonary resuscitation, or tracheostomy. During 27 months, seven women and three men, age 30-76 years, were assessed by a high diagnostic index of suspicion, an intensive history including psychosocial factors, physical examination of the airways, provocative asthma testing, and swallowing studies. Videolaryngoscopy, stroboscopy, and pulmonary flow-volume loop testing were definitive. The classic appearance was paradoxic inspiratory adduction of the anterior vocal folds with a posterior diamond-shaped glottic gap. During an attack of stridor or wheezing, attenuation of the inspiratory flow rate as depicted by the flow-volume loop suggested partial extrathoracic upper airway obstruction. Swallowing evaluation by videolaryngoscopy and videosophagography may uncover gastroesophageal reflux disease. Hallmarks of management include patient and family education by observation of laryngoscopic videos, a specific speech therapy program, psychotherapy, and medical treatment of associated disorders. Electromyography may become a valuable future adjunct. Unlike laryngeal dystonia, patients with EPL do not benefit from botulinum toxin type A.

Adult↗
PubMed1996

Prolactinomas in a large kindred with multiple endocrine neoplasia type 1: clinical features and inheritance pattern.

Multiple endocrine neoplasia type 1 (MEN 1) is associated with neoplasia and hyperfunction of the parathyroid and pituitary glands, pancreatic islet cells, and neuroendocrine cells of the gut. The inheritance pattern is autosomal dominant, and the underlying genetic defect is situated at chromosome 11q13. The MEN 1 gene behaves as a defective copy of a normally constitutive tumor suppressor gene. Development of the MEN 1 phenotype, however, is a multistep and multifactorial process. The Tasman 1 genealogy is the largest MEN 1 pedigree detected to date. Thus far, 90 related members with MEN 1 have been screened for evidence of prolactinoma. Prolactinomas were found in 18 patients (20%). Prolactinomas were not evenly distributed in the genealogy; in 2 branches of the overall genealogy prolactinomas were present in 50% or more of MEN 1-affected members. The familial distribution of prolactinomas in these branches was consistent with an autosomal dominant mode of inheritance. In the remainder of the pedigree, prolactinomas were uncommon and did not display this inheritance pattern. This pedigree represents one of the largest published MEN 1 genealogies in which the risk of developing prolactinoma follows an autosomal dominant pattern of transmission. It is the first to demonstrate an inheritance pattern for prolactinomas acting in addition to, yet distinct from, the inheritance of the underlying MEN 1 gene defect. These findings are consistent with the existence of an undefined second genetic defect involved in the pathogenesis of prolactinoma in MEN 1.

Adult↗
PubMed1996

Spectrum of pituitary disease in multiple endocrine neoplasia type 1 (MEN 1): clinical, biochemical, and radiological features of pituitary disease in a large MEN 1 kindred.

Prolactinomas and somatotropinomas are reported to be the pituitary lesions most frequently associated with multiple endocrine neoplasia type 1 (MEN 1). However, few reports have documented the full spectrum of pituitary disease in this condition. We report herein the clinical, biochemical (PRL, alpha-subunit, insulin-like growth factor-I, cortisol, and thyroid function), and radiological (magnetic resonance imaging and computerized tomography scan) characteristics of pituitary disease occurring in a single MEN 1 pedigree containing 165 MEN 1-affected members. Pituitary lesions were detected in 30 (18%) of 165 patients overall. In the subgroup of MEN 1 patients (n = 131) living after recognition of MEN 1 in the kindred, pituitary lesions were detected in 25 (19%). In 76% of patients with pituitary lesions, the diagnosis was made by prospective screening; the remainder sought medical attention for symptomatic pituitary disease. Prolactinomas accounted for 76%, and nonfunctioning adenomas accounted for the remaining 24%. alpha-Subunit elevation was observed in 29% of 41 patients tested, and an aggressive alpha-subunit secreting macroadenoma developed in 1 subject with a previously documented prolactinoma. Progression of pituitary disease occurred in 47% of patients with prolactinoma. There were no cases of Cushing's disease, thyrotropinoma, or somatotropinoma. We conclude that 1) in addition to prolactinomas, nonfunctioning pituitary tumors are common in MEN 1; 2) alpha-subunit hypersecretion is frequent in MEN 1; 3) comprehensive screening may identify many clinically significant but asymptomatic pituitary lesions; and 4) prolactinomas occurring in MEN 1 may behave more aggressively than sporadic prolactinomas.

Adenoma↗
PubMed1996

Folic acid and prevention of neural tube defects: a study of Canadian mothers of infants with spina bifida.

OBJECTIVES: To determine the diffusion of information about preventing neural tube defects (NTDs) through folic acid consumption by examining whether mothers of Canadian children born with spina bifida, who had become pregnant at least a year after evidence of the preventive effect of folic acid had been published, had taken sufficient amounts of folic acid in the periconceptional period and were aware of this important new information. DESIGN: Validated food-frequency questionnaire to assess folate intake. SETTING: The Hospital for Sick Children in Toronto between Jan. 4 and Aug. 16, 1994. PARTICIPANTS: Thirty mothers whose infants were being treated for spina bifida. MAIN OUTCOME MEASURES: The mothers' mean folate intake and knowledge about the protective effect of folic acid; demographic and health information. RESULTS: The mothers' mean folate intake was 0.182 mg/d (standard deviation 0.076 mg/d, range 0.02 to 0.53 mg/d), less than half the protective dose. Only 4 (13%) of the mothers had been aware of the relation between nutritional folate and NTDs when they conceived, but even they did not supplement their diets with sufficient folic acid. The medical data showed that, in addition to the failure of primary prevention of NTDs, secondary prevention through diagnostic tests during pregnancy were also inadequate. CONCLUSIONS: Our study, one of the first to be conducted after the role of folate in preventing NTDs was confirmed, reveals that, in one of the most advanced countries in the world, this new information has had no effect on patients' folate intake. Unless food is fortified with folate, the estimated 400 to 800 annual cases of NTDs in Canada will not be prevented.

Canada↗
PubMed1996

Freud and feminine subjectivity.

I have delineated a factor, subjectivity, to account for the difficulty in the psychoanalytic understanding of feminine sexuality, particularly the nature of feminine sexual pleasure. This factor has been unappreciated hitherto by psychoanalysts. Subjectivity is a notion that refers to the capacity of a person to posit him- or herself as an independent agent who determines or controls his or her own thoughts and actions. The construct feminine sexual pleasure, and by extension feminine subjectivity, was difficult for Freud and others to posit because of the implicit association among several mental phenomena. Subject, active, and libido (i.e., the source of active sexual pleasure) were, and to some extent still are, considered masculine attributes; whereas object, passive, and, by implication, the absence of an independent actively desirous state were considered feminine attributes. Freud's difficulty in accepting aggression in the mental life of women interfered with his gaining an implicit understanding of feminine subjectivity.

Adolescent↗
PubMed1995

Low levels of HIV-1 infection in cutaneous dendritic cells promote extensive viral replication upon binding to memory CD4+ T cells.

Earlier work has identified a cell population that replicates HIV-1 in the absence of standard T cell stimuli. The system consists of dendritic cells and memory T lymphocytes that emigrate from organ cultures of human skin and together support a productive infection with HIV-1. These emigrants resemble cells that can be found in mucous membranes and that normally traffic in afferent lymph. Here, we report that a low level of infection in the dendritic cell can initiate extensive HIV-1 replication in cocultures with T cells. First we extended our earlier work to larger skin specimens from cadavers. As long as the organ cultures were set up within 36 h of death, the emigrant leukocytes were comparable to cells from fresh surgical specimens in number, phenotype, and function. These mixtures of dendritic cells and T cells provided the milieu for a productive infection with several virus isolates. When purified dendritic cells were separately pulsed with virus and then mixed with T cells that had not been pulsed with HIV-1, active infection ensued. The infectivity of HIV-pulsed dendritic cells persisted for at least 1.5 d in culture, but was blocked if AZT was added during that time to block reverse transcription in the dendritic cells. The number of copies of proviral DNA in the dendritic cells corresponded to < 100 copies per 5 X 10(4) cells, but upon mixing with T cells, > 10(4) copies were found 5-7 d later. By contacting syngeneic T cells, extralymphoid depots of dendritic cells--even with a low viral burden as has been reported in vivo--may contribute to chronic HIV-1 replication in infected individuals.

Antiviral Agents↗
PubMed1995

Harvesting of the latissimus dorsi muscle: a small animal model for seroma formation.

A common complication of soft tissue dissection and muscle harvesting is seroma formation. In order to manage and understand the formation of seromas, we developed a small animal model for seromas in the Sprague Dawley rat. Skin flaps and subcutaneous tissue were elevated and the latissimus dorsi muscle was harvested in 20 animals. Eighteen of the 20 rats (90%) formed clinically significant seromas. Sixteen animals had associated skin flap necrosis and 12 required serial drainage for recurrent seromas. At necropsy, gross capsular formation occurred in all animals who developed seromas. Microscopically, a fibrous capsule enveloping the seroma was seen associated with a local chronic inflammatory cell infiltrate. We conclude: (1) Elevation of the latissimus dorsi muscle in the rat is a reliable and practical animal model for seroma formation; (2) Sequelae of clinically significant seromas are often as severe as skin flap necrosis; (3) An inflammatory reaction may be associated with seromas.

Animals↗
PubMed1995

[Energy and nitrogen metabolism of pregnant and lactating sows and suckling piglets. 6. Comparative studies of energy and nitrogen metabolism of non-pregnant and pregnant sows].

Aim of the studies was to attain new scientific findings for the influence of the physiological state of sows (non-pregnant and pregnant respectively) on energy and nitrogen metabolism. The experiments were carried out according to a 3 x 3 factorial experimental plan with 3 variants of litter number (1, 2 and 4) and 3 variants of energy supply (120, 100 and 80%). Within the variants the non-pregnant and pregnant sows were fed equally related to the metabolic live weight. The metabolism measurements run from the 1st to the 115th experimental and gestation day respectively. The methods of indirect calorimetry and slaughtering technique were applied. The chemical composition of the whole bodies of the non-pregnant sows was like that of the maternal bodies of the pregnant sows (dry matter 410 g/kg, protein 160 g/kg and fat 210 g/kg). The physiological state for the sows did not influence the nutrients digestibility (OM 77.0 and 76.7%) and the energy metabolizability. About conformable intakes of metabolizable energy (601 and 586 kJ/kg LW0.75.d) and of digestible nitrogen (0.77 and 0.75 g/kg LW0.75.d) in non-pregnant and pregnant sows resulted in higher deposition of energy (64 and 79 kJ/kg LW0.75.d) and of nitrogen (0.15 and 0.19 g/kg LW0.75.d) in the pregnant sows due to energy and nitrogen deposition in the conception products and in the reproductive organs. The energy maintenance requirement and the partial efficiency of the energy utilization for the deposition as well as the nitrogen maintenance requirement and the partial efficiency of the nitrogen utilization for the deposition in the non-pregnant and the pregnant sows were determined.

Animals↗